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. Mavacamten exposure-response models for VLVOTg (efficacy) and LVEF (safety) were developed using patient data from five clinical studies and characterized using nonlinear mixed-effects models. Simulations of five echocardiography-guided regimens were performed in virtual cohorts constructed based on either expected or equal population distributions of cytochrome P450 2C19 (CYP2C19) metabolizer phenotypes. Each regimen aimed to maximize the proportions of patients who achieved a VLVOTg below 30 mm Hg while maintaining LVEF above 50% over 40 weeks and 104 weeks, respectively. The exposure-response models successfully characterized mavacamten efficacy and safety parameters. Overall, the simulated regimen with the optimal benefit-risk profile across CYP2C19 phenotypes had steps for down-titration at weeks 4 and 8 (for VLVOTg <20 mm Hg), and up-titration at week 12 (for VLVOTg ≥30 mm Hg and LVEF ≥55%), and every 12 weeks thereafter. This simulation-optimized regimen is recommended in the mavacamten US prescribing information.

PmWebSpec: An Application to Create and Manage CDISC-Compliant Pharmacometric Analysis Dataset Specifications.

A well-documented pharmacometric (PMx) analysis dataset specification ensures consistency in derivations of the variables, naming conventions, traceability to the source data, and reproducibility of the analysis dataset. Lack of standards in creating the dataset specification can lead to poor quality analysis datasets, negatively impacting the quality of the PMx analysis. Standardization of the dataset specification within an individual organization helps address some of these inconsistencies. The recent introduction of the Clinical Data Interchange Standards Consortium (CDISC) Analysis Data Model (ADaM) Population Pharmacokinetic (popPK) Implementation Guide (IG) further promotes industry-wide standards by providing guidelines for the basic data structure of popPK analysis datasets. However, manual implementation of the standards can be labor intensive and error-prone. Hence, there is still a need to automate the implementation of these standards. In this paper, we present PmWebSpec, an easily deployable web-based application to facilitate the creation and management of CDISC-compliant PMx analysis dataset specifications. We describe the application of this tool through examples and highlight its key features including pre-populated dataset specifications, built-in checks to enforce standards, and generation of an electronic Common Technical Document (eCTD)-compliant data definition file. The application increases efficiency, quality and semi-automates PMx analysis dataset, and specification creation and has been well accepted by pharmacometricians and programmers internally. The success of this application suggests its potential for broader usage across the PMx community.

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation.

This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I-III studies. Apixaban exposure was characterized by a two-compartment PPK model with first-order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P-glycoprotein (P-gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non-Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P-gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose-reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5-mg and 5-mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant.