Population Pharmacokinetics of Metoclopramide in Infants,Children, and Adolescents

Metoclopramide is commonly used for gastroesophageal reflux. The aims of the present study were to develop a pediatric population pharmacokinetic (PopPK) model, which was applied to simulate the metoclopramide exposure following dosing used in clinical practice. Opportunistic pharmacokinetic data were collected from pediatric patients receiving enteral or parenteral metoclopramide per standard of care and these data were simultaneously fitted using NONMEM. Allometric scaling with body weight was included a priori in the model. Using the final model, the steady‐state maximum concentrations (C_ss,max) and the area under the metoclopramide plasma concentration‐time curve at steady state from 0 to 6 hours (AUC_ss,0–6h) were simulated following 0.1 or 0.15 mg/kg orally every 6 hours in virtual patients, and compared with previously reported ranges associated with toxicity or the efficacy for gastroesophageal reflux in infants. A two‐compartment model with first‐order absorption best characterized 87 concentration measurements from 50 patients (median [range] postnatal age of 8.89 years [0.01–19.13]). There were 20 infants (≤ 2 years), 9 children (2 years to age ≤ 12 years), and 21 adolescents (> 12 years). Body weight was the only covariate included in the final model. For > 75% of virtual patients, simulated C_ss,max and AUC_ss,0–6h estimates were within the range associated with efficacy for gastroesophageal reflux in infants; however, slightly lower exposures were predicted in virtual patients < 2 years. Our study suggests that a metoclopramide enteral dose of 0.1 mg/kg every 6 hours, which was previously recommended for pediatric patients, results in simulated exposure generally within suggested ranges for the treatment of gastroesophageal reflux.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Metoclopramide is a dopamine receptor antagonist used off‐label in children for gastroesophageal reflux (GER), gastroparesis, nausea, and vomiting. Only one population pharmacokinetic (PopPK) study of metoclopramide has been performed, which included data from 47 patients with cancer 10–80 years of age.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This study sought to characterize the PopPK of metoclopramide in pediatric patients, and to apply the model to evaluate simulated exposure following dosing used in clinical practice.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Our study suggests that a metoclopramide oral dose of 0.1 mg/kg every 6 hours, which was previously recommended for children, results in simulated exposure generally within suggested ranges for the treatment of GER.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ This study contributes to our understanding of metoclopramide pharmacokinetics and dosing in the pediatric population. When the dose‐response relationship of metoclopramide is further elucidated in future studies, our model could be used to further evaluate metoclopramide pediatric dosing. Metoclopramide is a drug with prokinetic and anti‐emetic properties that is prescribed for the treatment of gastrointestinal motility disorders, gastroesophageal reflux (GER), diabetic gastroparesis, nausea, and vomiting. ¹ , ² Metoclopramide injection is also used to facilitate small bowel intubation and radiological examination. ³ , ⁴ Metoclopramide''s peripheral gastrointestinal prokinetic effects and central anti‐emetic effects are mediated through antagonism of the dopamine 2 and 5‐hydroxytryptamine type 3 receptors, as well as through 5‐hydroxytryptamine type 4 receptor agonism. ⁵ , ⁶ In the United States, metoclopramide is not recommended by the US Food and Drug Administration (FDA) for use in children because its safety and effectiveness in this population have not been established except to facilitate small bowel intubation. ³ The FDA added a black box warning in metoclopramide''s product label related to tardive dyskinesia, a serious adverse event involving involuntary and repetitive body movement. Extrapyramidal side effects (e.g., dystonic reactions, tardive dyskinesia, and parkinsonian‐like symptoms) have also been reported with greater frequency in children compared with adults. ³ The European Medicines Agency recommends that metoclopramide not be used in children younger than 1 year of age, and as second‐choice treatment in children older than 1 year for short‐term use (up to 5 days) for the prevention of delayed nausea and vomiting after chemotherapy, as well as for the treatment of postoperative nausea and vomiting. ⁷ Although limited data are available to inform dosing in the pediatric population, metoclopramide is generally administered enterally or intravenously at a dosage of 0.1–0.2 mg/kg every 6–8 hours. ² , ⁸ , ⁹ , ¹⁰ The pharmacokinetics (PKs) of metoclopramide have been previously characterized in adults. ¹¹ , ¹² , ¹³ , ¹⁴ Metoclopramide undergoes metabolism via oxidation (primarily via cytochrome P450 2D6 (CYP2D6)) as well as glucuronide and sulfate conjugation. ¹⁵ , ¹⁶ Approximately 85% of the radioactivity of an orally administered dose is recovered in the urine, and half of it is present as parent or conjugated metoclopramide. Around 18–22% of the dose was recovered as free metoclopramide in urine. ⁴ Metoclopramide''s elimination half‐life in adults with normal renal function has been reported to be ~ 6 hours. ³ , ⁴ In adults with severe renal impairment, there is a reduction in metoclopramide clearance (CL), resulting in a prolongation in the terminal elimination half‐life (7.7–17.8 hours), and a dose adjustment is recommended. ¹⁴ Only one population pharmacokinetic (PopPK) study of metoclopramide has been performed, which included data from patients 10–80 years old. ¹⁷ In this single PopPK analysis, a two‐compartment model with linear elimination was used, and it was reported that body weight and serum alkaline phosphatase activity were significant covariates that explained interindividual variability (IIV) in the CL of metoclopramide. Given that metoclopramide is extensively metabolized in the liver, this suggests that metoclopramide''s PKs may be impacted by liver function, which has been confirmed in studies of adults with liver cirrhosis. ¹⁸ , ¹⁹ Additional studies focused on characterizing the PKs of metoclopramide in adults have also been published. ¹¹ , ¹² , ¹³ , ¹⁸ In the pediatric population, few studies have evaluated metoclopramide''s PKs in neonates, ⁸ infants, ²⁰ and children. ²¹ Whether the PKs of metoclopramide in adults and the pediatric population are similar remains unclear. ³ One study in preterm infants reported a greater metoclopramide weight‐normalized CL (mean CL of 0.80 L/hour/kg) compared with adults (mean CL of 0.29–0.53 L/hour/kg). ⁸ , ¹¹ , ¹⁷ Nevertheless, in two other studies performed in infants and children, the weight‐normalized PK parameters were comparable to those in adults. ²⁰ , ²¹ Metoclopramide exposure targets for efficacy and toxicity have not been well established in adult or pediatric populations. Conflicting study results have been reported regarding the efficacy of metoclopramide as a prokinetic drug in children. In some studies, metoclopramide''s favorable efficacy for the treatment of GER or vomiting was demonstrated in a pediatric population, ²⁰ , ²² , ²³ , ²⁴ , ²⁵ whereas in other studies it was shown that the metoclopramide treatment was ineffective in children. ²⁶ , ²⁷ One study in infants treated for GER suggested that the beneficial effects were associated with steady‐state maximum concentrations (C_ss,max). In 6 infants with C_ss,max ranging from 26 to 94 ng/mL, 4 of them had a 75% reduction in reflux time ²⁰ ; however, significant correlations were not found between metoclopramide exposures and pharmacodynamic parameters. Data evaluating the relationship between exposure and safety are also limited. One study reported that the metoclopramide plasma concentration measured in a child who developed dystonia after i.v. injection was 143 ng/mL. ²¹ The objectives of this study were to develop a PopPK model using opportunistic PK data collected from infants, children, and adolescents receiving metoclopramide and to apply the model to evaluate simulated exposure following dosing used in clinical practice.     

Estimation of Body Fat Percentage for Clinical Pharmacokinetic Studies in Children

Obesity is a prevalent childhood condition and the degree of adiposity appears likely to be an important covariate in the pharmacokinetics (PKs) of many drugs. We undertook these studies to facilitate the evaluation and, where appropriate, quantification of the covariate effect of body fat percentage (BF%) on PK parameters in children. We examined two large databases to determine the values and variabilities of BF% in children with healthy body weights and in those with obesity, comparing the accuracy and precision of BF% estimation by both clinical methods and demographically derived techniques. Additionally, we conducted simulation studies to evaluate the utility of the several methods for application in clinical trials. BF% was correlated with body mass index (BMI), but was highly variable among both children with healthy body weights and those with obesity. Bio‐impedance and several demographically derived techniques produced mean estimates of BF% that differed from dual x‐ray absorptiometry by < 1% (accuracy) and a SD of 5% or less (precision). Simulation studies confirmed that when the differences in precision among the several methods were small compared with unexplained between‐subject variability of a PK parameter, the techniques were of similar value in assessing the contribution of BF%, if any, as a covariate for that PK parameter. The combination of sex and obesity stage explained 68% of the variance of BF% with BMI. The estimation of BF% from sex and obesity stage can routinely be applied to PK clinical trials to evaluate the contribution of BF% as a potential covariate.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ The presence and degree of obesity is an important factor in the pharmacokinetics (PKs) of some drugs. Estimates of body fat percentage (BF%) or other quantitative assessments of the degree of obesity have rarely been included in PK studies in children.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ When considering BF% as a potential covariate in clinical PK studies in children, how do fat mass estimation methods compare in accuracy, precision, and clinical practicality?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Methods of BF% estimation in children vary in accuracy and precision, but are insignificant compared with typical between‐subject variability of PK parameters observed in clinical studies. For drugs in which BF% is an important determinant of alterations in drug disposition in children with obesity, the estimation of BF% from routine clinical demographics provides necessary accuracy and precision.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ To quantify the effect of adiposity on drug PK in children with obesity, BF% can be estimated from one of several anthropometric equations, or even more easily from the estimates of BF% based on obesity stage.

Approximately one‐third of children in the United States are overweight or obese, and this proportion has continued to increase over the last decade. ¹ , ² Fat and nonfat tissues have many distinct physical, chemical, and metabolic characteristics, so differences in drug disposition can occur relative to a child’s obesity status. Nevertheless, differences in drug pharmacokinetics (PKs) between children with and without obesity have been described for only a few drugs. ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ For most drugs, the effects of obesity on PKs in children are poorly characterized, ¹¹ , ¹² , ¹³ , ¹⁴ leaving clinicians with inadequate information on how to design appropriate dosage regimens for this population. Because the fraction of body mass represented by adipose tissue may vary considerably among children with obesity, it is likely that the degree of adiposity might be an important covariate in understanding changes in drug PKs in children with obesity.Body fat percentage (BF%) can be measured clinically by a variety of methods, such as bio‐impedance and dual energy x‐ray absorptiometry (DEXA), ¹⁵ , ¹⁶ , ¹⁷ or it can be estimated from subject demographics and anthropomorphic data. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ These methods differ in accuracy and precision, and their comparative suitability for studying the effect of BF% on drug disposition has not been explored.To evaluate the different approaches for estimating BF% in clinical PK trials in children, we characterized the variability of body fat in children with healthy body weights and children with obesity. We then compared the accuracy and precision of commonly used clinical means of fat mass estimation, including the development of a new anthropometric equation, and assessed the utility and desirable precision of fat percentage measurement methodologies for clinical PK studies in children.     

An Evaluation of Biometric Monitoring Technologies for Vital Signs in the Era of COVID‐19

The novel coronavirus disease 2019 (COVID‐19) global pandemic has shifted how many patients receive outpatient care. Telehealth and remote monitoring have become more prevalent, and measurements taken in a patient’s home using biometric monitoring technologies (BioMeTs) offer convenient opportunities to collect vital sign data. Healthcare providers may lack prior experience using BioMeTs in remote patient care, and, therefore, may be unfamiliar with the many versions of BioMeTs, novel data collection protocols, and context of the values collected. To make informed patient care decisions based on the biometric data collected remotely, it is important to understand the engineering solutions embedded in the products, data collection protocols, form factors (physical size and shape), data quality considerations, and availability of validation information. This article provides an overview of BioMeTs available for collecting vital signs (temperature, heart rate, blood pressure, oxygen saturation, and respiratory rate) and discusses the strengths and limitations of continuous monitoring. We provide considerations for remote data collection and sources of validation information to guide BioMeT use in the era of COVID‐19 and beyond.

