An untargeted metabolomics analysis of exogenous chemicals in human milk and transfer to the infant

Human milk is the optimal infant nutrition. However, although human‐derived metabolites (such as lipids and oligosaccharides) in human milk are regularly reported, the presence of exogenous chemicals (such as drugs, food, and synthetic compounds) are often not addressed. To understand the types of exogenous compounds that might be present, human milk (n = 996) was analyzed by untargeted metabolomics. This analysis revealed that lifestyle molecules, such as medications and their metabolites, and industrial sources, such as plasticizers, cosmetics, and other personal care products, are found in human milk. We provide further evidence that some of these lifestyle molecules are also detectable in the newborn''s stool. Thus, this study gives important insight into the types of exposures infants receiving human milk might ingest due to the lifestyle choices, exposure, or medical status of the lactating parent.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Although our ability to measure metabolites in human milk has greatly increased in the last decades, the true breadth and diversity of the human milk metabolome is still unknown. Endogenous (or human‐derived) compounds in milk have been extensively studied, but exogenous compounds in human milk due to environmental factors and lifestyle choices are relatively unexplored.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What exogenous metabolites exist in human milk and are they transferred to the infant?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We provide an analysis of exogenous metabolites in human milk, including medications, food metabolites, and industrial/environmental compounds. We also demonstrate that many of these metabolites can be transferred to the infant in detectable levels.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Several of the drug metabolites identified in this study have not been previously annotated, and demonstrate new ways in which we can address the pharmacokinetics of drugs in human milk.     

Identification of small molecules that mitigate vincristine‐induced neurotoxicity while sensitizing leukemia cells to vincristine

Vincristine (VCR) is one of the most widely prescribed medications for treating solid tumors and acute lymphoblastic leukemia (ALL) in children and adults. However, its major dose‐limiting toxicity is peripheral neuropathy that can disrupt curative therapy. Peripheral neuropathy can also persist into adulthood, compromising quality of life of childhood cancer survivors. Reducing VCR‐induced neurotoxicity without compromising its anticancer effects would be ideal. Here, we show that low expression of NHP2L1 is associated with increased sensitivity of primary leukemia cells to VCR, and that concomitant administration of VCR with inhibitors of NHP2L1 increases VCR cytotoxicity in leukemia cells, prolongs survival of ALL xenograft mice, but decreases VCR effects on human‐induced pluripotent stem cell‐derived neurons and mitigates neurotoxicity in mice. These findings offer a strategy for increasing VCR’s antileukemic effects while reducing peripheral neuropathy in patients treated with this widely prescribed medication.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Vincristine (VCR) is a widely prescribed drug, but its use is limited by its main side effect, neurotoxicity. There are currently no strategies to mitigate VCR neurotoxicity without altering its antileukemic effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

How to improve VCR efficacy while reducing its main side effect, neurotoxicity?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The present study shows for the first time the possibility of reduced VCR ‐induced neurotoxicity while improving VCR anti‐leukemia effect by using small molecules.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The current translational study could permit a safer and more efficient use of VCR.     

Clinical pharmacology information in regulatory submissions and labeling: A comparative analysis of orphan and non‐orphan drugs approved by the FDA

Clinical pharmacology is an integral discipline supporting the development, regulatory evaluation, and clinical use of drugs for the treatment of both common and rare diseases. Here, we evaluated the recommendations and information available from select clinical pharmacology studies in the therapeutic product labeling of new molecular entities (NMEs) approved from 2017 to 2019 for both common and rare diseases. A total of 151 NMEs, including 72 orphan and 79 non‐orphan drugs, were analyzed for recommendations and information available related to food–drug interaction, drug–drug interaction, renal impairment, hepatic impairment, QT assessment, and human radiolabeled mass balance studies using data collected from the original labeling and other regulatory documents. The analysis showed no statistically significant difference in the recommendations between orphan and non‐orphan drugs except for renal impairment related recommendations in section 8 of the labeling. Although not significant, fewer hepatic impairment labeling recommendations were available for orphan drugs when compared with non‐orphan drugs. At the time of initial approval, 79 postmarketing requirements (PMRs) and postmarketing commitments (PMCs) for 33 orphan drugs and 39 PMRs and PMCs for 19 non‐orphan drugs were established; with most difference observed for drug–drug interaction, hepatic impairment, and QT assessment. Overall, although there was a trend for more labeling recommendations and fewer postmarketing studies and clinical trials for non‐orphan drugs, there appeared to be no substantial differences in how these select clinical pharmacology studies are leveraged during the development and approval of orphan and non‐orphan drugs.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

