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.     

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.     

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.     

Model‐based approach to sampling optimization in studies of antibacterial drugs for infants and young children

Clinical trials for pediatric indications and new pediatric drugs face challenges, including the limited blood volume due to the patients’ small bodies. In Japan, the Evaluation Committee on Unapproved or Off‐labeled Drugs with High Medical Needs has discussed the necessity of pediatric indications against the background of a lack of Japanese pediatric data. The limited treatment options regarding antibiotics for pediatric patients are associated with the emergence of antibiotic‐resistant bacteria. Regulatory guidelines promote the use of model‐based drug development to reduce practical and ethical constraints for pediatric patients. Sampling optimization is one of the key study designs for pediatric drug development. In this simulation study, we evaluated the precision of the empirical Bayes estimates of pharmacokinetic (PK) parameters based on the sampling times optimized by published pediatric population PK models. We selected three previous PK studies of cefepime and ciprofloxacin in infants and young children as paradigms. The number of sampling times was reduced from original full sampling times to two to four sampling times based on the Fisher information matrix. We observed that the precision of empirical Bayes estimates of the key PK parameters and the predicted efficacy based on the reduced sampling times were generally comparable to those based on the original full sampling times. The model‐based approach to sampling optimization provided a maximization of PK information with a minimum burden on infants and young children for the future development of pediatric drugs.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The clinical trials in vulnerable populations, such as infants, face challenges, including the limited blood volume due to the small bodies. In Japan, the necessity of pediatric indications has been discussed against the background of a lack of Japanese pediatric data.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This simulation study aimed to apply a model‐based approach to the development of antibiotics for pediatric patients to reduce practical and ethical constraints.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The model‐based approach to sampling optimization provided a maximization of pharmacokinetic information with a minimum burden on infants and young children.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The approach will support future pediatric clinical trials and investigator‐initiated trials, as well as provide the valuable information for therapeutic drug monitoring and the administration plans for antibiotics in clinical settings.     

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.     

Propsective evaluation of high‐dose methotrexate pharmacokinetics in adult patients with lymphoma using novel determinants of kidney function

High‐dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single‐center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7‐hydroxy‐MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine‐ or cystatin C‐based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2–75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8–11.3) grams. Median clearance was similar across three dosing levels at 4.5–5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFR_cys (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4‐h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C‐based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Methotrexate (MTX) clearance has a relationship with glomerular filtration rate (GFR), which is often calculated using serum creatinine as a surrogate marker of renal clearance; however, kidney function estimation derived from serum creatinine‐based GFR formulas has several known limitations, particularly in patients with cancer.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study attempts to answer the question of which estimated GFR (eGFR) equation has the strongest correlation with MTX clearance.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Results of this study suggest that, when high‐dose MTX is administered, cystatin C based eGFR equations more strongly correlate with MTX clearance than eGFR equations based on serum creatinine alone.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Incorporating cystatin C into baseline evaluation when estimating kidney function has potential to improve MTX safety and optimize MTX exposure.     

Hydrogen sulfide donor protects against mechanical ventilation‐induced atrophy and contractile dysfunction in the rat diaphragm

AbstractMechanical ventilation (MV) is a clinical tool providing adequate alveolar ventilation in patients that require respiratory support. Although a life‐saving intervention for critically ill patients, prolonged MV results in the rapid development of inspiratory muscle weakness due to both diaphragmatic atrophy and contractile dysfunction; collectively known as “ventilator‐induced diaphragm dysfunction” (VIDD). VIDD is a severe clinical problem because diaphragmatic weakness is a risk factor for difficulties in weaning patients from MV. Currently, no standard treatment to prevent VIDD exists. Nonetheless, growing evidence reveals that hydrogen sulfide (H₂S) possesses cytoprotective properties capable of protecting skeletal muscles against several hallmarks of VIDD, including oxidative damage, accelerated proteolysis, and mitochondrial damage. Therefore, we used an established animal model of MV to test the hypothesis that treatment with sodium sulfide (H₂S donor) will defend against VIDD. Our results confirm that sodium sulfide was sufficient to protect the diaphragm against both MV‐induced fiber atrophy and contractile dysfunction. H₂S prevents MV‐induced damage to diaphragmatic mitochondria as evidenced by protection against mitochondrial uncoupling. Moreover, treatment with sodium sulfide prevented the MV‐induced activation of the proteases, calpain, and caspase‐3 in the diaphragm. Taken together, these results support the hypothesis that treatment with a H₂S donor protects the diaphragm against VIDD. These outcomes provide the first evidence that H₂S has therapeutic potential to protect against MV‐induced diaphragm weakness and to reduce difficulties in weaning patients from the ventilator. Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Mechanical ventilation (MV) results in diaphragm atrophy and contractile dysfunction, known as ventilator‐induced diaphragm dysfunction (VIDD). VIDD is important because diaphragm weakness is a risk factor for problems in weaning patients from MV. Currently, no accepted treatment exists to protect against VIDD. Growing evidence reveals that hydrogen sulfide (H₂S) donors protect skeletal muscle against ischemia‐reperfusion‐induced injury. Nonetheless, it is unknown if treatment with a H₂S donor can protect against VIDD.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can treatment with an H₂S donor protect against VIDD?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study provides the first evidence that treatment with a H₂S donor protects against VIDD.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These new findings provide the basis for further exploration of H₂S donors as a therapy to prevent VIDD and reduce the risk of problems in weaning patients from MV.     

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.     

Type‐2 airway inflammation in mild asthma patients with high blood eosinophils and high fractional exhaled nitric oxide

Type‐2 (T2) inflammation is a characteristic feature of asthma. Biological therapies have been developed to target T2‐inflammation in asthma. IL‐13 is a key component of T2‐inflammation in asthma, driving mucus hypersecretion, IgE‐induction, and smooth muscle contraction. Early phase clinical trials for treatments that target T2‐inflammation require biomarkers to assess pharmacological effects. The aim of this study was to examine levels of IL‐13 inducible biomarkers in the airway epithelium of patients with mild asthma compared to healthy controls. Ten patients with mild asthma with high blood eosinophil and high fractional exhaled nitric oxide (FeNO) were recruited, and six healthy subjects. Blood eosinophil and FeNO reproducibility was assessed prior to bronchoscopy. Epithelial brushings were collected and assessed for IL‐13 inducible gene expression. Blood eosinophil and FeNO levels remained consistent in both patients with asthma and healthy subjects. Of the 11 genes assessed, expression levels of 15LOX1, POSTN, CLCA1, SERPINB2, CCL26, and NOS2 were significantly higher in patients with asthma compared to healthy controls. These six genes, present in patients with mild asthma with T2 inflammation, have the potential to be used in translational early phase asthma clinical trials of novel therapies as bronchial epithelial biomarkers.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Type 2 (T2) inflammation is found in many patients with asthma and is not always controlled by inhaled corticosteroids. T2‐specific biomarkers may be useful for measuring the pharmacological effects of novel anti‐T2 treatments.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We sought to identify IL‐13 associated biomarkers in the airways of patients with asthma with T2 inflammatory phenotype.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Six genes were identified in airway epithelium whose expressions were elevated in patients with T2‐high asthma compared to healthy subjects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The six genes identified have the potential to be used as target engagement biomarkers in early phase clinical development for novel asthma treatments targeting T2‐inflammation.     

Pharmacokinetics and tolerability of apremilast in healthy Korean adult men

We performed a two‐part study to evaluate the pharmacokinetics, safety, and tolerability of oral apremilast, a phosphodiesterase 4 inhibitor indicated for the treatment of psoriasis, in healthy Korean adult men. In part 1, there were 12 subjects who randomly received a single oral dose of apremilast at 20, 30, or 40 mg in each of 3 periods in a crossover fashion. In part 2, there were 16 subjects who randomly received 30 mg of apremilast or its matching placebo in a ratio of 3:1 twice daily for 14 days. Apremilast was rapidly absorbed (maximum concentration: ~2–3 h postdose), and eliminated according to a monoexponential pattern with a terminal‐phase elimination half‐life of 8–9 h. The exposure to apremilast increased in a dose‐proportional manner and accumulation was 1.6‐fold at steady‐state. Apremilast was well‐tolerated after a single oral administration and multiple oral administrations in Korean adult men; all of the treatment‐emergent adverse events were mild and recovered without sequelae. In conclusion, apremilast was safe and well‐tolerated in healthy Korean adult men when administered single oral doses of 20, 30, or 40 mg or when administered multiple oral doses of 30 mg b.i.d. for 14 days. Overall exposures increased in an approximate dose proportional manner in healthy Korean adult men.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Apremilast, a phosphodiesterase 4 inhibitor, has been approved to treat patients with psoriasis in many countries, including the United States, Canada, and Japan. Although apremilast has shown a linear pharmacokinetic (PK) profile and little ethnic sensitivity, apremilast has never been studied specifically in Koreans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This two‐part study evaluated differences in PKs and tolerability of apremilast between healthy Korean adult men and previously studied ethnic populations.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our results clearly showed that apremilast was safe and well‐tolerated after single and multiple oral administrations in healthy Korean adult men. Linear PK profiles of apremilast were consistently observed in healthy Korean adult men.

• HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?

Our results support the notion that recommended apremilast dose of 30 mg b.i.d., after a first week of titration, would be also appropriate in Koreans.     

Effects of sevelamer carbonate versus calcium acetate on vascular calcification,inflammation, and endothelial dysfunction in chronic kidney disease

Hyperphosphatemia is present in most patients with end‐stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium‐based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL‐cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF‐23 levels and there was no change with CA treatment. The inflammatory markers IL‐8, IFN‐γ, and TNFα decreased with response to both treatments. The levels of IL‐6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti‐inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Non‐calcium‐based phosphate binders are effective in the patients with end stage kidney disease for lowering serum phosphorus and have demonstrated anti‐inflammatory effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study demonstrates a favorable reduction in systemic, vascular, and bone‐related inflammatory markers from treatment with sevelamer carbonate (SC) in the patients with chronic kidney disease (CKD) not on dialysis with normal serum phosphorus levels.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that patients with CKD not on dialysis may benefit from SC phosphate binders despite having a normal serum phosphorus level.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study offers insight to the role phosphates binder may play in lowering inflammation and vascular calcification in patients with CKD not on dialysis.     

Pharmacokinetics and safety of cenobamate,a novel antiseizure medication,in healthy Japanese,and an ethnic comparison with healthy non‐Japanese

Cenobamate (XCOPRI and ONTOZRY) is a novel antiseizure medication for the treatment of focal‐onset seizures. Nonetheless, there is limited information on the pharmacokinetics (PKs), safety, and efficacy of cenobamate in Asian people, including Japanese people. This study aimed to evaluate the PKs and safety of cenobamate after a single oral dose in healthy Japanese subjects and to compare the PKs with that reported in non‐Japanese subjects. A randomized, double‐blind, placebo‐controlled, single ascending dose study was conducted at four dose levels of 50, 100, 200, and 400 mg. Subjects were randomly assigned to cenobamate or placebo in a 6:2 ratio. Cenobamate was rapidly absorbed, reaching its maximum plasma concentration (C_max) in 0.75 to 2.25 h, and was eliminated with a mean half‐life of 37.0 to 57.7 h. The C_max increased dose proportionally, whereas area under the concentration‐time curve increased more than dose proportionally, which was consistent with the findings in non‐Japanese subjects. The systemic exposure of cenobamate was comparable between Japanese and non‐Japanese subjects at all dose levels evaluated. All adverse events were mild in severity, and their incidence did not show dose‐dependent trends. Furthermore, there were no clinically significant issues in safety parameters, including sedation tests, neurologic examinations, and Columbia Suicide Severity Rating Scale interviews. In conclusion, the systemic exposure of cenobamate after a single dose in Japanese subjects increased by dose, which was similar to the pattern in non‐Japanese subjects. In addition, a single dose of cenobamate was well‐tolerated in the dose range of 50 to 400 mg in healthy Japanese subjects.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Cenobamate is a novel antiseizure medication newly approved for the treatment of focal‐onset seizures in the United States and Europe. To date, properties of cenobamate including pharmacokinetics (PKs) have not been extensively studied in Asian people including Japanese people.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the PKs and safety of a single oral dose of cenobamate in healthy Japanese subjects and compared the PKs with that in non‐Japanese subjects previously reported.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Cenobamate showed similar PK profiles in Japanese and non‐Japanese subjects, which suggests its negligible ethnic sensitivity. In addition, a single dose of cenobamate was well‐tolerated in healthy Japanese subjects. Our results indicate that the currently approved dosing regimen of cenobamate may also be applicable to Japanese patients with reasonable exposure and tolerability profiles.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our study bridged the clinical pharmacology gap between ethnicities by providing new findings on the ethnic sensitivity as well as the PKs and safety of cenobamate in Asian people including Japanese people.     