In an effort to mitigate the spread of the novel coronavirus disease 2019 (COVID‐19), the disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), healthcare providers are increasingly using telehealth for remote patient visits. At the beginning of the pandemic, amidst fears of being infected and having to visit overcrowded hospitals, individuals were rapidly purchasing technologies, such as pulse oximeters, to use at home to monitor for early signs of infection. ¹ Entering early summer, the Centers for Disease Control and Prevention (CDC) reported an increase in cases in several regions of the United States; without a vaccine, experts are concerned for a second wave of the virus. ² , ³ , ⁴ , ⁵ As the healthcare system faces an unprecedented need for remote monitoring due to the COVID‐19 pandemic, Biometric Monitoring Technologies (BioMeTs) offer solutions for collecting disease‐related measurements from patients at home. ⁶ , ⁷ , ⁸ BioMeTs are internet‐connected digital medicine products, such as smart thermometers or heart rate monitors with Bluetooth connectivity, that process data captured by mobile sensors using algorithms to generate measures of behavioral and/or physiological function. ⁹ These connected technologies are used in a variety of contexts, including but not limited to healthcare delivery, ¹⁰ clinical trials, ¹¹ and public health. ¹² , ¹³ BioMeTs offer convenient opportunities to collect frequent and objective data and disease‐related measurements, which facilitates assessing trends ¹² and detecting changes in vital signs not traceable by conventional spot check data collection protocols. ¹⁴ In response to the COVID‐19 pandemic, BioMeTs can be used for many clinical needs, such as aiding preliminary patient physical assessments, assisting with triage of patients with COVID‐19 symptoms, and monitoring patients post‐hospital discharge for risks of readmission. ⁸ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ For clinical teams implementing remote monitoring for the first time or for those already familiar with these technologies and exploring new options, there is an overwhelming variety of BioMeTs available as the market has seen an exponential growth over the past 2 decades. ¹¹ Navigating engineering solutions, form factors (physical size and shape), corresponding data collection protocols, and knowing how to interpret generated values can be challenging, especially if a healthcare provider is unfamiliar with how a BioMeT compares with conventional clinical instruments. Healthcare providers may question the accuracy of measurements taken by patients at home without supervision and it may be unclear how a BioMeT collects and processes data. Understanding data quality and potential biases in data collection is key to drawing appropriate inferences, especially because some of the data may be used for clinical decision making.In this paper, we will discuss the following: (i) sources of information one can use to identify high‐quality BioMeTs, (ii) products and engineering solutions for remote vital sign monitoring, including temperature, heart rate, blood pressure (BP), oxygen saturation, and respiratory rate, and (iii) considerations for choosing a product, including form factors, usability and data collection protocols, and interfering factors that can produce altered readings. Although certain vital sign abnormalities have been associated with COVID‐19 and will be highlighted in this review, we believe the foundations of evaluating these BioMeTs can be applied broadly whenever remote vital sign monitoring is needed. Although overviews of wearable sensor applications for COVID‐19 have been published, ⁸ , ¹⁹ this paper provides a critical review of technologies and is intended as an aid to navigate the plethora of remote monitoring sensors.     

Early M‐Protein Dynamics Predicts Progression‐Free Survival in Patients With Relapsed/Refractory Multiple Myeloma

This study aimed to predict long‐term progression‐free survival (PFS) using early M‐protein dynamic measurements in patients with relapsed/refractory multiple myeloma (MM). The PFS was modeled based on dynamic M‐protein data from two phase III studies, POLLUX and CASTOR, which included 569 and 498 patients with relapsed/refractory MM, respectively. Both studies compared active controls (lenalidomide and dexamethasone, and bortezomib and dexamethasone, respectively) alone vs. in combination with daratumumab. Three M‐protein dynamic features from the longitudinal M‐protein data were evaluated up to different time cutoffs (1, 2, 3, and 6 months). The abilities of early M‐protein dynamic measurements to predict the PFS were evaluated using Cox proportional hazards survival models. Both univariate and multivariable analyses suggest that maximum reduction of M‐protein (i.e., depth of response) was the most predictive of PFS. Despite the statistical significance, the baseline covariates provided very limited predictive value regarding the treatment effect of daratumumab. However, M‐protein dynamic features obtained within the first 2 months reasonably predicted PFS and the associated treatment effect of daratumumab. Specifically, the areas under the time‐varying receiver operating characteristic curves for the model with the first 2 months of M‐protein dynamic data were ~ 0.8 and 0.85 for POLLUX and CASTOR, respectively. Early M‐protein data within the first 2 months can provide a prospective and reasonable prediction of future long‐term clinical benefit for patients with MM.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ M‐protein is a biomarker for tumor burden and its levels in the serum and urine have been used to assess treatment responses for patients with multiple myeloma (MM).

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ Whether early M‐protein data in the first several months can provide a prospective prediction for long‐term benefit and treatment effect.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ By using clinical data collected from two pivotal phase III trials of daratumumab in relapsed or refractory MM, we demonstrated that M‐protein dynamic data collected during the first 2 months of therapy can provide a prospective and reasonable prediction for not only long‐term progression‐free survival (PFS) but also the treatment effects of daratumumab on PFS compared with other active controls.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Early M‐protein dynamic data within the first 2 months of therapy may enable the designers of clinical trials to predict the probability of treatment success, and thus facilitate decision making in developing new drugs for MM.

Daratumumab is a human immunoglobulin G (IgGκ) monoclonal antibody that targets CD38 and kills malignant plasma cells via direct antitumor and immunomodulatory mechanisms of action. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ Daratumumab induces antitumor activity through several CD38 immune‐mediated actions, including complement‐dependent cytotoxicity, antibody‐dependent cellular cytotoxicity, antibody‐dependent cellular phagocytosis, apoptosis, and modulation of CD38 enzymatic activity. ¹ , ² , ³ , ⁴ , ⁵ Daratumumab also induces an immunomodulatory effect by minimizing the immune‐suppressive functions of CD38⁺ myeloid‐derived suppressor cells, regulatory T cells, and regulatory B cells, and increasing T‐cell clonality. ⁶ In the phase III clinical studies POLLUX (MMY3003) and CASTOR (MMY3004), daratumumab in combination with standards of care regimens lenalidomide and dexamethasone (Rd), and bortezomib and dexamethasone (Vd), respectively, reduced the risk of disease progression or death by ≥ 50%, doubled the rates of complete response or better, and more than tripled the rates of minimal residual disease negativity based on next‐generation sequencing at the 10^–5 sensitivity threshold vs. standard of care alone in patients with relapsed/refractory multiple myeloma (MM). ⁸ , ⁹ , ¹⁰ , ¹¹ These findings led to the approval of daratumumab (16 mg/kg) in combination with Rd, and Vd in patients with relapsed and refractory MM in many countries worldwide. Daratumumab has also been approved as monotherapy in many countries and in combination with pomalidomide and dexamethasone in the United States.In MM, tumor plasma cell produces a large amount of monoclonal IgG or IgG free light chain (FLC), known as M‐protein. M‐protein is a biomarker for tumor burden and its levels in the serum and urine have been used to assess treatment responses for patients with MM. ¹² Dispenzieri et al. ¹³ demonstrated the utility of FLC after 2 months of therapy to predict the overall response. Furthermore, several other studies have shown retrospective association between FLC/M‐protein reduction and the long‐term benefit, such as progression‐free survival (PFS) or overall survival, ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ which is critical for predicting antitumor activities for new agents and personalizing therapy for patients with myeloma.To date, the retrospective studies of the association between M‐protein dynamics and PFS or overall survival have been mainly based on complete M‐protein dynamic data collected up to the time of disease progression. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ Therefore, the prospective ability of M‐protein, particularly early measurements within 2–3 months of therapy, to predict long‐term survivals remains unknown. Moreover, because most of existing association studies were performed based on nonrandomized, single‐arm phase II studies, ¹³ , ¹⁴ , ¹⁵ , ¹⁷ , ¹⁹ translation of the significant association between M‐protein and survival in these studies to treatment effects compared with control arms in the randomized phase III studies is still challenging. Furthermore, existing association studies have mainly focused on reduction in the M‐protein level at a static single time point (e.g., end of 8 weeks) without considering dynamic information or features of M‐protein (e.g., variation in M‐protein levels over time, and rate of M‐protein changes). ¹³ , ¹⁴ , ¹⁸ Here, we investigated the usefulness of early M‐protein dynamic data collected during the first several months after treatment initiation as a predictor of PFS and the effects of treatment on PFS. This analysis is based on the clinical data of two, large‐scale phase III studies, POLLUX and CASTOR for daratumumab. We evaluated different features of M‐protein dynamics in addition to M‐protein reduction and compared the predictive performance of M‐protein dynamic data within different periods after treatment. With this analysis, we hypothesized that an early interim analysis based on M‐protein dynamics within a couple of months after treatment could prospectively predict the future long‐term treatment effect on PFS. Such predictions would contribute greatly to predictions of the probability of success of future clinical trials, decision making in drug development, and the prevision of individualized guidance for treatment and patient care.     

Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

Chemotherapy‐induced peripheral neuropathy (CIPN) is a dose‐limiting adverse event associated with treatment with paclitaxel and other chemotherapeutic agents. The prevention and treatment of CIPN are limited by a lack of understanding of the molecular mechanisms underlying this toxicity. In the current study, a human induced pluripotent stem cell–derived sensory neuron (iPSC‐SN) model was developed for the study of chemotherapy‐induced neurotoxicity. The iPSC‐SNs express proteins characteristic of nociceptor, mechanoreceptor, and proprioceptor sensory neurons and show Ca²⁺ influx in response to capsaicin, α,β‐meATP, and glutamate. The iPSC‐SNs are relatively resistant to the cytotoxic effects of paclitaxel, with half‐maximal inhibitory concentration (IC₅₀) values of 38.1 µM (95% confidence interval (CI) 22.9–70.9 µM) for 48‐hour exposure and 9.3 µM (95% CI 5.7–16.5 µM) for 72‐hour treatment. Paclitaxel causes dose‐dependent and time‐dependent changes in neurite network complexity detected by βIII‐tubulin staining and high content imaging. The IC₅₀ for paclitaxel reduction of neurite area was 1.4 µM (95% CI 0.3–16.9 µM) for 48‐hour exposure and 0.6 µM (95% CI 0.09–9.9 µM) for 72‐hour exposure. Decreased mitochondrial membrane potential, slower movement of mitochondria down the neurites, and changes in glutamate‐induced neuronal excitability were also observed with paclitaxel exposure. The iPSC‐SNs were also sensitive to docetaxel, vincristine, and bortezomib. Collectively, these data support the use of iPSC‐SNs for detailed mechanistic investigations of genes and pathways implicated in chemotherapy‐induced neurotoxicity and the identification of novel therapeutic approaches for its prevention and treatment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Sensory peripheral neuropathy is a common and dose‐limiting adverse event during chemotherapy. The lack of a molecular understanding of this toxicity limits options for its prevention and treatment.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ The current study tested whether sensory neurons differentiated from human induced pluripotent stem cells (iPSC‐SNs) can be used to investigate chemotherapy‐induced neurotoxicity, using paclitaxel as a model neurotoxic chemotherapeutic.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The iPSC‐SNs are a robust and reproducible model of paclitaxel‐induced neurotoxicity. Treatment of iPSC‐SNs with paclitaxel affects neurite networks, neuron excitability, and mitochondrial function.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ This novel stem cell model of chemotherapy‐induced neurotoxicity will be valuable for identifying genes and pathways critical for this toxicity and could be a useful platform for testing therapeutic approaches for treatment.

