Characterization of mavacamten pharmacokinetics in patients with hypertrophic cardiomyopathy to inform dose titration.

Mavacamten is a selective, allosteric, reversible cardiac myosin inhibitor that has been developed for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). A population pharmacokinetic (PopPK) model was developed to characterize mavacamten pharmacokinetics (PK) and the variation in mavacamten exposure associated with intrinsic and extrinsic factors. Data from 12 clinical studies (phases 1, 2, and 3) were used.

Recommendation of mavacamten posology by model-based analyses in adults with obstructive hypertrophic cardiomyopathy.

Mavacamten is the first cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). The phase III EXPLORER-HCM (NCT03470545) study used a dose-titration scheme based on mavacamten exposure and echocardiographic assessment of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Using population pharmacokinetic/exposure-response modeling and simulations of virtual patients, this in silico study evaluated alternative dose-titration regimens for mavacamten, including regimens that were guided by echocardiographic measures only.

Effects of Omeprazole and Verapamil on the Pharmacokinetics, Safety, and Tolerability of Mavacamten: Two Drug-Drug Interaction Studies in Healthy Participants.

Two open-label, Phase 1 studies assessed the effects of omeprazole (a weak to moderate cytochrome P450 [CYP] 2C19 inhibitor) and verapamil (a moderate CYP3A4 inhibitor) on the pharmacokinetics, safety, and tolerability of mavacamten. In the omeprazole study, healthy participants received mavacamten 15 mg alone or with a 31-day course of omeprazole 20 mg once daily. In the verapamil study, healthy participants received mavacamten 25 mg alone or with a 28-day course of verapamil 240 mg once daily.

Physiologically Based Pharmacokinetic Modeling and Simulation of Mavacamten Exposure with Drug-Drug Interactions from CYP Inducers and Inhibitors by CYP2C19 Phenotype.

Mavacamten is a first-in-class, oral, selective, allosteric, reversible cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association functional class II-III obstructive hypertrophic cardiomyopathy. Mavacamten is metabolized in the liver, predominantly via cytochrome P450 (CYP) enzymes CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). A physiologically-based pharmacokinetic (PBPK) model was developed using Simcyp version 19 (Certara, Princeton, NJ).

Safety, Pharmacokinetics, and Antifibrotic Activity of CC-90001 (BMS-986360), a c-Jun N-Terminal Kinase Inhibitor, in Pulmonary Fibrosis.

Approved treatments for idiopathic pulmonary fibrosis have tolerability concerns and limited efficacy. CC-90001, a c-Jun N-terminal kinase inhibitor, is under investigation as a therapy for fibrotic diseases. A Phase 1b safety, pharmacokinetics, and pharmacodynamics study of oral CC-90001 (100, 200, or 400 mg) administered once daily for 12 weeks was conducted in patients with pulmonary fibrosis (NCT02510937).

Safety, Pharmacokinetics, and Pharmacodynamics of CC-90001 (BMS-986360), a c-Jun N-terminal Kinase Inhibitor, in Phase 1 Studies in Healthy Participants.

CC-90001 selectively inhibits c-Jun N-terminal kinase (JNK), a stress-activated protein implicated in fibrosis. In 3 phase 1 trials evaluating CC-90001 pharmacokinetics, pharmacodynamics, and safety, healthy adults (N = 184) received oral CC-90001 in a single dose (10-720 mg) or multiple doses (30-480 mg once daily for 7-18 days) or placebo. CC-90001 was rapidly absorbed (median time to maximum concentration, 1-4 hours) and eliminated with a mean terminal elimination half-life of 12-28 hours.

Effect of fluconazole on the pharmacokinetics of a single dose of fedratinib in healthy adults.

Purpose: Fedratinib is an orally administered Janus kinase (JAK) 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. In vitro, fedratinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Coadministration of fedratinib with CYP3A4 inhibitors is predicted to increase systemic exposure to fedratinib.

CC-99677, a novel, oral, selective covalent MK2 inhibitor, sustainably reduces pro-inflammatory cytokine production.

Background: Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is activated downstream of p38 MAPK and regulates stability of mRNAs encoding inflammatory cytokines. CC-99677 is a novel, irreversible, covalent MK2 inhibitor under development for the treatment of ankylosing spondylitis (AS) and other inflammatory diseases. As part of a phase I clinical trial to assess safety and tolerability, we evaluated target engagement, pharmacokinetics, and pharmacodynamics of CC-99677.

Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety.

Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics.

Impact of fedratinib on the pharmacokinetics of transporter probe substrates using a cocktail approach.

Introduction: Fedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate).

Methods: In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.

Reappraisal of anticancer nanomedicine design criteria in three types of preclinical cancer models for better clinical translation.

Anticancer nanomedicines are designed to improve anticancer efficacy by increasing drug accumulation in tumors through enhanced permeability retention (EPR) effect, and to reduce toxicity by decreasing drug accumulation in normal organs through long systemic circulation. However, the inconsistent efficacy/safety of nanomedicines in cancer patients versus preclinical cancer models have provoked debate for nanomedicine design criteria. In this study, we investigate nanomedicine design criteria in three types of preclinical cancer models using five clinically used nanomedicines, which identifies the factors for better clinical translations of their observed clinical efficacy/safety compared to free drug or clinical micelle formulation.