Angiotensin 1‐7 protects against ventilator‐induced diaphragm dysfunction

Mechanical ventilation (MV) is a life‐saving instrument used to provide ventilatory support for critically ill patients and patients undergoing surgery. Unfortunately, an unintended consequence of prolonged MV is the development of inspiratory weakness due to both diaphragmatic atrophy and contractile dysfunction; this syndrome is labeled ventilator‐induced diaphragm dysfunction (VIDD). VIDD is clinically important because diaphragmatic weakness is an important contributor to problems in weaning patients from MV. Investigations into the pathogenesis of VIDD reveal that oxidative stress is essential for the rapid development of VIDD as redox disturbances in diaphragm fibers promote accelerated proteolysis. Currently, no standard treatment exists to prevent VIDD and, therefore, developing a strategy to avert VIDD is vital. Guided by evidence indicating that activation of the classical axis of the renin‐angiotensin system (RAS) in diaphragm fibers promotes oxidative stress and VIDD, we hypothesized that activation of the nonclassical RAS signaling pathway via angiotensin 1‐7 (Ang1‐7) will protect against VIDD. Using an established animal model of prolonged MV, our results disclose that infusion of Ang1‐7 protects the diaphragm against MV‐induced contractile dysfunction and fiber atrophy in both fast and slow muscle fibers. Further, Ang1‐7 shielded diaphragm fibers against MV‐induced mitochondrial damage, oxidative stress, and protease activation. Collectively, these results reveal that treatment with Ang1‐7 protects against VIDD, in part, due to diminishing oxidative stress and protease activation. These important findings provide robust evidence that Ang1‐7 has the therapeutic potential to protect against VIDD by preventing MV‐induced contractile dysfunction and atrophy of both slow and fast muscle fibers.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Prolonged mechanical ventilation results in ventilator‐induced diaphragm dysfunction (VIDD). This is significant because VIDD is a major risk factor for problems in weaning patients from the ventilator. Currently, no standard treatment exists to prevent VIDD. However, emerging evidence reveals that pharmacological inhibition of the classical axis of the renin‐angiotensin system (RAS) protects against VIDD. Although angiotensin 1‐7 (Ang1‐7) activates the nonclassical arm of the RAS and antagonizes classical RAS signaling, the therapeutic potential of Ang1‐7 to protect against VIDD remains unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Is Ang1‐7 a viable therapy to prevent VIDD?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Treatment of animals with Ang1‐7 protected the diaphragm against both MV‐induced diaphragmatic contractile dysfunction and fiber atrophy. Importantly, Ang1‐7 protected against MV‐induced atrophy of both fast and slow‐type fibers and contractile dysfunction.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These new findings provide a foundation for future testing of Ang1‐7, a potential therapy to protect against VIDD.     

Dose‐dependent inactivation of airway tryptase with a novel dissociating anti‐tryptase antibody (MTPS9579A) in healthy participants: A randomized trial

Tryptase is the most abundant secretory granule protein in human lung mast cells and plays an important role in asthma pathogenesis. MTPS9579A is a novel monoclonal antibody that selectively inhibits tryptase activity by dissociating active tetramers into inactive monomers. The safety, tolerability, pharmacokinetics (PKs), and systemic and airway pharmacodynamics (PDs) of MTPS9579A were assessed in healthy participants. In this phase I single‐center, randomized, observer‐blinded, and placebo‐controlled study, single and multiple ascending doses of MTPS9579A were administered subcutaneously (s.c.) or intravenously (i.v.) in healthy participants. In addition to monitoring safety and tolerability, the concentrations of MTPS9579A, total tryptase, and active tryptase were quantified. This study included 106 healthy participants (82 on active treatment). Overall, MTPS9579A was well‐tolerated with no serious or severe adverse events. Serum MTPS9579A showed a dose‐proportional increase in maximum serum concentration (C_max) values at high doses, and a nonlinear increase in area under the curve (AUC) values at low concentrations consistent with target‐mediated clearance were observed. Rapid and dose‐dependent reduction in nasosorption active tryptase was observed postdose, confirming activity and the PK/PD relationship of MTPS9579A in the airway. A novel biomarker assay was used to demonstrate for the first time that an investigative antibody therapeutic (MTPS9579A) can inhibit tryptase activity in the upper airway. A favorable safety and tolerability profile supports further assessment of MTPS9579A in asthma. Understanding the exposure‐response relationships using the novel PD biomarker will help inform clinical development, such as dose selection or defining patient subgroups.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

MTPS9579A is a novel monoclonal antibody that selectively inhibits tryptase activity by dissociating active tetramers into inactive monomers. In preclinical studies, MTPS9579A inhibited tryptase activity in the airway.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This phase I study reports the safety and tolerability, pharmacokinetics (PKs), pharmacodynamics, and dose response of MTPS9579A in healthy human participants.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

MTPS9579A was well‐tolerated at all tested dose levels and had linear PKs at high concentrations. MTPS9579A is pharmacologically active and inhibits the target (active tryptase) in the upper airway of healthy participants.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results allow further exploration into the clinical efficacy and optimization of doses for MTSP9579A in treating patients with asthma and other mast cell‐related diseases.     