Chemotherapy‐induced peripheral neuropathy (CIPN) is a dose‐limiting toxicity associated with a number of drugs used for the treatment of solid tumors and hematological cancers. ¹ , ² , ³ Drugs with diverse mechanisms of action, including microtubule disruptors, proteasome inhibitors, and DNA‐crosslinking agents, all cause significant peripheral neuropathy. CIPN typically presents as burning, tingling, or numbness in the hands and feet that occurs in a glove and stocking distribution. ² , ⁴ In addition to negatively affecting a patient’s quality of life, dose reductions, treatment delays, and discontinuation can impact the therapeutic effectiveness of these drugs. ² Despite years of research, there are no effective therapies to prevent and/or treat CIPN, highlighting the need to define the molecular basis of this toxicity to support the development of novel strategies for treatment.Most mechanistic studies of CIPN have used behavioral testing in rodent models or cell‐based studies using primary rodent dorsal root ganglion (DRG) neurons. Common mechanisms associated with the development of CIPN include axon degeneration, altered Ca²⁺ homeostasis, mitochondrial dysfunction, changes in neuronal excitability, and neuroinflammation, although the relative contribution of these mechanisms varies for individual drugs. ⁵ , ⁶ , ⁷ For example, the microtubule stabilizing effects of paclitaxel inhibit anterograde and retrograde transport of synaptic vesicles down the microtubules, resulting in axon degeneration and membrane remodeling. This phenomenon is thought to be a major contributor to paclitaxel‐induced peripheral neuropathy. ⁸ In contrast, the ability of DNA alkylators, like cisplatin and oxaliplatin, to form adducts with mitochondrial DNA and increase reactive oxygen species contributes significantly to their peripheral neuropathy. ⁵ Although these studies in preclinical models and primary cultures of rodent DRG neurons have enhanced our knowledge of potential mechanisms for CIPN, attempts to translate these findings into humans have been largely unsuccessful. ³ In recent years, human induced pluripotent stem cell (iPSC)‐derived neurons have been used for the study of CIPN. Commercially available iPSC‐derived neurons (e.g., iCell neurons and Peri.4U neurons) have been evaluated as a model of neurotoxicity, ⁹ used to screen for neurotoxic compounds, ¹⁰ , ¹¹ , ¹² , ¹³ and utilized for functional validation of genes identified in human genomewide association studies of CIPN. ⁹ , ¹⁴ , ¹⁵ , ¹⁶ The use of human iPSC‐derived neurons affords an advantage over rodent DRG neurons in their human origin and the potential to differentiate into specific peripheral sensory neuron populations. The iCell neurons are a mixture of postmitotic GABAergic and glutamatergic cortical neurons that are more characteristic of relatively immature forebrain neurons than the sensory neurons found in the DRG. ¹⁷ , ¹⁸ Peri.4U neurons are more peripheral‐like, expressing βIII‐tubulin, peripherin, MAP2, and vGLUT2, but have been minimally characterized with respect to functional properties. ¹⁰ , ¹⁹ Additionally, neurons derived from human fibroblasts, blood, and embryonic stem cells that express more canonical nociceptive markers, like ISL1, BRN3A, P2RX3, the NTRK receptors, and NF200, ²⁰ , ²¹ , ²² , ²³ have also been used to study chemotherapy toxicity. Although these human derived cells resemble the DRG sensory neurons that are targeted by chemotherapeutics, there is significant interindividual variation across donor samples that limits their routine use for mechanistic studies and confounds the evaluation of functional consequences of genetic variation associated with human CIPN. ²⁴ Despite advances made in recent years in the development of human cell‐based models for the study of CIPN, there remains a need for a robust, widely available, and reproducible model for detailed mechanistic studies of this dose‐limiting toxicity. The goal of the studies described below was to develop an iPSC‐derived sensory neuron (iPSC‐SN) model for the study of chemotherapy‐induced neurotoxicity. Paclitaxel was used as a model neurotoxic chemotherapeutic to evaluate morphological, mitochondrial, and functional changes associated with exposure of iPSC‐SNs to neurotoxic compounds.     

Clinical Evaluation of an Investigational 5 mL Wearable Injector in Healthy Human Subjects

An investigational wearable injector (WI), the BD Libertas Wearable Injector (BD Libertas is a trademark of Becton, Dickinson and Company), was evaluated in an early feasibility clinical study for functional performance, tissue effects, subject tolerability, and acceptability of 5 mL, non‐Newtonian ~ 8 cP subcutaneous placebo injections in 52 healthy adult subjects of 2 age groups (18–64 years and ≥ 65 years). Randomized WI subcutaneous injections (n = 208, 4/subject) were delivered to the right and left abdomen and thigh of each subject, 50% (1 thigh and 1 abdomen) with a defined movement sequence during injection. Injector functional performance was documented. Deposition was qualified and quantified with ultrasound. Tissue effects and tolerability (pain) were monitored through 24 hours with corresponding acceptability questionnaires administered through 72 hours. WI (n = 205) automatically inserted the needle, delivered 5 mL ± 5% in 5.42 minutes (SD 0.74) and retracted. Depots were entirely (93.2%) or predominantly (5.4%) localized within the target subcutaneous tissue. Slight to moderate wheals (63.9%) and erythema (75.1%) were observed with ≥ 50% resolution within 30–60 minutes. Subject pain (100 mm Visual Analog Scale) peaked mid‐injection (mean 9.1 mm, SD 13.4) and rapidly resolved within 30 minutes (mean 0.4 mm, SD 2.6). Subjects’ peak pain (≥ 90.2%), injection site appearance (≥ 92.2%) and injector wear, size, and removal (≥ 92.1%) were acceptable (Likert responses) with 100% likely to use the injector if prescribed. Injection site preference was divided between none (46%), abdomen (25%), or thigh (26.9%). The investigational WI successfully delivered 5 mL viscous subcutaneous injections. Tissue effects and pain were transient, well‐tolerated and acceptable. Neither injection site, movement or subject age affected injector functional performance or subject pain and acceptability.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Transitioning chronic disease therapies from intravenous infusion to large volume subcutaneous injection requires reliable and accurate delivery devices that may enable intuitive self or care‐giver administration. Limited options are commercially available.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ An investigational wearable injector’s functionality and tolerability for 5 mL, ~ 8 cP subcutaneous placebo injections to the thigh and abdomen with and without movement in healthy adults of 2 age groups (18–64 years and ≥ 65 years) is described. Depot location, corresponding local tissue effects, and acceptability are documented.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The investigational injector performed as designed, consistently delivering 5 mL ± 5% to the target subcutaneous tissue in ~ 5.5 minutes with transient, well‐tolerated tissue effects and pain. Neither injection site, movement or subject age affected injector functional performance or subject pain and acceptability.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The investigational injector demonstrated equivalent functional performance with broad acceptability across subject genders, body mass index categories, and age range with and without movement. Results indicate promising potential of device design and delivery boundaries.

Chronic disease biological therapies are transitioning from traditional intravenous to subcutaneous administration. Adapting intravenous therapies to subcutaneous administration creates delivery challenges, such as larger than traditional volumes and viscosities. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ Intuitive and reliable subcutaneous injection system design will help navigate the complexity of these new delivery challenges while ensuring patient ease of wear and use. Effective subcutaneous injection system design requires a strong understanding of the biomechanical and physiological impact to subcutaneous tissue of delivery at increased volumes and viscosities with corresponding subject tolerability and acceptability. ¹ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ Subcutaneous administration conveys many benefits, such as reduced cost and treatment time and increased patient autonomy, convenience, and tolerance/acceptance. ³ , ²¹ Multiple comparative studies report that both patients and health care providers (HCPs) prefer subcutaneous to intravenous administration, citing improved clinical management, efficiency, and convenience with decreased pain and adverse systemic effects. ¹² , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ Historically, literature has identified multiple thresholds for the subcutaneous bolus limit between 1.5 and 3 mL due to subject pain and tissue feasibility. ¹ , ² , ³ , ⁷ , ¹⁵ , ²⁶ Observation that injection volumes > 2 mL may create site wheals (surface tissue displacement) or induration (hardening of the soft tissue) likely contributed to the anticipated low tolerability of these injections despite the absence of relevant clinical evidence linking wheal formation or induration to pain. ² Multiple studies using pump‐driven injection systems as surrogates for functional subcutaneous injection devices document the feasibility and tolerability of 3 to 20 mL single subcutaneous bolus injections in human clinical subjects. ¹ , ¹⁰ , ¹² , ²⁷ , ²⁸ Subcutaneous administration is both feasible and convenient with the introduction of combination products, such as wearable or on‐body injectors, autoinjectors, and prefilled syringes that use fixed dosing to reduce dosing errors and enable patient choice in injection provider, device type, and setting. ² , ¹² Wearable injectors (WIs) complement and may exceed the volume and viscosity capacities currently available in prefilled syringes or autoinjectors; however, there are currently limited commercial on‐body or WI options available. ³ , ¹⁰ , ²⁹ The current study is a first‐in‐human clinical assessment of an investigational WI for functional performance and corresponding tissue effects, depot location, subject tolerability, and acceptability for 5 mL, ~ 8 cP injections of a viscous non‐Newtonian placebo, hyaluronic acid (HA) diluted in saline. The study included 52 healthy adult subjects of both genders and 2 age groups (18–64 years and ≥ 65 years). Each subject received four injections (2 abdominal and 2 thigh) with and without movement for each location. WI functional performance (injection duration, delivered volume, adherence, and status indicator) was documented from application through removal. Depot location was qualified and quantified via ultrasound. Site tissue effects (wheal and erythema) and subject pain tolerance (100 mm Visual Analog Scale, VAS) were monitored through 24 hours with corresponding acceptability documented via questionnaires through 72 hours postinjection.     

Safety and Pharmacokinetics of the Oral TYK2 Inhibitor PF‐06826647: A Phase I,Randomized, Double‐Blind,Placebo‐Controlled,Dose‐Escalation Study

Selective inhibition of tyrosine kinase 2 (TYK2) may offer therapeutic promise in inflammatory conditions, with its role in downstream pro‐inflammatory cytokine signaling. In this first‐in‐human study, we evaluated the safety, tolerability, and pharmacokinetics (PK) of a novel TYK2 inhibitor, PF‐06826647, in healthy participants. This phase I, randomized, double‐blind, placebo‐controlled, parallel‐group study included two treatment periods (single ascending dose (SAD) and multiple ascending dose (MAD)) in healthy participants and a cohort of healthy Japanese participants receiving 400 mg q.d. or placebo in the MAD period ({"type":"clinical-trial","attrs":{"text":"NCT03210961","term_id":"NCT03210961"}}NCT03210961). Participants were randomly assigned to PF‐06826647 or placebo (3:1). Participants received a single oral study drug dose of 3, 10, 30, 100, 200, 400, or 1,600 mg (SAD period), then 30, 100, 400, or 1,200 mg q.d. or 200 mg b.i.d. for 10 days (MAD period). Safety (adverse events (AEs), vital signs, and clinical laboratory parameters), tolerability, and PK were assessed. Overall, 69 participants were randomized to treatment, including six Japanese participants. No deaths, serious AEs, severe AEs, or AEs leading to dose reduction or temporary/permanent discontinuation were observed. All AEs were mild in severity. No clinically relevant laboratory abnormalities or changes in vital signs were detected. PF‐06826647 was rapidly absorbed with a median time to maximum plasma concentration of 2 hours in a fasted state, with modest accumulation (< 1.5‐fold) after multiple dosing and low urinary recovery. PF‐06826647 was well‐tolerated, with an acceptable safety profile for doses up to 1,200 mg q.d. for 10 days, supporting further testing in patients.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Tyrosine kinase 2 (TYK2) inhibitors offer therapeutic promise for the many patients with inflammatory conditions in which IL‐12/23 signaling is implicated, and who have an inadequate response to existing systemic treatment options.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ PF‐06826647 is an oral TYK2 inhibitor with potency against TYK2‐dependent signaling. We aimed to assess the safety, tolerability, and pharmacokinetics of PF‐06826647 in healthy participants.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ PF‐06826647 was well‐tolerated, with an acceptable safety profile at a single dose of up to 1,600 mg, or multiple doses up to 1,200 mg daily.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ PF‐06826647 may offer a future oral treatment option for patients with inflammatory and autoimmune conditions in which IL‐12/23 signaling is implicated.

