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

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.