Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan

Milademetan is a small‐molecule inhibitor of murine double minute 2 (MDM2) that is in clinical development for advanced solid tumors and hematological cancers, including liposarcoma and acute myeloid leukemia. Milademetan is a CYP3A and P‐glycoprotein substrate and moderate CYP3A inhibitor. The current study aims to understand the drug‐drug interaction (DDI) risk of milademetan as a CYP3A substrate during its early clinical development. A clinical DDI study of milademetan ({"type":"clinical-trial","attrs":{"text":"NCT03614455","term_id":"NCT03614455"}}NCT03614455) showed that concomitant administration of single‐dose milademetan with the strong CYP3A inhibitor itraconazole or posaconazole increased milademetan mean area under the curve from zero to infinity (AUC_inf) by 2.15‐fold (90% confidence interval [CI], 1.98–2.34) and 2.49‐fold (90% CI, 2.26–2.74), respectively, supporting that the milademetan dose should be reduced by 50% when concomitantly administered with strong CYP3A inhibitors. A physiologically‐based pharmacokinetic (PBPK) model of milademetan was subsequently developed to predict the magnitude of CYP3A‐mediated DDI potential of milademetan with moderate CYP3A inhibitors. The PBPK model predicted an increase in milademetan exposure of 1.72‐fold (90% CI, 1.69–1.76) with fluconazole, 1.91‐fold (90% CI, 1.83–1.99) with erythromycin, and 2.02‐fold (90% CI, 1.93–2.11) with verapamil. In addition, it estimated that milademetan’s original dose (160 mg once daily) could be resumed from its half‐reduced dose 3 days after discontinuation of concomitant strong CYP3A inhibitors. The established PBPK model of milademetan was qualified and considered to be robust enough to support continued development of milademetan.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Milademetan is a CYP3A and P‐gp substrate and moderate CYP3A inhibitor. Evaluation of drug‐drug interaction (DDI) risk of milademetan by combining clinical studies and physiologically‐based pharmacokinetic (PBPK) modeling has not previously been described.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Will milademetan PK be affected by the concomitant administration of strong or moderate CYP3A inhibitors? When can the original dose of milademetan be resumed after the discontinuation of strong CYP3A inhibitors?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study illustrates the use of a clinical DDI study and PBPK modeling in the early clinical development of milademetan to assess DDI risks in scenarios that have not yet been tested clinically at the time.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

PBPK modeling integrates in vitro and clinical data to facilitate the mechanistic understanding of PKs. Recommendations from PBPK modeling can support the design of clinical studies for the investigation of DDIs.     

Pharmacokinetics and pharmacodynamics of itepekimab in healthy adults and patients with asthma: Phase I first‐in‐human and first‐in‐patient trials

Itepekimab is a monoclonal antibody that targets interleukin (IL‐33) and has been shown to reduce airway inflammation and associated tissue damage in preclinical studies. We assessed the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamic profiles of single‐ascending and multiple‐ascending doses of itepekimab in two randomized, double‐blind, placebo‐controlled phase I studies. Healthy adults (N = 40) were randomized to the single‐dose study and patients with moderate asthma (N = 23) to the multiple‐dose study. Itepekimab was administered intravenously (0.3, 1, 3, or 10 mg/kg infusion) or subcutaneously (150 mg) in the single‐dose study and subcutaneously (75 or 150 mg weekly for 4 weeks) in the multiple‐dose study. Itepekimab exhibited linear PKs across studies and dose‐proportional increases in mean maximum concentration in serum and area under the concentration–time curve following single intravenous or multiple subcutaneous doses. Itepekimab demonstrated mean subcutaneous bioavailability of 59–73% and a long terminal half‐life (30.0–31.6 days). IL‐33 concentrations in most healthy participants and patients with asthma were undetectable at baseline. Following administration of itepekimab in both studies, total IL‐33 concentrations increased and blood eosinophils decreased, both with durable effect. Itepekimab was well‐tolerated in both studies with no detection of treatment‐emergent anti‐drug antibody responses.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Preclinical data suggest that itepekimab, a monoclonal antibody targeting IL‐33, may benefit patients with chronic inflammatory airway diseases by blocking IL‐33–mediated pathologic inflammation. Neither the pharmacokinetic (PK) profile of itepekimab nor its safety has been fully elucidated in first‐in‐human or first‐in‐patient studies.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study evaluated the initial safety of itepekimab, and its PK and pharmacodynamic activity in healthy adults and patients with asthma.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Itepekimab demonstrated linear and dose‐proportional PKs in our studies and was well‐tolerated, with no evidence of immunogenicity. These findings have facilitated dose and regimen selection for subsequent clinical studies in patients with asthma and chronic obstructive pulmonary disease.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Itepekimab is one of a few anti‐alarmin biologics under development; if successful, it may provide an alternative mechanism of action with which to target chronic inflammatory airway diseases, alone or in combination with other targeted therapies.     