Tyrosine kinase 2 (TYK2), a member of the Janus kinase (JAK) family, is essential for IL‐12/T‐helper cell 1 and IL‐23/T‐helper cell 17 signaling ¹ , ² and IFN type I/II receptor functioning, ² , ³ and both preclinical and clinical studies have implicated these pathways in the pathogenesis of autoimmune disorders, including psoriasis, inflammatory bowel disease, and systemic lupus erythematosous. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ In large, human, genome‐wide association studies, single nucleotide polymorphisms of the TYK2 gene have been shown to confer protection against psoriasis, ankylosing spondylitis, Crohn’s disease, multiple sclerosis, and ulcerative colitis. ⁵ Blocking signaling from the pro‐inflammatory cytokines, as well as their downstream pathways, with the TYK2 JH2 domain inhibitor BMS‐986165, ¹⁰ the TYK2/JAK1 inhibitor brepocitinib, ¹¹ or with the monoclonal antibodies ustekinumab (anti‐IL‐12 and IL‐23), ¹² , ¹³ , ¹⁴ risankizumab (anti‐IL‐23), ¹⁴ , ¹⁵ secukinumab (anti‐IL‐17A), ¹⁶ mirikizumab (anti‐IL‐23), ¹⁷ or guselkumab (anti‐IL‐23), ¹⁸ , ¹⁹ has shown efficacy in the treatment of various autoimmune conditions.PF‐06826647 is an oral TYK2 inhibitor with potency against TYK2‐dependent signaling (IFNα/IL‐12/IL‐23), but may have dose‐dependent inhibitory activity against other, TYK2‐independent pathways (IFNγ/erythropoeitin). PF‐06826647 is a compound with a low pKa (< 1.7), low solubility across physiological pH (~ 0.3 μg/mL at pH 6.5), and high cellular permeability (~ 17 × 10^‐6 cm/s). However, based on preclinical exposure data in rats, using a spray‐dried dispersion formulation, it was expected to be moderately‐to‐well absorbed at the predicted clinically effective dose range in the clinic. In addition, preclinical studies demonstrated limited drug clearance via renal and biliary excretion in rats, and the major human clearance pathway for PF‐06826647 was identified to be cytochrome P450 (CYP)‐mediated (via CYP1A2, CYP2D6, and CYP3A) metabolism. ²⁰ PF‐06826647 has shown minimal inhibition of transporter proteins (i.e., MATE1, MRP1, MRP2, MRP3, sodium/Na+ taurocholate co‐transporting polypeptide, OATP1B1, OATP1B3, and OCT2), with the exception of MATE2 inhibition. ²⁰ In a phase I, first‐in‐human study ({"type":"clinical-trial","attrs":{"text":"NCT03210961","term_id":"NCT03210961"}}NCT03210961), we evaluated the safety, tolerability, and pharmacokinetics (PK) of PF‐06826647 in healthy participants. In this report, we present safety, tolerability, and PK data for escalating single and multiple doses of PF‐06826647. We also present the impact of food on PK parameters, and a comparison of PK parameters in plasma and urine between Western participants and a Japanese cohort during the multiple ascending dose (MAD) period at an expected clinically relevant dose of 400 mg q.d. Doses for the single ascending dose (SAD) and MAD study periods were initially selected based on data from in vitro pharmacologic/toxicologic studies. ²⁰ During the dose escalation, the available safety data (adverse events (AEs), vital signs, electrocardiogram (ECG), clinical laboratory, hematology, and urinalysis) from the ongoing cohort were reviewed and the appropriate dose for the next cohort was selected to provide the projected average exposure (based on available PK data from all doses) being ~ ≤ 3‐fold of the exposure and less or equal to the PK stopping limit.     

Readiness to Change and Prospective Effects of Weight Management Programs in Pediatric Nonalcoholic Fatty Liver Disease

Non‐alcoholic fatty liver disease (NAFLD) is an increasing problem in pediatrics with limited treatment options. We prospectively assessed outcomes in patients managed in a hepatology clinic (HC) alone vs. those managed in combination with a multidisciplinary weight management program (MWMP). We describe each group’s readiness to change at the time of NAFLD diagnosis. Patients diagnosed with NAFLD were given a modified Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES) at enrollment (T1) to assess readiness to change. They were then followed at 3–9 months (T2) and at 10–15 months (T3). Linear mixed models were used to evaluate changes in body mass index (BMI), BMI z‐score, and transaminases over time and between the two groups. There were no significant treatment group main effects or treatment × time interactions for our primary end points for HC alone (n = 75) or with MWMP (n = 18). There was a significant main effect for time for BMI z‐score, with BMI z‐scores declining on average by 0.0568 (P = 0.004) from visit to visit. Low SOCRATES subscales scores in HC alone (n = 33) or with MWMP (n = 4) suggested a patient population with low recognition of disease and likelihood of taking steps for change. Patients with obesity and NAFLD had low scores on all three SOCRATES subscales. Despite this, both groups had improvement in BMI z‐score without significant difference between the two treatment groups in other primary end points. Further study is needed to identify the most effective patient selection and treatment strategies for pediatric patients with NAFLD, including pharmacotherapy and surgery.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Multidisciplinary clinics are often used in the treatment of obesity. Parental readiness to change is described in the literature.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What are the baseline characteristics, readiness to change, and prospective outcomes for patients seen in a hepatology clinic (HC) alone to those seen in combination with multidisciplinary weight management program (MWMP)? Were there baseline characteristics that accounted for differences in clinical outcomes?

• WHAT DOES THE STUDY ADD TO OUR KNOWLEDGE?

☑ Patients seen in an HC at a tertiary care clinic alone or with a MWMP are both able to achieve a reduction in body mass index z‐score without significant differences between groups. Readiness to change scores are low in a pediatric population newly diagnosed with nonalcoholic fatty liver disease.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Our study highlights an area where further development of pharmacotherapy is needed to improve modest outcomes.

Despite ongoing efforts to improve the public awareness and care of children in the United States, rates of obesity are increasing with 18.5% of US children and adolescents ages 2–19 years classified as obese in 2015–2016. ¹ , ² Decades of study have demonstrated interactions among genetics, nutrition, physical activity, culture, and public health policy in addition to emerging theories of infectobesity, the microbiome, circadian rhythm, and other potential contributors. ³ , ⁴ As a result, children are at increasing risk of developing metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), and premature mortality, and complication rates increase as they become adolescents. ⁵ Treatment options vary, but a staged approach is recommended for children and adolescents with obesity. This begins with counseling in the primary care setting for stage 1 and progresses to multidisciplinary services, medications, and bariatric surgery for those in stage 4 treatment. ⁶ Multidisciplinary weight management programs (MWMPs) have demonstrated success in weight reduction across a range of clinical settings and are frequently used to combat obesity at the patient level. ⁷ , ⁸ , ⁹ Assessment of readiness to change behaviors contributing to obesity is recommended at initiation of MWMP and is often informally performed as part of an overall motivational interviewing approach by the clinician during office visits. ¹⁰ With the increasing rates of obesity have come increasing rates of NAFLD, which is widely expected to become the most common liver disease of childhood. ¹¹ NAFLD is a spectrum of disease that ranges from simple steatosis to nonalcoholic steatohepatitis and advanced fibrosis. The etiology of NAFLD is similar to obesity; however, not all patients with obesity develop NAFLD and there are additional intrinsic and extrinsic factors involved. ¹² It is currently the second leading cause of liver transplantation in adults and is expected to eventually become the most common. ¹³ The mainstay of treatment is weight management prior to the onset of advanced fibrosis. Medications such as vitamin E and metformin have been trialed, but results have been inconclusive and newer therapies are still under investigation. ¹⁴ Patients with obesity and NAFLD are often followed by a gastroenterologist or hepatologist to monitor complications and provide treatment. Depending on patient interest and program availability, patients may be seen in a pediatric hepatology clinic (HC) alone or concurrently with an MWMP. Although the success of MWMP in weight management has been demonstrated, outcomes have not been prospectively compared with those resulting from care received in an HC alone. In this study, our aims were to describe and compare baseline characteristics, readiness to change, and prospective outcomes for patients seen in an HC alone to those seen in combination with MWMP. In addition, we sought to determine whether baseline characteristics accounted for differences in clinical outcomes.     

hIL‐7‐hyFc,A Long‐Acting IL‐7, Increased Absolute Lymphocyte Count in Healthy Subjects

A low lymphocyte count puts immune‐compromised patients at risk of mortality. hIL‐7‐hyFc is a homodimeric interleukin‐7 (IL‐7), a potent T‐cell amplifier, fused to the hybridizing IgD/IgG4 immunoglobulin domain. We performed a randomized, double‐blind, placebo‐controlled, dose‐escalation, phase I study to assess the pharmacokinetic, pharmacodynamic, safety, tolerability, and immunogenicity profiles of hIL‐7‐hyFc administered s.c. and i.m. to healthy volunteers. Thirty subjects randomly received hIL‐7‐hyFc or its matching placebo in an 8:2 ratio at 20, 60 μg/kg s.c., or 60 μg/kg i.m. The hIL‐7‐hyFc was slowly absorbed and its terminal half‐life was 63.26 hours after i.m. administration. The hIL‐7‐hyFc increased absolute lymphocyte count, mostly in T‐cells, which peaked 3 weeks after administration and then lasted for several additional weeks. The hIL‐7‐hyFc was well‐tolerated after a single s.c. and i.m. administration. Injection site reaction was the most common treatment‐emergent adverse event, which resolved spontaneously without treatment. The hIL‐7‐hyFc can be developed into a beneficial treatment option for patients with compromised T‐cell immunity. This trial was registered at www.clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT02860715","term_id":"NCT02860715"}}NCT02860715.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC?