As a discipline, clinical pharmacology can be leveraged to support development, regulatory evaluation, and clinical use of drugs for common and rare diseases. However, analyses have not been performed to examine how select clinical pharmacology studies have been utilized to inform labeling recommendations and information for orphan drugs (for rare diseases) when compared to non‐orphan drugs.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study aimed to compare the labeling of orphan and non‐orphan drugs approved by the US Food and Drug Administration from 2017 to 2019 to understand the availability of recommendations and information from the select clinical pharmacology studies at the time of original drug approval. In addition, we assessed if any postmarketing studies and clinical trials were established to address knowledge gaps related to these studies.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

There appeared to be no substantial difference in how the select clinical pharmacology studies were leveraged during the development and approval of orphan and non‐orphan drugs, although there was a trend for more labeling recommendations and information as well as fewer postmarketing studies and clinical trials for non‐orphan drugs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The findings suggest that leveraging clinical pharmacology principles during drug development and evaluation can help promote therapeutic optimization, and as a result, help the right patient receive the right drug, at the right dose, and at the right time.     

Machine learning approach to identify adverse events in scientific biomedical literature

Monitoring the occurrence of adverse events in the scientific literature is a mandatory process in drug marketing surveillance. This is a very time‐consuming and complex task to fulfill the compliance and, most importantly, to ensure patient safety. Therefore, a machine learning (ML) algorithm has been trained to support this manual intellectual review process, by automatically providing a classification of the literature articles into two types. An algorithm has been designed to automatically classify “relevant articles” which are reporting any kind of drug safety relevant information, and those which are not reporting an adverse drug reaction as “not relevant.” The review process is consisted of many rules and aspects which needed to be taken into consideration. Therefore, for the training of the algorithm, thousands of documents from previous screenings have been used. After several iterations of adjustments and fine tuning, the ML approach is definitively a great achievement in pre‐sorting the articles into “relevant” and “non‐relevant” and supporting the intellectual review process.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Using machine learning (ML) to make decisions based on previous decisions is becoming more prominent in the digital world. However, to implement such a workflow in a very regulated field is a big challenge.

• WHAT QUESTION DID THIS STUDY ADDRESS?

To what extend is it possible to replace human decisions needing intellectual input by ML?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

It shows that it is to a certain extent possible to detect drug safety‐related information to the drugs in focus in written text. Furthermore, it combines the methodologies to show which technical solutions are best.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Using ML in more and more processes will gain efficiency and will make drug discovery, drug development, and postmarketing surveillance more efficient and, most importantly, it will increase the patients’ safety.     

Discovery of preventive drugs for cisplatin‐induced acute kidney injury using big data analysis

Cisplatin is effective against many types of carcinoma. However, a high rate of renal damage is a clinical problem. Thus, there is a need to establish a method to prevent it. Although various compounds have been reported to be effective against cisplatin‐induced renal injury, there are no examples of their clinical application. Therefore, we attempted to search for prophylactic agents with a high potential for clinical application. We used Cascade Eye to identify genes that are altered during cisplatin‐induced renal injury, Library of Integrated Network‐based Cellular Signatures (LINCS) to identify drugs that inhibit changes in gene expression, and a large database of spontaneous adverse drug reaction reports to identify drugs that could prevent cisplatin‐induced kidney injury in clinical practice. In total, 10 candidate drugs were identified. Using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), we identified drugs that reduce cisplatin‐induced kidney injury. Fenofibrate was selected as a candidate drug to prevent cisplatin‐induced kidney injury based on the FAERS analysis. A model was used to evaluate the efficacy of fenofibrate against cisplatin‐induced renal injury. Studies using HK2 cells and mouse models showed that fenofibrate significantly inhibited cisplatin‐induced renal injury but did not inhibit the antitumor effect of cisplatin. Fenofibrate is a candidate prophylactic drug with high clinical applicability for cisplatin‐induced renal injury. Analysis of data from multiple big databases will improve the search for novel prophylactic drugs with high clinical applicability. For the practical application of these findings, evaluation in prospective controlled trials is necessary.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Current coping strategies in clinical practice do not completely prevent cisplatin‐induced renal injury, warranting development of supportive care.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Many drugs and compounds have been reported to be effective against cisplatin‐induced renal injury in basic in vitro and in vivo studies, but none have been applied clinically. In this study, we used medical big data to identify candidate prophylactic drugs with high potential for clinical application.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study used an artificial intelligence tool called Cascade Eye and two large medical information databases, Library of Integrated Network‐based Cellular Signatures (LINCS) and US Food and Drug Administration Adverse Event Reporting System (FAERS), to identify candidate drugs that reduce cisplatin‐induced kidney injury and found that the candidate drug fenofibrate has the potential to prevent cisplatin‐induced kidney injury.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The developed methods can be applied to the development of prophylactic drugs against various adverse drug reactions and will have an impact on future clinical pharmacology and translational research.     