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.     

Novel Bruton’s Tyrosine Kinase inhibitor remibrutinib: Drug‐drug interaction potential as a victim of CYP3A4 inhibitors based on clinical data and PBPK modeling

Remibrutinib, a novel oral Bruton’s Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib. The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first‐pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady‐state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27‐fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically‐based pharmacokinetic (PBPK) model, which well‐described the therapeutic dose range of 25–100 mg. Simulations of untested scenarios revealed an absence of drug‐drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration‐time curve ratio [AUCR] <1.25), and a moderate effect with the CYP3A4 inhibitor erythromycin (AUCR: 2.71). Predictions with the moderate and strong CYP3A4 inducers efavirenz and rifampicin, suggested a distinct remibrutinib exposure decrease of 64% and 89%. Oral bioavailability of remibrutinib was 34%. The inclusion of an intravenous microtracer allowed the determination of all relevant remibrutinib PK parameters, which facilitated construction of the PBPK model. This will provide guidance on the selection or restriction of comedications and prediction of DDI risks.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Remibrutinib is an irreversible Bruton’s Tyrosine Kinase inhibitor and moderate CYP3A4 substrate to be administered with caution with strong inhibitors.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study explored the drug‐drug interaction (DDI) risk of remibrutinib as a victim with CYP3A4 inhibitors.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Using a specifically tailored study design, most model‐relevant pharmacokinetic (PK) parameters were determined, including fractions of the dose escaping intestinal and hepatic first‐pass metabolism, absolute bioavailability, systemic drug clearance, apparent volume of distribution at steady‐state, and fraction of the drug metabolized via CYP3A4.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The clinical study design offers opportunities to obtain important PK parameters, which enabled physiologically‐based pharmacokinetic (PBPK) model building of complex PK compounds. Taken together, the PK parameters and the PBPK simulations allowed robust DDI predictions of untested scenarios.     

Investigation of CYP3A induction by PF‐05251749 in early clinical development: comparison of linear slope physiologically based pharmacokinetic prediction and biomarker response

PF‐05251749 is a dual inhibitor of casein kinase 1 δ/ε under clinical development to treat disruption of circadian rhythm in Alzheimer''s and Parkinson''s diseases. In vitro, PF‐05251749 (0.3–100 μM) induced CYP3A in cryopreserved human hepatocytes, demonstrating non‐saturable, dose–dependent CYP3A mRNA increases, with induction slopes in the range 0.036–0.39 μM⁻¹. In a multiple‐dose study (B8001002) in healthy participants, CYP3A activity was explored by measuring changes in 4β‐hydroxycholesterol/cholesterol ratio. Following repeated oral administration of PF‐05251749, up to 400 mg q.d., no significant changes were observed in 4β‐hydroxycholesterol/cholesterol ratio; this ratio increased significantly (~1.5‐fold) following administration of PF‐05251749 at 750 mg q.d., suggesting potential CYP3A induction at this dose. Physiologically based pharmacokinetic (PBPK) models were developed to characterize the observed clinical pharmacokinetics (PK) of PF‐05251749 at 400 and 750 mg q.d.; the PBPK induction model was calibrated using the in vitro linear fit induction slope, with rifampin as reference compound (Ind_max = 8, EC₅₀ = 0.32 μM). Clinical trial simulation following co‐administration of PF‐05251749, 400 mg q.d. with oral midazolam 2 mg, predicted no significant drug interaction risk. PBPK model predicted weak drug interaction following co‐administration of PF‐05251749, 750 mg q.d. with midazolam 2 mg. In conclusion, good agreement was obtained between CYP3A drug interaction risk predicted using linear‐slope PBPK model and exploratory biomarker trends. This agreement between two orthogonal approaches enabled assessment of drug interaction risks of PF‐05251749 in early clinical development, in the absence of a clinical drug–drug interaction study.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Physiologically based pharmacokinetic (PBPK) predictions are commonly applied in clinical development to predict drug interaction risks associated with CYP3A inducers. Changes in 4β‐hydroxycholesterol levels are explored to assess the clinical relevance of CYP3A induction in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