☑ Exogenously administered interleukin (IL)‐7 has shown to increase T cells in various immune‐deficient patients. However, exogenously administered IL‐7, particularly nonglycosylated IL‐7, are known to have a relatively short half‐life.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ We performed this study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability profiles of hIL‐7‐hyFc, a novel long‐acting IL‐7, in humans.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Our results clearly showed that hIL‐7‐hyFc stays longer in the body, is well‐tolerated, and increases T cells in a dose‐dependent manner.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Our results provide evidence that a single dose of hIL‐7‐hyFc can be further developed into a beneficial treatment option for a variety of patients with a low T‐cell count or compromised T‐cell immunity. Several phase II studies in immune‐compromised patients or patients with a low T‐cell count are currently ongoing (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03478995","term_id":"NCT03478995"}}NCT03478995, {"type":"clinical-trial","attrs":{"text":"NCT03619239","term_id":"NCT03619239"}}NCT03619239, {"type":"clinical-trial","attrs":{"text":"NCT03733587","term_id":"NCT03733587"}}NCT03733587, and {"type":"clinical-trial","attrs":{"text":"NCT03752723","term_id":"NCT03752723"}}NCT03752723). Decrease in lymphocyte counts caused by anticancer therapy is associated with frequent relapse, severe toxicity, and mortality. ¹ , ² , ³ Likewise, increased neutrophil‐to‐lymphocyte ratio was a poor prognostic predictor in patients with cancer. ⁴ Furthermore, patients with a low lymphocyte count were significantly less benefited from immune checkpoint inhibitors. ⁵ Additionally, low lymphocyte count increased the risk for serious opportunistic infections in patients with AIDS, primary immunodeficiency, and idiopathic CD4 lymphopenia or patients receiving chronic immunosuppressive therapy. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ Interleukin‐7 (IL‐7) plays a critical role in the development, proliferation, maintenance, and reinvigoration of T‐cells. ¹² The effects of IL‐7 are mediated via a heterodimeric receptor consisting of the IL‐7 receptor α‐chain (IL‐7Rα) and the common cytokine receptor γ‐chain. IL‐7Rα, expressed on naïve T‐cells, is downregulated upon activation of IL‐7‐mediated signaling and re‐expressed in memory T‐cells. ¹³ , ¹⁴ Exogenously administered IL‐7 to humans and mice proliferated T‐cells in the peripheral blood, increased tumor infiltrating lymphocytes, enhanced the survival of T‐cells, and generated memory T‐cells. ¹⁵ , ¹⁶ , ¹⁷ Furthermore, exogenously administered IL‐7 was well‐tolerated and increased the number of T‐cells in a dose‐dependent manner in patients with viral infections (e.g., HIV and hepatitis B and C), cancer, and rare disease, such as progressive multifocal leukoencephalopathy and idiopathic CD4 lymphopenia. ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² However, exogenously administered IL‐7 had a relatively short half‐life in humans, particularly for non‐glycosylated IL‐7, which ranged only 6.46–9.80 hours, ¹⁵ similar to other cytokines. ²³ , ²⁴ Therefore, a novel long‐standing formulation of IL‐7 has been an unmet medical need.The hIL‐7‐hyFc is a homodimeric IL‐7 fused to the hybridizing IgD/IgG4 immunoglobulin domain (hyFc). The hyFc region in hIL‐7‐hyFc is composed of the hinge and N‐terminal portion of the heavy chain constant region 2 (hinge‐CH2) of human IgD, which is fused to the C‐terminal region of CH2 and the entire CH3 region of human IgG4. The hyFc region helps IL‐7 stay longer in the body through neonatal Fc receptor‐mediated recycling. ²⁵ A single s.c. administration of hIL‐7‐hyFc at 0.1, 0.3, or 1.0 mg/kg in rats increased the peripheral lymphocyte count by ~ 1.5‐fold. Additionally, the terminal half‐life of hIL‐7‐hyFc after a single s.c. administration in rats ranged from 19–25 hours.Based on the preclinical findings that support the notion that hIL‐7‐hyFc can be developed as a beneficial therapeutic option for patients with low lymphocyte count, we performed a phase I study to assess the pharmacokinetic (PK), pharmacodynamic (PD), safety, tolerability, and immunogenicity profiles of hIL‐7‐hyFc in humans.     

Evaluating Potential Disease‐Mediated Protein‐Drug Interactions in Patients With Moderate‐to‐Severe Plaque Psoriasis Receiving Subcutaneous Guselkumab

This open‐label, multicenter, phase I therapeutic protein‐drug interaction study was designed to evaluate the potential effect of guselkumab, a fully human anti‐interleukin‐23 immunoglobulin G1 lambda monoclonal antibody, on the pharmacokinetics of a cocktail of representative cytochrome P450 (CYP) probe substrates (midazolam (CYP3A4), S‐warfarin (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and caffeine (CYP1A2)). Fourteen participants with psoriasis received a single subcutaneous dose of guselkumab 200 mg on day 8 and an oral probe cocktail on days 1, 15, and 36. Blood samples were collected for measuring plasma concentrations of these probe substrates on days 1, 15, and 36. No consistent trends in observed maximum plasma concentration and area under the curve from time 0 to infinity values of each probe CYP‐substrate before (day 1) and after guselkumab treatment (days 15 and 36) could be identified in each individual patient, suggesting that the use of guselkumab in patients with psoriasis is unlikely to influence the systemic exposure of drugs metabolized by CYP isozymes (CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2). The probe cocktail was generally well‐tolerated when administered in combination with guselkumab in patients with psoriasis.Clinicaltrials.gov Identifiers: {"type":"clinical-trial","attrs":{"text":"NCT02397382","term_id":"NCT02397382"}}NCT02397382.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Therapeutic proteins (TPs) that modulate cytokine concentrations and activity can indirectly influence expression of cytochrome P450 (CYP) isoenzymes and may alter CYP‐mediated metabolism of concomitantly administrated small molecule drugs. An in vitro study ¹ and two phase I studies ² , ³ were previously conducted to assess if interleukin (IL)‐23 modulates the expression or activity of multiple CYP isoenzymes (including CYP1A2, 2C9, 2C19, 2D6, and 3A4). These results suggest that potential TP‐drug interactions between guselkumab and drugs metabolized by CYP450 could be low.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This phase I study evaluated whether treatment with guselkumab, which selectively binds and inhibits IL‐23, affects CYP450 isoenzyme activity in patients with moderate‐to‐severe psoriasis.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Subcutaneous administration of guselkumab to patients with psoriasis has no effect on the pharmacokinetics (PK) of the evaluated CYP substrates.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ These results suggest that guselkumab can be used for the treatment of psoriasis without significant PK interactions with drugs metabolized by CYP3A4, CYP2C9, CYP2C19, CYP2D6, or CYP1A2.

Psoriasis is a chronic inflammatory disease affecting 1–3% of the world’s population. ⁴ Traditional systemic therapies for psoriasis have not fully met patients’ needs. ⁵ Highly effective antibody‐based or fusion protein‐based biologics targeting key inflammatory mediators have been developed for psoriasis treatment. ⁶ Based on their mechanisms of action, biological psoriasis therapies can be classified as: (i) T‐cell modulating agents, (ii) tumor necrosis factor (TNF)‐α antagonists, (iii) interleukin (IL)‐12/23 and/or IL‐23 inhibitors, and (iv) IL‐17 inhibitors. ⁴ , ⁷ Guselkumab (Tremfya, Janssen Research & Development, Spring House, PA) is a fully human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody (mAb) that selectively binds and inhibits IL‐23, a critical driver of pathogenic T cells in chronic plaque psoriasis. Clinical trials have demonstrated that guselkumab had favorable efficacy and safety profiles for the treatment of moderate‐to‐severe plaque psoriasis. ⁸ , ⁹ , ¹⁰ As a fully human IgG1λ mAb, guselkumab is expected to be metabolized in the same manner as any other endogenous IgG antibody (degraded into small peptides and amino acids via catabolic pathways) and subject to similar routes for elimination. ¹¹ Therefore, the likelihood of direct therapeutic protein (TP)‐drug interaction occurring during co‐administration of guselkumab and other concomitant small molecule medications is assumed to be low. In line with this, clinically relevant information has been published about potential TP‐drug interactions, ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ and supports that mAbs do not elicit a direct effect on the metabolic/clearance pathways of small molecular therapeutics. However, the immunomodulatory properties of mAbs may indirectly alter the clearance of certain small molecules through noncatabolic hepatic metabolism pathways. ¹⁴ , ¹⁵ An in vitro study ¹ using cryopreserved human hepatocytes to assess whether IL‐12 and/or IL‐23 modulate the expression or activity of multiple cytochrome P450 (CYP) enzymes (i.e., CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) suggested that TP‐drug interactions between guselkumab and CYP450 substrates are unlikely. However, in vitro studies may have limitations in predicting clinical interactions between TPs and small molecule drugs. ¹⁷ To confirm these findings, we conducted a phase I study in patients with moderate‐to‐severe plaque psoriasis to determine if blocking IL‐23 with guselkumab for treatment of psoriasis would clinically alter the metabolism of probe substrates metabolized by CYP isozymes (CYP3A4, CYP2C9, CYP2C19, CYP2D6, or CYP1A2).     

Predicting Resolvin D1 Pharmacokinetics in Humans with Physiologically‐Based Pharmacokinetic Modeling

Sjögren’s syndrome (SS) is an autoimmune disease with no effective treatment options. Resolvin D1 (RvD1) belongs to a class of lipid‐based specialized pro‐resolving mediators that showed efficacy in preclinical models of SS. We developed a physiologically‐based pharmacokinetic (PBPK) model of RvD1 in mice and optimized the model using plasma and salivary gland pharmacokinetic (PK) studies performed in NOD/ShiLtJ mice with SS‐like features. The predictive performance of the PBPK model was also evaluated with two external datasets from the literature reporting RvD1 PKs. The PBPK model adequately captured the observed concentrations of RvD1 administered at different doses and in different species. The PKs of RvD1 in virtual humans were predicted using the verified PBPK model at various doses (0.01–10 mg/kg). The first‐in‐human predictions of RvD1 will be useful for the clinical trial design and translation of RvD1 as an effective treatment strategy for SS.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Sjögren’s syndrome (SS) is a complex inflammatory disorder with no clinically approved treatment options. Resolvin D1 (RvD1), a specialized pro‐resolving mediator with potent anti‐inflammatory effects, has shown promise in preclinical studies to restore the salivary gland function and promote tissue repair.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ We leveraged physiologically‐based pharmacokinetic (PBPK) modeling to predict the RvD1 pharmacokinetics (PKs) in humans by extrapolation from PK data obtained from in vivo experiments in a mouse model of SS.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The PBPK model provides an appropriate dose and estimates of clearance and other PK parameters for RvD1 in humans. These PK parameters and dose will inform the initial dosing of RvD1 for first‐in‐human clinical studies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ This study significantly advances the potential for clinical translation of RvD1 into clinical trials for the treatment of SS.

Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disease characterized by the diminished secretory function of the exocrine glands. ¹ It affects ~ 1% of the general population and up to 3% of people above the age of 50 years. ² Women account for > 90% of diagnosed cases. ² Diagnostic hallmarks for SS include xerostomia or dry mouth, impaired tear production, lymphocytic infiltration into salivary glands, and presence of anti‐Ro and anti‐La autoantibodies in plasma. ¹ SS reduces salivary gland function and leads to oral diseases, such as gingivitis and caries, and candidiasis. ³ The advanced complications of reduced salivary gland function include recurrent infection of the parotid gland ⁴ and lymphomas. ⁵ Together, these issues impose significant physical, psychological, and economic burdens on patients with SS. ⁶ Furthermore, the cause of SS is still unknown, and current therapeutic interventions are ineffective and limited to the use of saliva substitutes and medications that provide only temporary relief. ⁷ Therefore, the development of alternative treatments to restore salivary gland function are an urgent and unmet medical need.Viral and bacterial infections, in conjunction with the activation of susceptibility genes, stimulates chronic salivary gland inflammation. ⁸ A state of chronic inflammation causes tissue damage followed by cytokine and chemokine release. ⁸ When resolution mechanisms are working correctly, neutrophils and M2 macrophages can clear the site of injury or infection. ⁹ However, in SS, these resolution mechanisms are impaired, ¹⁰ and the dead cells involved in the process cannot be removed from the injury/infection site leading to the production of autoantigens and elevations in proinflammatory cytokine levels. ¹¹ The increased production of autoantigens and proinflammatory cytokines stimulate peripheral lymphocytes to bind to and infiltrate across the vascular endothelium into the salivary gland. ¹² Lymphocyte infiltration exacerbates the pathologic proinflammatory state, tissue damage, and hastens salivary gland dysfunction. ¹³ The cascade of events leading to inflammation resolution is an actively regulated process mediated in part by a family of endogenous lipid‐based specialized pro‐resolving mediators, which include resolvins, maresins, lipoxins, and protectins. ¹⁴ The administration of pro‐resolving lipid mediators have demonstrated efficacy in treating diseases having a pathologic proinflammatory basis, such as osteoarthritis, by terminating proinflammatory signaling, thereby enhancing tissue regeneration. ¹⁵ These pro‐resolving lipid mediators have been detected in animal models of infection and chronic inflammation. ¹⁶ Specific to SS, exogenous resolvin administration has the potential to reduce inflammation and restore salivary gland function. ¹⁷ Naturally occurring resolvin subtypes include the D series (derived from docosahexaenoic acid), the E series (derived from eicosapentaenoic acid), and six analogs of the D series, which are produced in response to aspirin. ¹⁸ Previously, we identified resolvin D1 (RvD1) as a therapeutic candidate for the treatment of SS. ¹⁹ RvD1 reduced inflammation and restored salivary gland tissue integrity in animal models of SS. ¹⁹ , ²⁰ , ²¹ In addition, the progression of SS‐like features in NOD/ShiLtJ mice can be halted using an aspirin‐triggered form of RvD1. In this circumstance, mice treated systemically, prior to disease onset, displayed downregulation of proinflammatory cytokines, upregulation of anti‐inflammatory mediators, and intact saliva production. ²² , ²³ Based on the preclinical safety and efficacy data of RvD1, we are preparing for phase I studies in humans. Therefore, the purpose of this study was to perform first‐in‐human predictions of RvD1 pharmacokinetics (PKs) in plasma and saliva using a verified whole‐body physiologically‐based pharmacokinetic (PBPK) model. The mouse PBPK model of RvD1 was developed using the physical, chemical, and biological properties of RvD1 and was optimized with plasma and salivary gland PK data obtained in SS‐like mice. The mouse PBPK model was then extrapolated to humans to generate appropriate first‐in‐human dose predictions.     