Metabolomics analysis of the serum from children with urolithiasis using UPLC‐MS

Pediatric urolithiasis is a common urologic disease with high morbidity and recurrence rates. Recent studies have shown that metabolic dysfunction plays a vital role in the pathogenesis of urolithiasis, especially in children, but the specific mechanism is still unclear. Metabolomics is an ideal technology for exploring the mechanism of metabolic disorders in urolithiasis. In the present study, a serum metabolomics based on ultra‐performance liquid chromatography mass spectrometry was performed. A total of 50 children subjects were recruited for the study, including 30 patients with kidney stones and 20 normal controls (NCs). Principal component analysis and orthogonal partial least‐squares determinant analysis were carried, and 40 metabolites were found to be significantly altered in patients with kidney stones, mainly involving retinol metabolism, steroid hormone biosynthesis, and porphyrin and chlorophyll metabolism. The kidney stone group appeared to have a lower serum level of bilirubin, but a relative higher level of retinal, all‐transretinoic acid, progesterone, and prostaglandin E2 compared with those of the NC group. All the findings suggest that patients with urolithiasis have several metabolic characteristics, which are related to stone formation or compensation. These metabolites and pathways are very likely associated with development of kidney stones and should be considered as potential novel targets for treatment and prevention.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Metabolic disorders can be found in most children with kidney stones, suggesting that it plays a vital role in the pathogenesis of pediatric urolithiasis. Metabolomics is an ideal strategy to explore the mechanism of metabolic disorders in kidney stones.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We aimed to identify the changes of serum metabolites in children with urolithiasis compared with normal controls by using ultra‐performance liquid chromatography mass spectrometry.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We found the special metabolic characteristics in patients with pediatric urolithiasis, which are related to stone formation or compensation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our findings indicate that the metabolic phenotype of serum in pediatric patients with urolithiasis is significantly different from that in normal controls. These metabolites and metabolic pathways associated with stone formation will help to develop novel therapeutic strategies and preventive interventions.     

Patients with geographic barriers to health care access are prescribed a higher proportion of drugs with pharmacogenetic testing guidelines

Pharmacogenetic (PGx) testing may be particularly beneficial in medically underserved populations by reducing the number of appointments required to optimize drug therapy and increasing the effectiveness of less expensive off‐patent drugs. The objective of this study was to identify patient populations with poor health care access and assess prescribing trends for drugs with published PGx testing guidelines. We used electronic health record data from 67,753 University of Florida Health patients, geographic access scores calculated via the 2‐step floating catchment area method, and a composite measure of socioeconomic status. Comparing the poorest (Q4) and greatest (Q1) access score quartiles, poor geographic access was significantly associated with fewer prescriber encounters (incidence rate ratio [IRR] 0.88, 95% confidence interval [CI] 0.86–0.91), fewer total unique drugs (IRR 0.92, 95% CI 0.9–0.95), and fewer PGx guideline drugs (IRR 0.94, 95% CI 0.9–0.99). After correcting for number of unique drugs, patients in low‐access areas were prescribed a greater proportion of PGx guideline drugs (IRR 1.08, 95% CI 1.04–1.13). We detected significant interactions between Black race and access score. Compared to Q1, Black patients with Q4 access scores were disproportionately affected and had fewer encounters (IRR 0.76, 95% CI 0.7–0.82) and a higher proportion of PGx drugs (IRR 1.26, 95% CI 1.13–1.41), creating further disparity. Overall, these results suggest that improved geographic access to PGx testing may allow prescribers to make more efficient use of limited opportunities to optimize therapy for drugs with PGx testing guidelines.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drugs with pharmacogenetic (PGx) testing guidelines are often off patent and cheaper than newer alternatives. Medically underserved patients may benefit from PGx testing, but little is known about how PGx drugs are currently used in these populations.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Are patients with barriers to health care access prescribed more drugs with published PGx guidelines?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Patients with poor geographic access, as determined using the two‐step floating catchment area method, use a higher proportion of PGx drugs. Additionally, this study may serve as a model for the use of geospatial analysis in PGx implementation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Improved geographic access to PGx testing may allow prescribers to make more efficient use of limited opportunities to optimize therapy for drugs with PGx testing guidelines.     