PF‐05251749 was identified as a potential CYP3A inducer in vitro. The objective of this analysis was to investigate clinical drug–drug interaction (DDI) risk associated with PF‐05251749 during early clinical development, using PBPK and biomarker outcomes.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study exemplifies the assessment of drug interaction risks in early clinical development, using changes in 4β‐hydroxycholesterol/cholesterol ratio as preliminary evidence of CYP3A activity, leading to investigation using a PBPK model‐informed approach. This PBPK model was developed using in vitro CYP3A mRNA induction linear‐fit‐slope. This investigation shows good concordance of linear‐fit‐slope‐calibrated PBPK predictions with observed trends in hepatic CYP3A biomarker changes.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Measuring changes in 4β‐hydroxycholesterol/cholesterol ratio should be considered for potential CYP3A inducers during phase I multiple‐dose studies. Assessment of DDI risks during early development should consider totality of data including in vitro, in vivo/biomarker, and PBPK approaches.     

Safety,tolerability, pharmacokinetic,and pharmacodynamic characteristics of vutiglabridin: A first‐in‐class,first‐in‐human study

This study aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of vutiglabridin, a potential anti‐obesity treatment under development, for the first time in humans. A randomized, placebo‐controlled, single‐ and multiple‐ascending dose study (SAD and MAD, respectively) was performed in healthy Koreans and Whites. Subjects randomly received a single oral dose of 30–720 mg vutiglabridin or placebo at a ratio of 8:2 in the SAD study or 240–480 mg vutiglabridin or placebo once daily for 14 days in the MAD study. Food effect was also evaluated in 240 mg single dose group. Pharmacokinetics were evaluated through plasma concentrations, and pharmacodynamic biomarkers related to obesity or inflammation were analyzed. Safety and tolerability were assessed throughout the study. Single and multiple doses of vutiglabridin were generally well‐tolerated. The pharmacokinetic parameters show less than dose‐proportionality increase, and plasma concentrations increased more than two‐fold after multiple administrations. The mean half‐life of Koreans and Whites in the MAD study was 110 and 73 h, respectively. The systemic exposure of vutiglabridin was significantly increased when taken with a high‐fat meal, and the systemic exposure was lower in Whites than in Koreans. Vutiglabridin was well‐tolerated in healthy Koreans and Whites. The plasma concentration increased less than the dose‐proportionality manner. These results justify further investigation of vutiglabridin in patients with obesity.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

A treatment with multifunctional effects is needed for obesity. Because the chronic inflammation caused by obesity plays an essential role in the progression of metabolic disorders, suppressing inflammatory pathways may be another important treatment goal.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What is the safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics of vutiglabridin, a novel anti‐obesity agent, in healthy Korean and White individuals?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Vutiglabridin was well‐tolerated in both Korean and White individuals. The pharmacokinetic parameters of vutiglabridin did not show dose‐proportionality, and after multiple administrations, vutiglabridin showed accumulation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study provides safety, pharmacokinetic, and pharmacodynamic information about vutiglabridin, which will be used for further trials for the treatment of obesity.     

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.     

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.     

Hybrid physiologically‐based pharmacokinetic model for remdesivir: Application to SARS‐CoV‐2