Phase I and scintigraphy studies to evaluate safety,tolerability, pharmacokinetics,and lung deposition of inhaled GDC‐0214 in healthy volunteers

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (^99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. ^99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma C_max similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many factors drive asthma pathogenesis, including several cytokines that signal through the Janus kinase 1 (JAK1) pathway. Inhibition of JAK1 is a possible target for asthma treatments, but previous studies show oral JAK1 inhibitors lead to increased risk of severe infections, malignancy and cardiovascular events.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the safety, pharmacokinetics, and lung deposition of GDC‐0214, an inhaled JAK1 inhibitor designed to target the lungs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Inhaled delivery of a JAK inhibitor for 14 days exhibited low systemic exposure, leading to few adverse events and limited systemic toxicity, while demonstrating high deposition in the lungs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Local pulmonary application of JAK inhibitors may be an effective treatment for asthma with limited systemic risks.     

Safety,tolerability, pharmacokinetics,and pharmacodynamics of a TLR7 agonist prodrug RO6870868 in healthy volunteers

RO6870868 is an oral prodrug of the toll‐like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first‐in‐human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200–2000 mg). Single oral doses were generally well‐tolerated with a predictable safety profile associated with dose‐dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half‐life ranging 2–6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC_0‐∞) increasing proportionally with dose. A pattern of dose and time‐dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose‐dependent manner with adequate safety and tolerability. Single‐dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Toll‐like receptor 7 (TLR7) agonists induce broad immune‐enhancing effects and may play a role in overcoming the adaptive and innate immune defects in chronic hepatitis B infection.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of RO6870868 (a prodrug of the specific TLR7 agonist RO6871765) in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

RO6870868 was safe and acceptably tolerated across the dose range in healthy volunteers. Oral administration results in the rapid appearance of the active TLR7 agonist RO6871765 and leads to a profile of gene expression typical for TLR7 agonism, including activation of interferon and interferon‐response genes. Gene activation occurs at RO6871765 exposure associated with single RO6870868 doses greater than or equal to 800 mg, with a plateau for several markers at doses between 1200 mg and 1600 mg.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The study results help to guide dose and regimen selection for clinical trials with RO6870868 and other potent TLR7 activators.     

Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin,a novel dual‐acting glucokinase activator

Dorzagliatin is a novel allosteric glucokinase activator targeting both pancreatic and hepatic glucokinase currently under clinical investigation for treatment of type 2 diabetes (T2D). This study aimed to investigate the effect of renal impairment (RI) on dorzagliatin’s pharmacokinetics (PKs) and safety, and to guide appropriate clinical dosing in patients with diabetic kidney disease, including end‐stage renal disease (ESRD). Based on the results from physiologically‐based pharmacokinetic modeling, the predicted outcome of RI on dorzagliatin PK property would be minimum that the plasma exposure area under concentration (AUC) of dorzagliatin in patients with ESRD would increase at about 30% with minimal change in peak concentration (C_max) comparing to those in healthy volunteers (HVs). To definitively confirm the prediction, a two‐part RI study was designed and conducted based on regulatory guidance starting with the patients with ESRD matched with HVs. Results of the RI study showed minimum difference between patients with ESRD and HVs with respect to dorzagliatin exposure with geometric mean ratio of ESRD to HV at 0.81 for C_max and 1.11 for AUC. The elimination half‐life, volume of distribution, and systemic clearance for dorzagliatin were similar between the two groups. Dorzagliatin was well‐tolerated in patients with ESRD during the study. Therefore, RI showed no significant impact on dorzagliatin PK, suggesting that dorzagliatin can be readily used in patients with T2D at all stages of RI without need for dose adjustment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Currently, there are limited safe and effective anti‐hyperglycemia treatments for patients with diabetic kidney disease (DKD) and end‐stage renal disease (ESRD). Dorzagliatin has exhibited favorable absorption, distribution, metabolism, and excretion/drug metabolism and pharmacokinetic properties with good safety and efficacy profiles in multiple preclinical and clinical studies, demonstrating its potential as a novel glucose sensitizer for the treatment of type 2 diabetes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The impact of renal impairment (RI) on dorzagliatin pharmacokinetics (PKs). Whether dorzagliatin can be used in patients with DKD without dose adjustment.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

RI had no significant impact on dorzagliatin PKs. Dorzagliatin can be used without dose adjustment in patients with DKD at any stage, including ESRD.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

A reduced study was designed based on regulatory guidance. Physiologically‐based pharmacokinetic (PBPK) modeling accurately predicted minimal impact of RI on dorzagliatin exposure, further supporting the study design. Subsequent clinical study results confirmed in silico prediction and validated the PBPK model. Therefore, integrating computational approach using scientifically well‐founded PBPK models can be powerful in critical decision making in drug development to reduce expenses and increase confidence.