Adverse drug event risk assessment by the virtual addition of COVID‐19 repurposed drugs to Medicare and commercially insured patients’ drug regimens: A drug safety simulation study

Drug safety is generally established from clinical trials, by pharmacovigilance programs and during observational phase IV safety studies according to drug intended or approved indications. The objective of this study was to estimate the risk of potential adverse drug events (ADEs) associated with drugs repurposed for coronavirus disease 2019 (COVID‐19) treatment in a large‐scale population. Drug claims were used to calculate a baseline medication risk score (MRS) indicative of ADE risk level. Fictitious claims of repurposed drugs were added, one at a time, to patients’ drug regimens to calculate a new MRS and compute a level of risk. Drug claims data from enrollees with Regence health insurance were used and sub‐payer analyses were performed with Medicare and commercial insured groups. Simulated interventions were conducted with hydroxychloroquine and chloroquine, alone or combined with azithromycin, and lopinavir/ritonavir, along with terfenadine and fexofenadine as positive and negative controls for drug‐induced Long QT Syndrome (LQTS). There were 527,471 subjects (56.6% women; mean [SD] age, 47 years [21]) were studied. The simulated addition of each repurposed drug caused an increased risk of ADEs (median MRS increased by two‐to‐seven points, p < 0.001). The increase in ADE risk was mainly driven by an increase in CYP450 drug interaction risk score and by drug‐induced LQTS risk score. The Medicare group presented a greater risk overall compared to the commercial group. All repurposed drugs were associated with an increased risk of ADEs. Our simulation strategy could be used as a blueprint to preemptively assess safety associated with future repurposed or new drugs.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Although medications provide therapeutic benefits, they also carry a risk for adverse drug events (ADEs). Some repurposed drugs currently being used in patients with coronavirus disease 2019 (COVID‐19) have known risk of ADEs.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study conducted a risk assessment for ADEs of five COVID‐19 repurposed drug regimens in Medicare and commercially insured patient populations, totaling about 525,000 subjects. A medication risk score analysis was used to predict the risk of ADEs by simulating the addition of the repurposed drugs into existing patient drug regimens.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In these COVID‐19 simulations, an increased risk for ADEs was identified, driven by QT prolongation and CYP450 drug interactions. The combination of hydroxychloroquine or chloroquine with azithromycin, and lopinavir/ritonavir showed the greatest increase in risk. The Medicare population remained at higher risk overall.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This simulation strategy can be used preemptively with new or repurposed drugs to quantitatively estimate ADE risk in large populations.     

Evaluation of the potential complication of interstitial lung disease associated with antifibrotic drugs using data from databases reporting spontaneous adverse effects

Interstitial lung disease (ILD), as an adverse effect of certain drugs, leads to inflammation and damage in the walls of the alveoli, making it difficult for the alveoli to take up oxygen. Interstitial pneumonia with no identifiable cause is called idiopathic interstitial pneumonia (IIP), and, among the major IIPs, idiopathic pulmonary fibrosis (IPF) is diagnosed in about half of patients. Current treatment options are limited, among which the antifibrotic drugs nintedanib (Ofev) and pirfenidone (Pirespa) are the first‐line drugs. In this study, we investigated the incidence of ILD possibly caused by antifibrotic agents using data from the Japanese Adverse Drug Event Report (JADER) database, a database of spontaneous adverse event reports published by the Pharmaceuticals and Medical Devices Agency (PMDA), and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), published by the FDA. We used the FAERS and JADER to detect the signals of adverse events on the basis of reporting odds ratios. The relationship between indications and adverse events was clarified by separating indications and adverse events using the spontaneous adverse event reporting database with novel drug involvement. Regarding the involvement of nintedanib and pirfenidone in the development of ILD, JADER and FAERS showed signals for both nintedanib and pirfenidone as suspect drugs, and no signals for nintedanib or pirfenidone as concomitant drug interactions were detected. We highlight this because there are only a few effective drugs for IPF, and effective and safe drug therapies should be implemented by taking into consideration drug‐induced ILD.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