A novel coronavirus, severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) or coronavirus disease 2019 (COVID‐19), has caused a pandemic that continues to cause catastrophic health and economic carnage and has escalated the identification and development of antiviral agents. Remdesivir (RDV), a prodrug and requires intracellular conversions to the active triphosphate nucleoside (TN) has surfaced as an active anti‐SARS‐CoV‐2 drug. To properly design therapeutic treatment regimens, it is imperative to determine if adequate intracellular TN concentrations are achieved in target tissues, such as the lungs. Because measurement of such concentrations is unrealistic in patients, a physiologically‐based pharmacokinetic (PBPK) model was developed to characterize RDV and TN disposition. Specifically, a hybrid PBPK model was developed based on previously reported data in humans. The model represented each tissue as a two‐compartment model—both extracellular and intracellular compartment wherein each intracellular compartment contained a comprehensive metabolic model to the ultimate active metabolite TN. Global sensitivity analyses and Monte‐Carlo simulations were conducted to assess which parameters and how highly sensitive ones impacted peripheral blood mononuclear cells and intracellular lung TN profiles. Finally, clinical multiple‐dose regimens indicated that minimum lung intracellular TN concentrations ranged from ~ 9 uM to 4 uM, which suggest current regimens are effective based on in vitro half‐maximal effective concentration values. The model can be used to explore tissue drug disposition under various conditions and regimens, and expanded to pharmacodynamic models.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

There is limited information on the tissue distribution and metabolism of remdesivir (RDV)—an antiviral agent recently US Food and Drug Administration (FDA)‐approved for patients with severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2)—and none in the patients.

• WHAT QUESTION DID THIS STUDY ADDRESS?

RDV is known to undergo intracellular conversion to an active triphosphate nucleoside (TN) metabolite, and the computational investigation used a physiologically‐based pharmacokinetic (PBPK) of RDV to characterize the tissue distribution of RDV and the intracellular metabolite kinetics and the production of TN.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The PBPK model of RDV characterizes the extent of RDV tissue distribution and the associated intracellular metabolism in target tissues, such as the lungs. The model simulations can be used to assess the efficacy of current clinical dosing regimens based on TN intracellular concentration profiles.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The PBPK model of RDV serves as a foundation to rationally design clinical dosing protocols for RDV and may be extended to viral dynamic and pharmacodynamic models, and further support the development of PBPK models for other antivirals used for SARS‐CoV‐2.     

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.     

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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

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

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

A first‐in‐human study of KMRC011, a potential treatment for acute radiation syndrome,to explore tolerability,pharmacokinetics, and pharmacodynamics

KMRC011 is a novel Toll‐like receptor 5 agonist under development as a treatment for acute radiation syndrome (ARS). The aim of this first‐in‐human study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of a single intramuscular dose of KMRC011 in healthy subjects. A randomized, single‐blind, placebo‐controlled, single dose‐escalation study was conducted with the starting dose of 5 μg. Eight (4 only for 5 μg cohort) subjects per cohort were randomly assigned to KMRC011 or placebo in a 3:1 ratio. Dose‐limiting toxicity (DLT) was assessed throughout the study. Serum concentrations of KMRC011, granulocyte colony‐stimulating factor (G‐CSF), and interleukin‐6 (IL‐6) were measured up to 48 h postdose. Based on safety review, the dose of KMRC011 escalated up to 20 μg, and consequently, a total of 4 dose levels (5, 10, 15, and 20 μg) were explored. The most common adverse event was injection site reaction, showing no dose‐related trend. Three DLTs (2 cases of hepatic enzyme increased and 1 of pyrexia) were observed; 1 in the 15 μg cohort and 2 in the 20 μg cohort. A developed method could not detect any KMRC011 in serum. KMRC011 15 μg and 20 μg showed significant increases of G‐CSF, IL‐6, and absolute neutrophil counts, compared with the placebo. A single intramuscular administration of KMRC011 ranging from 5 to 15 μg was tolerated in healthy subjects. Doses of KMRC011 equal to or greater than 15 μg exerted TLR5 agonist‐like activities by increasing serum G‐CSF and IL‐6. It suggests that KMRC011 has the potential for a treatment for ARS.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Toll‐like receptor 5 (TLR5) can be a target for acute radiation syndrome (ARS), and KMRC011 is a novel TLR5 agonist being developed as a treatment for ARS. In animal models of irradiation, TLR5 agonists showed radioprotective and radiomitigative effect, and granulocyte colony‐stimulating factor (G‐CSF) and interleukin‐6 (IL‐6) have been proposed as efficacy biomarkers for TLR5 agonists. For further development, properties of KMRC011 including tolerability in humans need to be evaluated.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does KMRC011, a novel TLR5 agonist, show acceptable safety profiles and clinically meaningful changes in efficacy biomarkers in healthy humans?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

A single intramuscular administration of KMRC011 was tolerated in healthy humans. In addition, KMRC011 exerted TLR5 agonist‐like activities by increasing the levels of serum G‐CSF and IL‐6. As a result, KMRC011 demonstrates acceptable tolerability and preliminary activity in humans as well as animal models, and thus, KMRC011 may have the potential for a treatment for ARS.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our first‐in‐human study provided new clinical pharmacology information, such as safety and pharmacodynamics (PDs) of KMRC011 in humans. These findings are expected to be integrated with previous animal PD data, translate animal efficacy to humans, and ultimately contribute to the drug approval under the Animal Rule.     