Therapeutic Opportunities for Intestinal Angioectasia‐ Targeting PPARγ and Oxidative Stress

Recurrent and acute bleeding from intestinal tract angioectasia (AEC) presents a major challenge for clinical intervention. Current treatments are empiric, with frequent poor clinical outcomes. Improvements in understanding the pathophysiology of these lesions will help guide treatment. Using data from the US Food and Drug Administration (FDA)’s Adverse Event Reporting System (FAERS), we analyzed 12 million patient reports to identify drugs inversely correlated with gastrointestinal bleeding and potentially limiting AEC severity. FAERS analysis revealed that drugs used in patients with diabetes and those targeting PPARγ‐related mechanisms were associated with decreased AEC phenotypes (P < 0.0001). Electronic health records (EHRs) at University of Cincinnati Hospital were analyzed to validate FAERS analysis. EHR data showed a 5.6% decrease in risk of AEC and associated phenotypes in patients on PPARγ agonists. Murine knockout models of AEC phenotypes were used to construct a gene‐regulatory network of candidate drug targets and pathways, which revealed that wound healing, vasculature development and regulation of oxidative stress were impacted in AEC pathophysiology. Human colonic tissue was examined for expression differences across key pathway proteins, PPARγ, HIF1α, VEGF, and TGFβ1. In vitro analysis of human AEC tissues showed lower expression of PPARγ and TGFβ1 compared with controls (0.55 ± 0.07 and 0.49 ± 0.05). National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) RNA‐Seq data was analyzed to substantiate human tissue findings. This integrative discovery approach showing altered expression of key genes involved in oxidative stress and injury repair mechanisms presents novel insight into AEC etiology, which will improve targeted mechanistic studies and more optimal medical therapy for AEC.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ The clinical detection of angioectasia (AEC) has increased using push‐enteroscopy, capsule enterography, colonoscopy, and esophagogastroduodenoscopy. Management is difficult. Currently, endoscopic ablation is an option for lesions within endoscopic reach, whereas angiogenesis inhibitors and octreotide are pharmacological agents additionally used in the treatment of AEC often with limited clinical benefit. The precise pathophysiology of AEC is unknown; however, AECs are known to result from an imbalance between the pro‐angiogenic and anti‐angiogenic factors.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ How do intestinal AEC develop and how can we design targeted therapeutic discovery for AEC.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Insight into the development of intestinal AEC and a targeted approach for novel therapeutic strategies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The results of this study demonstrate the complexity of AEC development and novel therapeutic directions that could impact patient care and treatment.

Angioectasia (AEC) lesions are common vascular abnormalities characterized by ectatic, dilated, and proliferated blood vessels, and are a significant source of obscure gastrointestinal (GI) bleeding. These aberrant blood vessels are typically < 10 mm in diameter, thin walled with little or no smooth muscle, malformed, and uncommunicative, ¹ , ² and symptomatically present with overt and occult GI hemorrhage, ¹ melena, hematochezia, and resulting anemia. ¹ , ³ The clinical procedure of endoscopy has shown the presence of AEC in the upper GI tract, ¹ small bowel, ¹ , ³ descending colon, ¹ , ⁴ and linked their existence to upper and lower GI hemorrhage. ¹ , ⁵ AECs are also significantly correlated with occurrence of synchronous lesions ⁶ , ⁷ , ⁸ and aging. ¹ , ⁹ The clinical detection of AEC has increased using push‐enteroscopy, capsule enterography, colonoscopy, and esophagogastroduodenoscopy, and management of these lesions is difficult with options for treatment being suboptimal. ¹ , ¹⁰ , ¹¹ Currently, endoscopic ablation is an option for lesions within endoscopic reach, whereas angiogenesis inhibitors, such as thalidomide, lenalidomide (thalidomide derivative), and octreotide, are pharmacological agents additionally used in the treatment of AEC often with limited clinical benefit. ¹¹ , ¹² The precise pathophysiology of AEC is unknown; however, AECs are known to result from an imbalance between the pro‐angiogenic and anti‐angiogenic factors and expression of growth factors, including VEGF in AECs, is suggestive of angiogenesis playing a role in their development. ¹ Angiogenesis promotes formation of new functional microvascular networks in human tissues in response to hypoxia or ischemia. ¹ AEC formation appears to be linked to patients with von Willebrand factor in Heyde’s syndrome and left ventricular assist device, whereas mutations in several genes in the TGFβ pathway are common in patients with hereditary hemorrhagic telangiectasia. ¹³ The VEGF‐dependent proliferation and migration represents an important angiogenesis‐hemostasis relationship that may have therapeutic implications in the management of AEC. ¹ , ¹⁴ , ¹⁵ , ¹⁶ Understanding the role of key mediators in AEC development will be important in identifying novel therapeutic strategies that will overcome this unmet clinical need.In this report, we describe a novel integrative systems biology‐based approach and clinical validation study that evaluates the pathophysiology of these lesions. We sought to identify if reduction in severity or decrease in rate of AEC and AEC‐correlated events occurred with use of specific drugs, hence using the medication’s own mechanism of action to ascertain a “first‐cut” of the inflammatory processes at work in vivo. To understand how therapeutic agents may impact AEC‐associated disease pathology, we used in silico drug discovery and gene regulatory networks analysis to identify key pathways/proteins involved in the pathophysiology of AEC and test candidate therapeutics for their protective mechanisms.     

Dose‐Dependent Acute Effects of Everolimus Administration on Immunological,Neuroendocrine and Psychological Parameters in Healthy Men

The rapamycin analogue everolimus (EVR) is a potent inhibitor of the mammalian target of rapamycin (mTOR) and clinically used to prevent allograft rejections as well as tumor growth. The pharmacokinetic and immunosuppressive efficacy of EVR have been extensively reported in patient populations and in vitro studies. However, dose‐dependent ex vivo effects upon acute EVR administration in healthy volunteers are rare. Moreover, immunosuppressive drugs are associated with neuroendocrine changes and psychological disturbances. It is largely unknown so far whether and to what extend EVR affects neuroendocrine functions, mood, and anxiety in healthy individuals. Thus, in the present study, we analyzed the effects of three different clinically applied EVR doses (1.5, 2.25, and 3 mg) orally administered 4 times in a 12‐hour cycle to healthy male volunteers on immunological, neuroendocrine, and psychological parameters. We observed that oral intake of medium (2.25 mg) and high doses (3 mg) of EVR efficiently suppressed T cell proliferation as well as IL‐10 cytokine production in ex vivo mitogen‐stimulated peripheral blood mononuclear cell. Further, acute low (1.5 mg) and medium (2.25 mg) EVR administration increased state anxiety levels accompanied by significantly elevated noradrenaline (NA) concentrations. In contrast, high‐dose EVR significantly reduced plasma and saliva cortisol as well as NA levels and perceived state anxiety. Hence, these data confirm the acute immunosuppressive effects of the mTOR inhibitor EVR and provide evidence for EVR‐induced alterations in neuroendocrine parameters and behavior under physiological conditions in healthy volunteers.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Everolimus (EVR) is a potent inhibitor of mTOR and clinically used to prevent organ rejection and to fight tumor growth. EVR is associated with neurobehavioral and psychological changes in patient studies. However, the effects of EVR under normal physiological conditions are unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What is the impact of clinically employed doses of EVR on immunological, psychological and neuroendocrine parameters in healthy male individuals?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Our data demonstrate that oral intake of medium and high doses of EVR suppressed T cell proliferation as well as IL‐10 cytokine production in ex vivo mitogen‐stimulated PBMCs. Acute low and medium EVR administration increased state anxiety and noradrenaline concentrations. In contrast, high dose EVR reduced cortisol levels but did not affect state anxiety levels.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ These findings demonstrate a dose dependent impact of EVR on state anxiety and neuroendocrine functions under normal physiological conditons in healthy individuals providing important information for monitoring drug efficacy and unwanted drug side effect for future clinical studies employing immunopharmacotherapy with EVR.

Everolimus (EVR) is a macrolide rapamycin analogue initially developed as an immunosuppressive drug with improved pharmacokinetic properties, including increased solubility, bioavailability, and reduced half‐life in comparison to other rapalogues. ¹ , ² EVR efficiently inhibits the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase and substrate of the PI3K/Akt signaling pathway, crucial for the regulation of cellular homeostasis, including cell growth, proliferation, protein synthesis, cellular stress, and survival. ³ Further, mTOR has been shown to play an essential role in innate and adaptive immune responses either by regulating T cell and B cell proliferation and differentiation as well as inflammatory cytokine and antibody production. ² , ⁴ So far, EVR is the only clinically used mTOR inhibitor approved by the US Food and Drug Administration (FDA) for the oral administration and treatment of malignancies, including breast carcinoma, gastrointestinal tract‐derived neuroendocrine tumors, renal cell carcinoma, and to prevent allograft rejection after heart, kidney, and liver transplantations. ¹ , ² , ⁵ Pharmacokinetic studies with transplant recipients obtaining EVR either with 0.75 mg/dose or 1.5 mg/dose twice a day combined with cyclosporin revealed maximal blood concentration of 11.1 ± 4.6 µg/L and 20.3 ± 8.0 µg/L, respectively, after 1 to 2 hours. ⁶ , ⁷ The elimination half‐life amounts for 18–32 hours and steady‐state is achieved between 4 and 7 days. ⁶ , ⁷ However, in patient studies, EVR intake is frequently accompanied with other immunosuppressive drugs like cyclosporin affecting the pharmacokinetic profile of EVR. ² Pharmacokinetics derived from healthy probands receiving a single 2 mg and 4 mg EVR dose revealed maximal EVR blood concentrations of 17.9 ± 5.9 µg/L and 44.2 ± 13.3 µ/L, respectively, reached after 0.5 to 1 hour with an elimination half‐life of 32 hours ⁸ , ⁹ and that single doses up to 5 mg are well‐tolerated. ¹⁰ Experimental and clinical studies in animal models and patients showed the potent immunosuppressive efficacy of the rapamycin analogue EVR in vitro mediated by blocking lymphocyte proliferation and in vivo by preventing rejections of transplanted organs. ¹¹ , ¹² , ¹³ , ¹⁴ Further, impaired renal function exerted by other medication regimens solely using calcineurin inhibitors in patients improved after acute and chronic treatment with EVR. ¹⁵ , ¹⁶ However, in patient studies, it is difficult to discriminate whether the examined effects solely were induced by EVR because the patients usually obtain a combination therapy consisting of more than one immunosuppressive drug. ¹¹ , ¹⁷ , ¹⁸ Accumulating clinical evidence document that patients receiving immunosuppressive medication, including calcineurin inhibitors like tacrolimus or cyclosporin A, frequently develop affective and cognitive dysfunctions, such as depression or anxiety, and exhibit neurotoxic side effects, including tremor and peripheral neuropathy potentially manifesting in psychoses and seizures. ¹⁹ , ²⁰ , ²¹ , ²² Although a growing body of studies in experimental animal models and clinical trials documented neurobehavioral effects exerted by mTOR inhibitors, the observed findings are controversial. EVR treatment improves neuropsychological deficits and autism in patients with tuberous sclerosis complex ²³ and has beneficial effects on memory and psychiatric symptoms in heart transplant recipients. ¹⁹ However mTOR inhibition also has been linked to depressive and anxiety‐like behavior in rodents and the induction of euphoria followed by melancholy, mimicking biopolar disorder in patients with breast cancer. ²⁴ , ²⁵ , ²⁶ , ²⁷ These observations indicate that mTOR inhibition is associated with neurobehavioral and psychiatric symptoms but the impact of comorbidities on the action of EVR is inconclusive since the findings have been acquired from patient studies. Hence, so far, no data exist documenting whether and to what extent clinically used doses of the mTOR inhibitor EVR affect cellular immunosuppressive responses, central functions on behavioral, neuroendocrine and psychological levels, and, thus, may contribute to central side effects, including anxiety in healthy individuals. Against this background, the present study determined systemic blood levels of EVR after an acute, four‐time oral administration of three different, pharmacological relevant doses of the drug along with its effects on T cell specific cytokine production and proliferation as well as behavioral and neuroendocrine parameters in healthy men.     