In this study, we aimed to analyze the association of the onset of interstitial lung disease (ILD) as an adverse event with the use of the drugs nintedanib and pirfenidone. These antifibrotic agents are widely used as the first‐line treatment for idiopathic pulmonary fibrosis (IPF).

• WHAT QUESTION DID THIS STUDY ADDRESS?

We analyzed data from two widely used postmarket adverse reporting databases, the Japanese Adverse Drug Event Report (JADER) database and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). We calculated reporting odds ratios and confidence intervals to determine signals for the adverse event of ILD associated with nintedanib and pirfenidone.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The results of the database analysis suggest that nintedanib and pirfenidone are not only used for the treatment of ILD but are also suspected of causing ILD. As only a limited number of effective drugs for IPF are available, effective and safe drug therapy should be implemented by taking into consideration drug‐induced ILD.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Through clinical pharmacology and translational science, this study may lead to the creation of safer and more effective therapies for the treatment of sudden pulmonary fibrosis, which currently has only limited treatment options, namely antifibrotic agents.     

A detailed analysis of expedited regulatory review time of marketing authorization applications for new anticancer drugs in the US and EU

The aim of this study was to assess the effect of expedited regulatory approval programs used by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), type of product (small molecule or biotechnology‐derived product) and consulting scientific advisory committees on the regulatory review time of the marketing authorization applications (MAAs) for new anticancer drugs. A dataset composed of 76 new anticancer drugs was constructed. The date of submission of the MAAs in the United States and the European Union were comparable. The typical review time of MAAs was 136 days shorter in the United States (201 days [median]) than in the European Union (337 days [median]). The type of product did not have a high impact on the review time. The review time of the MAAs for drugs undergoing priority review in the United States or accelerated assessment in the European Union at the stage of review of MAA was generally shorter than that for drugs following the standard regulatory pathway. The regulatory pathway using at least one expedited regulatory program at the stages of drug development, review of MAA, and approval of drug in the United States (172 days [median]), and that at the stages of review of MAA and approval of drug in the European Union (183 days [median]) enabled the shortest review time of MAAs. Referral to advisory committee meeting increased the review time of MAAs for drugs undergoing one or more expedited regulatory approval programs in the United States and the European Union close to that for drugs undergoing the standard regulatory approval pathway.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The US Food and Drug Administration (FDA) has more expedited regulatory approval programs than the European Medicines Agency (EMA), suggested to result in earlier availability of anticancer drugs in the United States compared to in the European Union.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The effect of expedited regulatory approval programs, type of product, and consulting scientific advisory committees on the regulatory review time of the marketing authorization applications (MAAs) for new anticancer drugs in the United States and the European Union.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

It was shown that the review of MAAs for new anticancer drugs was finalized typically 136 days later and expedited regulatory programs were less frequently employed in the European Union compared to in the United States. The regulatory pathways leading to shortest review time of MAAs for new anticancer drugs were identified.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

A field of improvement for the regulatory framework in the European Union to enable earlier drug availability was indicated. Insight for the industry into combinations of expedited regulatory approval programs advantageous to apply for was provided.     

A retrospective analysis of actionable pharmacogenetic/genomic biomarker language in FDA labels

The primary goal of precision medicine is to maximize the benefit‐risk relationships for individual patients by delivering the right drug to the right patients at the right dose. To achieve this goal, it has become increasingly important to assess gene‐drug interactions (GDIs) in clinical settings. The US Food and Drug Administration (FDA) periodically updates the table of pharmacogenetic/genomic (PGx) biomarkers in drug labeling on their website. As described herein, an effort was made to categorize various PGx biomarkers covered by the FDA‐PGx table into certain groups. There were 2 major groups, oncology molecular targets (OMT) and drug‐metabolizing enzymes and transporters (DMETs), which constitute ~70% of all biomarkers (~33% and ~35%, respectively). These biomarkers were further classified whether their labeling languages could be actionable in clinical practice. For OMT biomarkers, ~70% of biomarkers are considered actionable in clinical practice as they are critical for the selection of appropriate drugs to individual patients. In contrast, ~30% of DMET biomarkers are considered actionable for the dose adjustments or alternative therapies in specific populations, such as CYP2C19 and CYP2D6 poor metabolizers. In addition, the GDI results related to some of the other OMT and DMET biomarkers are considered to provide valuable information to clinicians. However, clinical GDI results on the other DMET biomarkers can possibly be used more effectively for dose recommendation. As the labels of some drugs already recommend the precise doses in specific populations, it will be desirable to have clear language for dose recommendation of other (or new) drugs if appropriate.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

