Characterizing Population Pharmacokinetics of Vatiquinone in Healthy Volunteers and Patients with Friedreich's Ataxia.

Abstract

Introduction: Vatiquinone is a first-in-class, small molecule designed to maintain mitochondrial function in the disorders like Friedreich's ataxia (FA). Vatiquinone inhibits 15-lipoxygenase, consequently decreasing oxidative stress and neuroinflammatory response pathways. Methods: Population pharmacokinetic modeling analysis was conducted to characterize vatiquinone pharmacokinetic profiles in healthy volunteers and patients and explore the effects of covariates on vatiquinone exposures. Results: A two-compartment model with parallel zero- and first-order absorption was developed and verified. The values of essential parameters were: absorption fraction through the first-order process, 74.4%; absorption rate constant, 0.20 h^-1; delay time, 2.79 h; zero-order absorption duration, 6.03 h; apparent volume of distribution, 180.75 L for the central and 4852.69 L for the peripheral compartment; and apparent clearance, 162.72 L/h. Strong CYP3A4 inducers could reduce exposure by 50%; strong CYP3A4 inhibitors could increase it by 252%. Vatiquinone exposure was 19% lower in patients with Friedreich's ataxia versus healthy volunteers. A medium-fat meal increased exposure up to 25-fold versus a fasted status. Body weight and body mass index had significant clinical relevance to exposures. Conclusions: A two-compartment model effectively described the pharmacokinetic profiles of vatiquinone after oral administration. Covariates significantly impacted exposures, including body weight, meals, disease status, comedications and body mass index.