Pharmacokinetic evaluation of radiolabeled intraocular anti‐CLEC14a antibody in preclinical animal species and application in humans

Anti‐angiogenic antibodies are widely used in the treatment of neovascular macular degeneration. Human antibody targeting C‐type lectin domain family 14 member A (CLEC14a) is potential therapeutic agents owing to its antiangiogenic activity. In the present study, we aimed to predict the human intraocular pharmacokinetic (PK) properties of an anti‐CLEC14a antibody. I‐125 labeled aflibercept and anti‐CLEC14a antibody were intravitreally injected into mice, rats, and rabbits. Single photon emission computed tomography/computed tomography imaging was performed, and the intraocular radioactivity concentration (%ID/ml) was obtained. The PK parameters in those three animal species were obtained by compartmental analysis. The PK parameters in humans were estimated by allometric scaling of the animal PK parameters with consideration of the hydrodynamic radius of the antibody. The mean half‐life values of intraocular I‐125‐labeled aflibercept in mice, rats, and rabbits were 1.13 days, 1.25 days, and 4.91 days, respectively, by analysis with a one‐compartment model. The predicted human half‐life of intraocular aflibercept was 5.75 days based on vitreal volume by allometric scaling. The half‐life values of intraocular I‐125‐labeled anti‐CLEC14a in mice, rats and rabbits were 1.05 days, 1.84 days, and 6.37 days, respectively, by analysis with a one‐compartment model. The predicted human half‐life of intraocular anti‐CLEC14a was 10.29 days based on vitreal volume. According to the hydrodynamic volume of the anti‐CLEC14a, the predicted human half‐life of intraocular anti‐CLEC14a was 9.81 days. The PK characteristics of the intraocular anti‐CLEC14a antibody were evaluated noninvasively in animals using I‐125 labeling, and the intraocular PK characteristics in humans were predicted using these animal data. This methodology can be applied for the development of new antiangiogenic antibodies to treat macular degeneration.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Allometric scaling based on multiple species of animals could be used in first‐in‐human studies.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Could molecular imaging using radiolabeled antibodies be used in the pharmacokinetic (PK) analysis of intravitreally injected antibodies and precise prediction of human PK parameters?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Molecular imaging using radiolabeled antibodies can be used in PK analysis.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Methodologies using molecular imaging can be applied for the development of new antibodies to treat macular degeneration by intravitreal injection.     

Physiologically‐based pharmacokinetic model‐based translation of OATP1B‐mediated drug–drug interactions from coproporphyrin I to probe drugs

The accurate prediction of OATP1B‐mediated drug–drug interactions (DDIs) is challenging for drug development. Here, we report a physiologically‐based pharmacokinetic (PBPK) model analysis for clinical DDI data generated in heathy subjects who received oral doses of cyclosporin A (CysA; 20 and 75 mg) as an OATP1B inhibitor, and the probe drugs (pitavastatin, rosuvastatin, and valsartan). PBPK models of CysA and probe compounds were combined assuming inhibition of hepatic uptake of endogenous coproporphyrin I (CP‐I) by CysA. In vivo K_i of unbound CysA for OATP1B (K_i,OATP1B), and the overall intrinsic hepatic clearance per body weight of CP‐I (CL_int,all,unit) were optimized to account for the CP‐I data (K_i,OATP1B, 0.536 ± 0.041 nM; CL_int,all,unit, 41.9 ± 4.3 L/h/kg). DDI simulation using K_i,OATP1B reproduced the dose‐dependent effect of CysA (20 and 75 mg) and the dosing interval (1 and 3 h) on the time profiles of blood concentrations of pitavastatin and rosuvastatin, but DDI simulation using in vitro K_i,OATP1B failed. The Cluster Gauss–Newton method was used to conduct parameter optimization using 1000 initial parameter sets for the seven pharmacokinetic parameters of CP‐I (β, CL_{int, all}, F_aF_g, R_dif, f_bile, f_syn, and v _syn), and K_i,OATP1B and K_i,MRP2 of CysA. Based on the accepted 546 parameter sets, the range of CL_{int, all} and K_i,OATP1B was narrowed, with coefficients of variation of 12.4% and 11.5%, respectively, indicating that these parameters were practically identifiable. These results suggest that PBPK model analysis of CP‐I is a promising translational approach to predict OATP1B‐mediated DDIs in drug development.