• WHAT QUESTION DID THIS STUDY ADDRESS?

Pharmacogenetic/genomic (PGx) biomarkers are increasingly being used for precision medicine to focus on maximizing therapeutic efficacy while minimizing adverse events. The US Food and Drug Administration (FDA) provides an updated summary table of PGx biomarkers in the labels of approved drugs (FDA‐PGx table).

• WHAT QUESTION DID THIS STUDY ADDRESS?

PGx biomarkers listed in the FDA‐PGx table were analyzed to categorize into certain groups (e.g., as oncology molecular targets [OMTs] and drug‐metabolizing enzymes and transporters [DMETs]), and then classify whether their labeling language could be actionable in clinical practice.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

There are 2 major groups in the FDA‐PGx table, OMT and DMET biomarkers, accounting of ~70% of all biomarkers. Among them, ~70% of OMT biomarkers and ~30% of DMET biomarkers are considered actionable in clinical practice.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The gene‐drug interaction results related to some DMET biomarkers can be used more effectively and practically for dose recommendation in specific populations. It will be therefore desirable to have clear labeling language on dose recommendation for other (or new) drugs if appropriate.     

A permeability‐ and perfusion‐based PBPK model for improved prediction of concentration‐time profiles

To improve predictions of concentration‐time (C‐t) profiles of drugs, a new physiologically based pharmacokinetic modeling framework (termed ‘PermQ’) has been developed. This model includes permeability into and out of capillaries, cell membranes, and intracellular lipids. New modeling components include (i) lumping of tissues into compartments based on both blood flow and capillary permeability, and (ii) parameterizing clearances in and out of membranes with apparent permeability and membrane partitioning values. Novel observations include the need for a shallow distribution compartment particularly for bases. C‐t profiles were modeled for 24 drugs (7 acidic, 5 neutral, and 12 basic) using the same experimental inputs for three different models: Rodgers and Rowland (RR), a perfusion‐limited membrane‐based model (K_p,mem), and PermQ. K_p,mem and PermQ can be directly compared since both models have identical tissue partition coefficient parameters. For the 24 molecules used for model development, errors in V_ss and t _1/2 were reduced by 37% and 43%, respectively, with the PermQ model. Errors in C‐t profiles were reduced (increased EOC) by 43%. The improvement was generally greater for bases than for acids and neutrals. Predictions were improved for all 3 models with the use of parameters optimized for the PermQ model. For five drugs in a test set, similar results were observed. These results suggest that prediction of C‐t profiles can be improved by including capillary and cellular permeability components for all tissues.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Compared to compartmental models, concentration‐time profiles of drugs are often not well‐predicted by perfusion‐limited PBPK models.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can C‐t profiles be better predicted by including capillary, cellular and membrane permeability in a new PBPK framework?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that variable capillary permeability for different tissues is an important anatomical component for drug distribution. Apparent permeability and membrane partitioning can be used to model clearances in and out of membranes. Early distribution kinetics observed in the C‐t profile of basic drugs indicates that an additional shallow distribution compartment is necessary. Parameters optimized for input into the new PermQ framework also decrease the prediction errors in perfusion‐limited PBPK models.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Improved prediction of drug concentration‐time profiles with new modeling frameworks such as the PermQ model can result in improved therapeutic outcomes for healthy and special populations.     