Perioperative Dexmedetomidine Improves Outcomes of Kidney Transplant

Graft function is crucial for successful kidney transplantation. Many factors may affect graft function or cause delayed graft function (DGF), which decreases the prognosis for graft survival. This study was designed to evaluate whether the perioperative use of dexmedetomidine (Dex) could improve the incidence of function of graft kidney and complications after kidney transplantation. A total of 780 patients underwent kidney transplantations, 315 received intravenous Dex infusion during surgery, and 465 did not. Data were adjusted with propensity scores and multivariate logistic regression was used. The primary outcomes are major adverse complications, including DGF and acute rejection in the early post‐transplantation phase. The secondary outcomes included length of hospital stay (LOS), infection, overall complication, graft functional status, post‐transplantation serum creatinine values, and estimated glomerular filtration rate (eGFR). Dex use significantly decreased DGF (19.37% vs. 23.66%; adjusted odds ratio, 0.744; 95% confidence interval, 0.564–0.981; P = 0.036), risk of infection, risk of acute rejection in the early post‐transplantation phase, the risk of overall complications, and LOS. However, there were no statistical differences in 90‐day graft functional status or 7‐day, 30‐day, and 90‐day eGFR. Perioperative Dex use reduced incidence of DGF, risk of infection, risk of acute rejection, overall complications, and LOS in patients who underwent kidney transplantation.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Graft function is crucial for successful kidney transplantation. Dexmedetomidine (Dex) has been shown to have renal protective effect in preclinical and other surgeries.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ The objective of this study was to evaluate whether the perioperative Dex administration was associated with improved graft kidney function or decreased complications after kidney transplantation.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ This study demonstrated that perioperative Dex administration was associated with improved kidney function and outcomes in patients who underwent kidney transplantation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The results from this study suggest perioperative Dex administration could be beneficial to donor kidney grafts.

The cost to care for patients with chronic kidney disease and endstage renal disease (ESRD) is significant with total spending over US $120 billion for Medicare beneficiaries alone representing 33.8% of total Medicare fee‐for‐service spending according to the United States Renal Data System 2019 annual data report. ¹ There were nearly 500,000 patients receiving maintenance dialysis treatments and well over 200,000 living with a kidney transplant in the United States by the end of 2015. ² Thus, ESRD is a major public health problem due to its high morbidity and mortality as well as social and financial implications. ³ Treatment outcomes vary depending on different modalities like hemodialysis, peritoneal dialysis, and renal transplantation. Renal transplantation has an obvious survival advantage over dialysis treatments for patients with ESRD along with better quality of life. ⁴ , ⁵ , ⁶ However, the 5‐year graft survival rate was 74.4% in deceased‐donor transplants and 85.6% in living‐donor transplants. ⁷ The etiology of graft kidney dysfunction is multifactorial and involves immunologic factors, surgical techniques, hemodynamic alterations, inflammatory mechanisms, apoptosis, and ischemia/reperfusion (I/R) injury. ⁸ Although advances in immunosuppressive therapy and treatment of hypertension and hyperlipidemia have improved outcomes following kidney transplantation, poor initial graft function occurs in up to 5% of living donor recipients and up to 20% of deceased donor recipients. Infection occurs in up to 30% of renal transplant recipients during the first 3 months post‐transplantation. ⁹ , ¹⁰ The transplant population has expanded to older and sicker patients, and only about 7.3% candidates on the US kidney transplant waiting list received deceased donor kidney transplantations. ¹¹ Approximately 15% of procured kidneys were discarded despite long waiting lists. ¹¹ At the same time, graft rejection episodes occur in about 20% of low‐risk transplant recipients within the first 26 weeks post‐transplantation. ⁹ The probability of first‐year all‐cause graft failure (return to dialysis, repeat transplantation, or death with a functioning transplant) for deceased donor kidney transplant recipients was about 7.7%. ³ , ¹² , ¹³ It is important to identify factors responsible for decreased graft function and find appropriate interventions.It is well known that renal function is closely associated with hemodynamic performance, sympathetic activity, inflammatory responses, and I/R injury. The hemodynamic stabilizing and sympatholytic effects produced by alpha₂ agonists have been shown to prevent the deterioration of renal function after cardiac surgery. ¹² , ¹⁴ , ¹⁵ The mechanisms could be inhibition of renin release, increased glomerular filtration, and increased excretion of sodium and water via the kidneys. ¹⁶ Dexmedetomidine (Dex) is a short‐acting selective alpha₂ agonist in comparison to clonidine and has an alpha₂ to alpha₁ selectivity ratio of 1,600:1. ¹⁷ Dex has a stabilizing effect on hemodynamics mediated by reducing sympathetic tone, decreasing inflammatory response, alleviating I/R injury, inhibiting renin release, increasing glomerular filtration rate, increasing secretion of sodium and water by the kidneys, and decreasing insulin secretion. ¹⁸ , ¹⁹ Although Dex has been shown to alleviate acute kidney injury (AKI) in other surgeries, ¹⁴ , ¹⁵ no study has demonstrated the benefit of Dex on graft function in renal transplantation. Thus, this study was designed to determine whether the perioperative use of Dex is associated with improved graft kidney function and decreased incidence of complications after renal transplantation.     

Identification of Critical Windows of Metabolic Programming of Metabolism and Lung Function in Male Offspring of Obese Dams

Perinatal nutritional determinants known as metabolic programming could be either detrimental or protective. Maternal obesity in the perinatal period determines susceptibility for diseases, such as obesity, metabolic disorders, and lung disease. Although this adverse metabolic programming is well‐recognized, the critical developmental window for susceptibility risk remains elusive. Thus, we aimed to define the vulnerable window for impaired lung function after maternal obesity; and to test if dietary intervention protects. First, we studied the impact of high‐fat diet (HFD)‐induced maternal obesity during intrauterine (HFD^iu), postnatal (HFD^post), or perinatal (i.e., intrauterine and postnatal (HFD^peri) phase on body weight, white adipose tissue (WAT), glucose tolerance, and airway resistance. Although HFD^iu, HFD^post, and HFD^peri induced overweight in the offspring, only HFD^peri and HFD^iu led to increased WAT in the offspring early in life. This early‐onset adiposity was linked to impaired glucose tolerance in HFD^peri‐offspring. Interestingly, these metabolic findings in HFD^peri‐offspring, but not in HFD^iu‐offspring and HFD^post‐offspring, were linked to persistent adiposity and increased airway resistance later in life. Second, we tested if the withdrawal of a HFD immediately after conception protects from early‐onset metabolic changes by maternal obesity. Indeed, we found a protection from early‐onset overweight, but not from impaired glucose tolerance and increased airway resistance. Our study identified critical windows for metabolic programming of susceptibility to impaired lung function, highlighting thereby windows of opportunity for prevention.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Maternal and perinatal obesity determine metabolism of the offspring. Obesity and adverse metabolic conditions are related to impaired lung development and reduced lung function. The condition, in which adverse perinatal metabolic influences have lifelong impact on health, has been coined as “perinatal metabolic programming.”

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ The study aimed to identify which window during development is critical for determining the metabolism and lung function later in life.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The present study does not only highlight the importance of perinatal metabolic influences on long‐term body composition and metabolism in male offspring, but also its impact on lung function. Moreover, we identified critical developmental windows for metabolic programming of glucose metabolism and susceptibility to impaired lung function, highlighting thereby windows of opportunity for prevention.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Perinatal nutrition, including postnatal feeding of newborns, is a highly relevant pediatric topic. Our study highlights that early nutritive interventions could beneficially affect the offspring’s health in later life.

The incidence of chronic lung diseases, such as bronchial asthma and chronic obstructive pulmonary disease, has increased over the last decades in adults and children. ¹ , ² The pathogenesis of lung diseases is multifactorial, not only including environmental factors and genetic predisposition, but also obesity. ³ Obesity and childhood obesity have become a worldwide epidemic and were recognized to contribute to impaired lung function. ⁴ Recent studies have shown that metabolic dysregulation, including cytokines secreted by the adipose tissue, occurs in patients with chronic lung diseases and could thereby be pathomechanistically important for chronic obstructive pulmonary disease, bronchopulmonary dysplasia, and asthma. ⁵ , ⁶ , ⁷ , ⁸ Children of obese women are not only at high risk to become overweight or obese, ⁹ but also to evolve wheezing illnesses, asthma, and atopic diseases. ¹⁰ The condition, in which perinatal metabolic influences have lifelong impact on health, has been coined as “perinatal metabolic programming.” ¹¹ , ¹² Although some studies have shown positive effects on metabolic programming, ¹³ experimental animal studies demonstrate that exposure of a maternal high‐fat diet (HFD) impairs fetal lung development and increases risk for bronchiolitis. ¹⁴ , ¹⁵ Moreover, our group showed that catch‐up growth after intrauterine growth restriction (IUGR) or postnatal maternal HFD increase respiratory airway resistance. These findings were related to increased production of adipocytokines in white adipose tissue (WAT), ¹⁶ , ¹⁷ a condition that has been previously linked with the pathogenesis of pulmonary diseases, such as bronchial asthma. ¹⁸ , ¹⁹ Although there is strong evidence that maternal obesity or maternal exposure to HFD adversely affect the developing lung, the critical window for metabolic programming of metabolism, obesity, and increased airway resistance remains uncertain. The aim of the present study was to define the critical window for programming of obesity, metabolism, and lung function in the offspring using a mouse model of maternal obesity.     