Abbreviations

AUC

area under the concentration time curve

AUCR

area under the concentration time curve ratio (rifampicin/control)

BCRP

breast cancer resistance protein

CGNM

Cluster Gauss–Newton method

C_max

maximum concentration

CV

coefficient of variation

CysA

cyclosporin A

DDI

drug–drug interaction

K_i

inhibition constant

MRP2

multidrug resistance protein 2

OATP1B1

organic anion transporting polypeptide 1B1

OATP1B3

organic anion transporting polypeptide 1B3

PBPK

physiologically‐based pharmacokinetic

T_max

time to maximum concentration

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Physiologically‐based pharmacokinetic (PBPK) models are used to predict transporter‐mediated drug–drug interactions (DDIs). Endogenous OATP1B biomarkers, such as coproporphyrin I (CP‐I), are strongly predicted to improve DDI prediction in drug development.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can PBPK model analysis of the clinical CP‐I data successfully predict OATP1B‐mediated DDIs using probe drugs?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The value of the most important DDI parameter, K_i,OATP1B, estimated by PBPK model‐based analysis of clinical CP‐I data, was able to overcome the discrepancy between the in vitro and in vivo effects of CysA on OATP1B, and could be applied to predict the change in the blood concentration time profiles of OATP1B probe drugs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The collection of endogenous OATP1B biomarker data is a feasible strategy to capture DDI potential. PBPK models aids in the prediction of its clinical impact more precisely, help to reduce risk in drug development, and impact the regulatory decision tree for DDI risk assessment.     

Safety,tolerability, and pharmacokinetics of oral baicalein tablets in healthy Chinese subjects: A single‐center,randomized, double‐blind,placebo‐controlled multiple‐ascending‐dose study

Baicalein is a biologically important flavonoid in extracted from the Scutellaria baicalensis Georgi, which can effectively inhibit the influenza virus. This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials. In this multiple‐ascending‐dose placebo‐controlled trial, 36 healthy subjects were randomized to receive 200, 400, and 600 mg of baicalein tablet or placebo once daily on day 1 and day 10, 3 times daily on days 4–9. All groups were intended to produce safety and tolerability outcomes (lowest dose first). Blood and urine samples were collected from subjects in the 600 mg group for baicalein PK analysis. Our study had shown that Baicalein tablet was generally safe and well‐tolerated. All adverse events were mild and resolved without any intervention except one case of fever reported in the 600 mg group, which was considered as moderate but not related with baicalein as judged by the investigator. Oral baicalein tablets were rapidly absorbed with peak plasma levels being reached within 2 h after multiple administration. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many studies have shown that baicalin has an anti‐influenza effect in cell and animal experiments. The primary mechanism of action is that baicalein has a strong inhibitory effect on the sialidase of the influenza virus.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our study results have shown that baicalein tablets were administered multiple times within the studied dose range were safe and well‐tolerated in healthy Chinese subjects with no serious or severe adverse effects. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend. Oral baicalein tablets were rapidly absorbed with peak plasma levels reached within 2 h after multiple administration.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our study addresses the safety outcomes of baicalein tablets and emphasizes the PKs of baicalein, which provides a better understanding and a scientific basis of the clinical application of baicalein for further evaluation.     