Quantitative protein expression of blood‐brain barrier transporters in the vasculature of brain metastases of patients with lung and breast cancer

This study determined absolute transporter protein abundances in isolated microvessels of human noncancerous cerebral cortex as well as brain metastases of patients with lung and breast cancer, using a validated targeted proteomics approach. As compared with those in microvessels of noncancerous cerebral cortex, the median protein abundances of glucose transporter 1 (a brain endothelial marker) and sodium‐potassium pump (Na/K ATPase, a plasma membrane marker) were decreased by ~ 80% in brain metastasis microvessels. The major efflux transporters (ABCB1 and ABCG2) fell to undetectable in microvessels of more than 80% of brain metastasis specimens. Monocarboxylate transporter 1 was undetectable in microvessels of more than 80% of brain metastases, whereas large neutral amino acid transporter 1 levels remained unchanged. In conclusion, the integrity of the physical and biochemical barrier with respect to transporter protein expression is largely disrupted in brain metastasis tumor vasculatures. Differential transporter protein abundances at the blood‐brain barrier and blood‐brain tumor barrier provided mechanistic and quantitative basis for prediction of heterogeneous drug penetration into human brain and brain tumors, which is critical not only to the understanding of the success or failure of systemic chemotherapy in the treatment of brain tumors but also to the development of more effective therapeutic strategies.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Systemic chemotherapy for brain metastases is controversial, at least partly due to the incomplete understanding of the blood‐brain barrier (BBB) and blood‐brain tumor barrier (BBTB) with respect to transporter protein expression and function.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study determined the absolute protein abundances of major BBB transporters in isolated microvessels of brain metastases from lung and breast cancer patients as well as non‐cancerous brain cortex from primary or metastatic brain cancer patients.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study complemented our previous knowledge on transporter expression in microvessels of human normal brain cortex and glioblastoma, which collectively provided a comprehensive dataset on the quantitative protein expression of BBB transporters in the vasculatures of human normal brain, primary and metastatic brain tumors.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Differential transporter protein abundances at the BBB and BBTB provided mechanistic and quantitative basis for prediction of heterogeneous drug penetration into human brain and brain tumors, which is critical not only to the understanding of the success or failure of systemic chemotherapy in the treatment of brain tumors but also to the development of more effective therapeutic strategies.     

Non‐synonymous alterations in AKR7A3 and ABCA6 correlate with bleeding in aged patients treated with rivaroxaban

Rivaroxaban is an oral anticoagulant that inhibits thrombin and blocks coagulation cascade through directly inactivating factors Xa. Despite rivaroxaban is widely used for prevention and treatment of venous thrombosis, and its common adverse reactions have been reported, including abnormal coagulation, mucosal hemorrhage, hematuria, and intracranial hemorrhage. To explore potential drivers of individual differences in adverse reactions induced by rivaroxaban, we performed whole‐exome sequencing and found that AKR7A3 rs1738023/rs1738025 and ABCA6 rs7212506 are susceptible sites for rivaroxaban‐related bleeding in aged patients treated with rivaroxaban. Gene functional annotation and signaling pathway enrichment indicated that homozygous mutations in AKR7A3 and ABCA6 might alter normal rivaroxaban transport and metabolism, and lead to continuous accumulation of activated drugs and toxic substances in vivo. Our results suggested that interindividual differences in bleeding events induced by rivaroxaban may be potentially driven by genetic alterations related to abnormal metabolism and transport of rivaroxaban.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Although rivaroxaban has been wildly used for the prevention and treatment of prevent of deep vein thrombosis without requiring routine coagulation monitoring, the adverse events, such as bleeding following rivaroxaban treatment, has not been fully addressed.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The correlation between genetic variations and rivaroxaban treatment‐induced side effects (e.g., bleeding).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The AKR7A3 rs1738023/rs1738025 and ABCA6 rs7212506 confer susceptibility to adverse reactions caused by rivaroxaban.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY AND TRANSLATIONAL SCIENCE?

This study identified AKR7A3 and ABCA6 genes involved in drug metabolism and transport associated with susceptibility to rivaroxaban‐related bleeding events, and provided supporting evidence for the prevention and treatment of anticoagulant‐caused adverse effects.     