Effects of strong and moderate CYP3A4 inducers on the pharmacokinetics of fedratinib in healthy adult participants.

Purpose: Fedratinib is an oral and selective Janus kinase 2 inhibitor that is indicated for treatment of adults with intermediate-2 or high-risk primary or secondary myelofibrosis. Fedratinib is metabolized by cytochrome P450s (CYPs), primarily CYP3A4. The objective of this study was to determine the effects of the strong CYP3A4 inducer rifampin and moderate CYP3A4 inducer efavirenz on the pharmacokinetics of single doses of fedratinib.

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.

Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator.

Ozanimod is approved for the treatment of relapsing forms of multiple sclerosis. Absorption, metabolism, and excretion of ozanimod were investigated after a single oral dose of 1.0 mg [C]ozanimod hydrochloride to six healthy subjects.

Recurrent or progressive pediatric brain tumors: population pharmacokinetics and exposure-response analysis of pomalidomide.

Background: Pomalidomide, an immunomodulatory drug, was investigated for pediatric brain tumors. The objectives of this analysis were to characterize the PK of pomalidomide and to examine exposure-response relationship in pediatric patients with recurrent or progressive primary brain tumors.

Methods: Nonlinear mixed effects modeling was employed in developing a population PK model of pomalidomide using a total of 343 concentrations from 70 patients.

Concentration-QTc Modeling of Ozanimod's Major Active Metabolites in Adult Healthy Subjects.

Ozanimod, approved by regulatory agencies in multiple countries for the treatment of adults with relapsing multiple sclerosis, is a sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 and 5. The relationships between plasma concentrations of ozanimod and its major active metabolites, CC112273 and CC1084037, and the QTc interval (C-QTc) from a phase I multiple-dose study in healthy subjects were analyzed using nonlinear mixed effects modeling. QTc was modeled linearly as the sum of a sex-related fixed effect, baseline, and concentration-related random effects that incorporated interindividual and residual variability.

First-in-Human, Single- and Multiple-Ascending-Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator.

Pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide (CC-220), a highly potent oral cereblon E3 ligase modulator (CELMoD), were evaluated in escalating single-dose (0.03, 0.1, 0.

Evaluation of iberdomide and cytochrome p450 drug-drug interaction potential in vitro and in a phase 1 study in healthy subjects.

Purpose: Iberdomide is a cereblon E3 ligase modulator capable of redirecting the protein degradation machinery of the cell towards the elimination of target proteins potentially driving therapeutic effects. In vitro studies demonstrated that iberdomide predominantly undergoes oxidative metabolism mediated by cytochrome P450 (CYP) 3A4/5 but had no notable inhibition or induction of CYP enzymes. Consequently, the potential of iberdomide as a victim of drug-drug interactions (DDI) was evaluated in a clinical study with healthy subjects.

Excretion balance and pharmacokinetics following a single oral dose of [C]-fedratinib in healthy subjects.

Purpose: Fedratinib is an oral and selective kinase inhibitor with activity against wild type and mutationally activated Janus kinase 2 and FMS-like tyrosine kinase 3, for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. This open-label mass balance study in healthy subjects investigated the excretion balance and systemic exposure of radioactivity after oral administration of [C]-fedratinib; and the pharmacokinetics of fedratinib and its contribution to overall exposure of radioactivity.

Methods: Six healthy males received a single oral dose of 200 mg [C]-fedratinib base (2.

A Phase 1, Open-Label Study in Healthy Subjects to Evaluate the Absolute Bioavailability of AG-221 by a Microtracer Approach.

Introduction: The purpose of this study was to evaluate the absolute bioavailability (BA) of AG-221 following a single oral dose of 100 mg AG-221 and an intravenous (IV) dose of ~ 100 μg AG-221 containing approximately 300 nCi of [C]-AG-221.

Methods: This was a phase 1, open-label study. Six subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled in the study.

Evaluation of the Potential for QTc Prolongation With Repeated Oral Doses of Fedratinib in Patients With Advanced Solid Tumors.

The impact of repeated daily 500-mg fedratinib (an oral selective Janus kinase [JAK] 2 inhibitor) on QTc and other electrocardiogram (ECG) parameters was assessed in 60 patients with advanced solid tumors. Patients received placebo on day 1 and fedratinib 500 mg daily for 14 days. Concentration-QTc analysis was performed with change-from-baseline QTc corrected by Fridericia's formula (ΔQTcF) as the dependent variable.

Pharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies.

Background: Voclosporin, a more potent derivative of cyclosporine, has been studied extensively in patients with immunologic disorders such as psoriasis, organ transplantation, uvetitis and lupus nephritis. Although better tolerated and safer than cyclosporine, voclosporin is inferior to cyclosporine in treating psoriasis, non-inferior to tacrolimus in organ transplantation and efficacious in treating lupus nephritis.

Methods: The pharmacokinetic dispositions of voclosporin and cyclosporine in central and peripheral compartments were analyzed and correlated with their distinct clinical efficacy and safety profiles.