Pharmacokinetics of asciminib in the presence of CYP3A or P‐gp inhibitors,CYP3A inducers,and acid‐reducing agents

Asciminib is a first‐in‐class inhibitor of BCR::ABL1, specifically targeting the ABL myristoyl pocket. Asciminib is a substrate of CYP3A4 and P‐glycoprotein (P‐gp) and possesses pH‐dependent solubility in aqueous solution. This report summarizes the results of two phase I studies in healthy subjects aimed at assessing the impact of CYP3A and P‐gp inhibitors, CYP3A inducers and acid‐reducing agents (ARAs) on the pharmacokinetics (PK) of asciminib (single dose of 40 mg). Asciminib exposure (area under the curve [AUC]) unexpectedly decreased by ~40% when administered concomitantly with the strong CYP3A inhibitor itraconazole oral solution, whereas maximum plasma concentration (C_max) decreased by ~50%. However, asciminib exposure was slightly increased in subjects receiving an itraconazole capsule (~3%) or clarithromycin (~35%), another strong CYP3A inhibitor. Macroflux studies showed that cyclodextrin (present in high quantities as excipient [40‐fold excess to itraconazole] in the oral solution formulation of itraconazole) decreased asciminib flux through a lipid membrane by ~80%. The AUC of asciminib was marginally decreased by concomitant administration with the strong CYP3A inducer rifampicin (by ~13–15%) and the strong P‐gp inhibitor quinidine (by ~13–16%). Concomitant administration of the ARA rabeprazole had little or no effect on asciminib AUC, with a 9% decrease in C_max. The treatments were generally well tolerated. Taking into account the large therapeutic window of asciminib, the observed changes in asciminib PK following multiple doses of P‐gp, CYP3A inhibitors, CYP3A inducers, or ARAs are not considered to be clinically meaningful. Care should be exercised when administering asciminib concomitantly with cyclodextrin‐containing drug formulations.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Asciminib is a first‐in‐class BCR::ABL1 inhibitor, specifically targeting the ABL myristoyl pocket, and a substrate of CYP3A4 and P‐gp. Asciminib displays pH‐dependent solubility in aqueous solution.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study explored the drug–drug interaction risk of asciminib as a victim with CYP3A inhibitors, CYP3A inducers, P‐gp inhibitors, and acid‐reducing agents (ARAs).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Asciminib as a victim was weakly affected by concomitantly administered P‐gp inhibitors, strong CYP3A inhibitors, strong CYP3A inducers, or ARAs. However, a substantial effect of cyclodextrin (as an excipient in itraconazole oral solution) was observed; indirect evidence showed that cyclodextrin markedly decreased asciminib bioavailability.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results support the concomitant use of CYP3A and P‐gp inhibitors, CYP3A inducers and ARAs in patients treated with asciminib. Care should be exercised when using itraconazole oral solution or other cyclodextrin‐containing formulations in clinical studies due to their potential impact on absorption of orally co‐administered compounds.     

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.     

Pharmacogenetic variants and risk of remdesivir‐associated liver enzyme elevations in Million Veteran Program participants hospitalized with COVID‐19

Remdesivir is the first US Food and Drug Administration (FDA)‐approved drug for the treatment of coronavirus disease 2019 (COVID‐19). We conducted a retrospective pharmacogenetic study to examine remdesivir‐associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID‐19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log‐transformed enzyme values, stratified by population, adjusted for age, sex, baseline liver enzymes, comorbidities, and 10 population‐specific principal components. Patients on remdesivir had higher peak alanine aminotransferase (ALT) values following treatment initiation compared with patients not receiving remdesivir. Remdesivir administration was associated with a 33% and 24% higher peak ALT in non‐Hispanic White (NHW) and non‐Hispanic Black (NHB) participants (p < 0.001), respectively. In a multivariable model, NHW CYP2C19 intermediate/poor metabolizers had a 9% increased peak ALT compared with NHW normal/rapid/ultrarapid metabolizers (p = 0.015); this association was not observed in NHB participants. In summary, remdesivir‐associated ALT elevations appear to be multifactorial, and further studies are needed.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Remdesivir is associated with liver injury in patients with coronavirus disease 2019 (COVID‐19), yet the mechanism of this injury is unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We utilized a genetically guided approach to investigate whether polymorphisms in drug metabolizing genes or transporters were associated with alanine aminotransferase (ALT) elevations following remdesivir treatment.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE

Remdesivir was associated with a 30% increase in peak ALT in patients hospitalized with COVID‐19 which differs by population. Non‐Hispanic White (NHW) individuals with the CYP2C19 intermediate or poor metabolizer phenotype experienced a higher peak ALT than NHW individuals with normal, rapid, or ultrarapid metabolizer phenotype.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Pharmacogenetic approaches to investigation of severe adverse events may be useful in elucidating the mechanisms of drug metabolism and toxicity.