Pediatric growth patterns in youth‐onset type 2 diabetes mellitus: Implications for physiologically‐based pharmacokinetic models

An accurate understanding of the changes in height and weight of children with age is critical to the development of models predicting drug concentrations in children (i.e., physiologically‐based pharmacokinetic models). However, curves describing the growth of a typical population of children may not accurately characterize growth of children with various conditions, such as obesity. Therefore, to develop height and weight versus age growth curves for youth who were diagnosed with type 2 diabetes, we extracted data from electronic medical records. Robust nonlinear models were parameterized to the equations describing height and weight versus age as defined by the Centers for Disease Control and Prevention (CDC). CDC z‐scores were calculated using an internal program. The growth curves and z‐scores were compared to CDC norms. Youth with type 2 diabetes were increasingly heavier than CDC norms from early childhood. Except for a period around puberty, youth with type 2 diabetes were, on average, shorter than CDC norms, resulting in shorter average adult height. Deviations in growth were apparent in youth who develop type 2 diabetes; such deviations may be expected for other conditions as well, and disease‐specific growth curves should be considered during development of model‐informed drug development for pediatric conditions.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The Centers for Disease Control and other agencies have developed growth curves that represent typical children, but they do not extend beyond the 97th percentile. The growth of many children with type 2 diabetes is therefore not represented by these curves.

• WHAT QUESTION DID THIS STUDY ADDRESS?

How does the height and weight of children who are diagnosed with type 2 diabetes change with age relative to a population of typically developing children?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Children who develop type 2 diabetes have growth patterns that deviate from the norm.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Given that physiologically‐based pharmacokinetic scaling factors, such as liver volume, are based on body surface area, which is, itself, derived from height and weight, disease‐specific growth curves should be considered for modeling and simulation of dosing for pediatric drug development and clinical applications.     

Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat

Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO₂). The current study used that model to assess the impact on respiration of non‐benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO₂ above the oxycodone effect. Analyses indicated that most pCO₂ interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO₂ recorded with oxycodone‐paroxetine co‐administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug‐drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co‐administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Benzodiazepines exacerbate opioid‐induced respiratory depression. The impact of other sedative psychotropic drugs on respiration alone or co‐administered with an opioid is often unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed whether a rat model could detect increased partial pressure of carbon dioxide, indicative of respiratory depression, for sedative psychotropic drugs with previously unknown influence on respiration, alone or in combination with an opioid.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that drug‐drug interactions between designated sedative psychotropic drugs and opioids could exacerbate opioid‐induced respiratory depression and that additional clinical studies would be informative.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Dependent upon outcomes in clinical studies, this work could define a model for early screening of drug‐drug interactions and respiratory depression risk as well as inform the need for additional clinical interaction studies with respiration as the end point.     

Efficacy of add‐on therapy with intravenous immunoglobulin in steroid hyporesponsive DRESS syndrome

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, potentially life‐threatening, delayed, drug‐induced hypersensitivity reaction. Immediate withdrawal of the culprit drug and administration of systemic corticosteroids is the most widely accepted treatment. However, it is difficult to manage patients with DRESS syndrome who are not responsive to systemic steroids. We studied the efficacy of intravenous immunoglobulins (IVIGs) in patients with DRESS syndrome unresponsive to systemic steroids. We retrospectively reviewed patients with DRESS syndrome who received IVIG in addition to systemic steroids during 2012–2017 and compared the clinical features and course of DRESS syndrome, before and after IVIG treatment. Eighteen DRESS patients (9 men) were included. The most frequent offending drugs were dapsone in five patients, followed by vancomycin in three patients, and carbamazepine in three patients. Rash, fever, lymphadenopathy, atypical lymphocytes, and hepatic involvement were common clinical findings. IVIG treatment was added within a median time of 7 days from the commencement of systemic steroid therapy. After IVIG treatment (total dosage: 1–2 g/kg), the fever resolved within a median time of 1 day (range, 0–3) and liver enzymes improved substantially within a median time of 13 days (range, 0–27). No severe adverse reactions related to IVIG therapy were observed in this study; however, there was one case of mortality. The addition of IVIG in DRESS syndrome in cases refractory to systemic steroid treatment may be helpful in hastening recovery. However, comparative studies using a placebo group are needed.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe delayed drug reaction. The main treatment is administration of systemic steroids. However, treatment of steroid hyporesponsive adults is unclear.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We studied the efficacy of intravenous immunoglobulins (IVIGs) in patients with DRESS syndrome unresponsive to systemic steroids.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We describe cases of adults with steroid hyporesponsive DRESS syndrome who were successfully treated with add‐on IVIG therapy with systemic steroids with minimal side effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our results show the benefits of IVIG add‐on treatment with systemic steroids in steroid hyporesponsive DRESS syndrome, and suggest pretreatment medication may result in fewer side effects.