Evaluation of the Effect of Maribavir on Cardiac Repolarization in Healthy Participants: Thorough QT/QTc Study

Maribavir is an orally bioavailable benzimidazole riboside in clinical development for treatment of cytomegalovirus infection in patients who undergo transplantation. Maribavir was evaluated in a thorough QT (TQT) study to determine any effects on cardiac repolarization. The effect of maribavir 100 and 1,200 mg oral doses on the baseline‐adjusted and placebo‐adjusted corrected QT (QTc) interval (delta delta QTc (ddQTc)) and other electrocardiogram (ECG) parameters was assessed in a randomized, phase I, placebo‐controlled, four‐period crossover study in healthy participants (men and women ages 18–50 years). Additionally, maribavir pharmacokinetics, safety, and tolerability were investigated. Moxifloxacin (400 mg) was used as a positive control to demonstrate the study’s ability to detect QT prolongation. Digital 12‐lead Holter ECG monitoring was performed over 22 hours following study drug administration. Individual, Fridericia’s, and Bazett’s QTc intervals were calculated. Of 52 randomized participants (29 ± 8.1 years old; 31 men (60%)), 50 (96%) completed the study. For both 100‐mg and 1200‐mg doses of maribavir, analysis of ddQTc demonstrated that the upper bound of the two‐sided 90% confidence interval was below the 10‐ms threshold at all time points. The concentration–effect analysis demonstrated no relationship between ddQTc and plasma concentrations of maribavir (and its metabolite). There were no clinically meaningful changes in heart rate and systolic blood pressure. The most common adverse event was dysgeusia; no serious adverse events were reported. This TQT study demonstrated that maribavir did not have impact on cardiac repolarization.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ The effect of maribavir on the QT/corrected QT (QTc) interval in healthy participants is not known.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ Maribavir’s potential effect on the QT/QTc interval was investigated in healthy participants in accordance with International Conference on Harmonization E14 guidelines.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The study provides the evidence of maribavir’s supratherapeutic dose of 1,200 mg in healthy adult participants.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The study provides the evidence of cardiovascular safety of maribavir, an orally bioavailable benzimidazole riboside drug currently in phase III development for cytomegalovirus infection in patients who undergo transplantation.

Cytomegalovirus (CMV) infection or reactivation is a significant complication following both hematopoietic stem cell transplantation (HSCT) and solid organ transplantation, and it is associated with increased morbidity and reduced long‐term survival. ¹ , ² Use of approved anti‐CMV agents may carry risks of treatment‐limiting toxicities or of significant drug interactions leading to contraindication or requiring dose adjustment and monitoring. ³ , ⁴ , ⁵ , ⁶ , ⁷ Such drawbacks may contribute to failure to prevent CMV infection and disease, or to the development of drug resistance. ⁸ , ⁹ , ¹⁰ Maribavir (1263W94, GW 1263, GW 1263W94, VP 41263, SHP620, and TAK‐620) is a potent and selective, orally bioavailable, benzimidazole riboside drug with a novel mechanism of action that exerts its effects primarily on viral DNA assembly and on egress of CMV viral capsids from the nuclei of infected cells. ¹¹ , ¹² Maribavir is metabolized to its primary metabolite VP 44469 by cytochrome (CYP) P450 isoenzymes CYP3A4 (and, to a minor extent, CYP1A2 and CYP2C19). ¹³ , ¹⁴ Originally developed for CMV prophylaxis in transplant recipients, ¹⁵ , ¹⁶ maribavir is now in phase III clinical development for the treatment of CMV infection and disease. In January 2018, the US Food and Drug Administration (FDA) granted maribavir a “breakthrough therapy” designation based on data from phase II studies for the treatment of CMV infection and disease ({"type":"clinical-trial","attrs":{"text":"NCT00223925","term_id":"NCT00223925"}}NCT00223925 and {"type":"clinical-trial","attrs":{"text":"NCT01611974","term_id":"NCT01611974"}}NCT01611974).Maribavir is rapidly absorbed, and peak plasma concentration (C_max) is generally achieved between 1 and 3 hours after dosing. In single‐dose studies in healthy participants (50–1,600 mg) and patients with HIV (100–1,600 mg), the pharmacokinetics (PKs) of maribavir and VP 44469 were approximately linear. ¹⁷ In an ascending, multiple‐dose study in patients with HIV, there was a dose‐proportional increase in plasma maribavir area under the curve to infinity (AUC_∞), C_max, and area under the concentration‐time curve over 24 hours steady‐state (AUC_24,ss) over the dose range tested on the first day of maribavir administration (100–200 mg) and following 28 days of drug administration (100, 200, or 400 mg t.i.d., or 600, 900, or 1,200 mg b.i.d.). ¹⁸ In phase II studies, maribavir at doses ranging from 400 mg b.i.d. to 1,200 mg b.i.d. was generally well‐tolerated; taste disturbance (dysgeusia), nausea, and diarrhea were notable treatment‐emergent adverse events (TEAEs) that seemed to be associated with maribavir. ¹⁹ , ²⁰ , ²¹ Currently, maribavir at a dose of 400 mg b.i.d. is under investigation in two phase III studies for the treatment of transplant recipients with CMV infection, including resistant or refractory CMV and CMV disease ({"type":"clinical-trial","attrs":{"text":"NCT02927067","term_id":"NCT02927067"}}NCT02927067 and {"type":"clinical-trial","attrs":{"text":"NCT02931539","term_id":"NCT02931539"}}NCT02931539).The potential of maribavir to prolong ventricular repolarization was previously evaluated in an in vitro study according to the International Conference on Harmonisation (ICH) S7B guidelines. ²² In line with the ICH E14 guidance, ²³ this study was conducted in healthy participants to determine the effect of maribavir on the corrected QT (QTc) interval prolongation when compared with placebo as a negative control and moxifloxacin as a positive control. In addition, the PK of maribavir and its metabolite VP 44469, as well as the safety and tolerability of maribavir were evaluated.     

Characterizing Pharmacogenetic Testing Among Children’s Hospitals

Although pharmacogenetic testing is becoming increasingly common across medical subspecialties, a broad range of utilization and implementation exists across pediatric centers. Large pediatric institutions that routinely use pharmacogenetics in their patient care have published their practices and experiences; however, minimal data exist regarding the full spectrum of pharmacogenetic implementation among children’s hospitals. The primary objective of this nationwide survey was to characterize the availability, concerns, and barriers to pharmacogenetic testing in children’s hospitals in the Children’s Hospital Association. Initial responses identifying a contact person were received from 18 institutions. Of those 18 institutions, 14 responses (11 complete and 3 partial) to a more detailed survey regarding pharmacogenetic practices were received. The majority of respondents were from urban institutions (72%) and held a Doctor of Pharmacy degree (67%). Among all respondents, the three primary barriers to implementing pharmacogenetic testing identified were test reimbursement, test cost, and money. Conversely, the three least concerning barriers were potential for genetic discrimination, sharing results with family members, and availability of tests in certified laboratories. Low‐use sites rated several barriers significantly higher than the high‐use sites, including knowledge of pharmacogenetics (P = 0.03), pharmacogenetic interpretations (P = 0.04), and pharmacogenetic‐based changes to therapy (P = 0.03). In spite of decreasing costs of pharmacogenetic testing, financial barriers are one of the main barriers perceived by pediatric institutions attempting clinical implementation. Low‐use sites may also benefit from education/outreach in order to reduce perceived barriers to implementation.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE OF THE TOPIC?

☑ Implementation of pharmacogenetic testing is well‐described at select institutions; however, it is poorly understood how widespread implementation is, particularly at pediatric hospitals.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ The primary objective of this survey was to characterize pharmacogenetic testing in addition to determining availability, concerns, and barriers to pharmacogenetic testing in pediatric hospitals.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Although this study gives a general sense of pharmacogenetic implementation among pediatric hospitals, it also highlights the considerable differences between sites with limited vs. more extensive implementation, in particular the need for additional education of providers.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The results of this survey provide important information to institutions that have limited implementation of pharmacogenetic testing or for those considering implementation.

The implementation of pharmacogenetic testing has made remarkable progress in recent years, with select institutions introducing preemptive or reactive clinical testing. ¹ , ² Widely available resources, such as PharmVar, ³ the Pharmacogenomics Knowledge Base (PharmGKB), ⁴ and Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines, ⁵ now provide laboratories with consolidated data on pharmacogenetic variants and clinicians with up‐to‐date clinical information in addition to formal dosing recommendations for drug‐gene pairs. The formalization of these resources has undoubtedly contributed to progress in pharmacogenetic implementation. The number of well‐characterized specific drug‐gene interactions (DGIs) is growing exponentially along with our ability to rapidly test for and act on clinically relevant gene variants, allowing for translation of laboratory knowledge into clinical practice. ⁶ Although not every DGI results in a medication or dosing change, there are institutions where genetic testing for clinically significant variants is part of routine care. CPIC first released guidelines for TPMT and thiopurines in March 2011, with subsequent updates in April 2013 ⁷ and most recently in November 2018, where the guideline was updated to include NUDT15. ⁸ Within pediatric oncology, patients with acute lymphoblastic leukemia are routinely tested for TPMT and NUDT15 variants prior to initiation of therapy with thiopurines. ⁹ TPMT is also routinely tested for in pediatric inflammatory bowel disease, which has improved dosing of thiopurines across pediatric centers participating in the ImproveCareNow network. ¹⁰ Recently, CPIC has also included pediatric‐specific genotype‐dosing recommendations for voriconazole based on CYP2C19 genotype and atomoxetine based on CYP2D6 genotype. ¹¹ , ¹² Implementation requires a collaboration of resources, including laboratories for genotyping, bioinformatics/information technology for interpretation and communication of results, and clinicians to incorporate the results into patient care. Historically, such resources were costly and often not sufficient for incorporation into clinical care, but current and evolving technologies are and will be available to make the process both possible and cost‐efficient. ¹³ The US Food and Drug Administration (FDA) has also made changes to facilitate the incorporation of pharmacogenetics into clinical practice. The FDA has implemented a voluntary program allowing companies to submit genomics data with new drug applications and has recently released a Table of Pharmacogenomic Associations that includes > 100 medications. The table includes subsections for those associations that they recommend therapeutic changes (dose or medication selection), associations that indicate an impact on safety or response, and associations that have an impact on pharmacokinetics only. Over 200 drug labels have been updated to include pharmacogenetic findings. There are several examples of newly approved targeted therapies with companion diagnostic tests (crizotinib and vemurafenib), drugs with required pharmacogenetic testing (eliglustat, pimozide, and tetrabenazine), and others with potential pharmacogenetic considerations included in the label.The increase in pharmacogenetic data and progress in implementation are encouraging to physicians and other clinicians eager to provide safer and more effective therapy for their patients through precision medicine. Although discovery and implementation of clinically relevant DGIs require considerable resources and effort, the benefits have the potential to make such expenditures worthwhile, especially as costs decrease with improved technology. Collaborative networks, such as the Pharmacogenomics Research Network (PGRN), ¹⁴ the Electronic Medical Records and Genomics (eMERGE) Network, ¹⁵ the Implementing Genomics in Practice (IGNITE) ¹⁶ and the Canadian Pharmacogenomics Network, ¹⁷ allow for distribution of knowledge and effort across multiple institutions. Despite these recent advances in the utility, feasibility, and cost efficacy of pharmacogenetic testing, there are still many institutions that have not implemented routine pharmacogenetic testing into clinical practice. Analysis of the barriers to pharmacogenetic implementation have found that information technology, ¹⁸ clinical utility concerns, ¹⁹ and training ²⁰ were major barriers to implementation in nonpediatric institutions. However, there has been no analysis of barriers to pharmacogenetic implementation specific to pediatric institutions. In order to assess this, we sought to better understand the landscape of pharmacogenetic testing in pediatric populations, and from there propose solutions to overcome these barriers. Thus, the primary objective of this survey was to characterize pharmacogenetic testing in addition to determining availability, concerns, and barriers to pharmacogenetic testing in pediatric hospitals.