Semi-Mechanistic Joint Population Pharmacokinetic Modeling of the Novel Antituberculosis Drug Sorfequiline and Its Metabolite M3 in Healthy Volunteers

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• Picked for Pharmacology (medical) (paper of the day, 12 September 2026): Population PK model informs dosing in TB drug development clinical

Abstract

Sorfequiline is a novel diarylquinoline in development for treatment of tuberculosis. In vitro data suggest metabolism via CYP3A4, carrying the potential for presystemic metabolism and drug-drug interactions. Its major metabolite, M3, is pharmacologically active. We developed a semi-mechanistic joint population pharmacokinetic model of sorfequiline and M3 in healthy volunteers. Data were pooled from two studies (CL-001 and CL-002). CL-001 comprised a single-ascending-dose part (10-800 mg suspension fasted plus 100 mg fed), a multiple-ascending-dose part (25, 75, or 200 mg/day for 14 days, fed), and a relative bioavailability assessment including 100 mg in tablet form under fed and fasted conditions. In CL-002, fed participants received 200 mg/day suspension for 8 days followed by 165 mg/day for 4 days. Plasma concentrations were quantified using HPLC-MS/MS, and pharmacokinetic modeling and simulations were conducted in NONMEM. A three-compartment disposition model for both analytes, with transit-compartment absorption, adequately described the data. A fraction of the dose was assumed to be absorbed as M3 due to gut first-pass metabolism. This fraction was 46% (95% CI: 41%-50%) in fasted and 15% (13%-19%) in fed participants. Overall bioavailability decreased by 46% (32%-61%) at fasted doses ≥ 400 mg. Model-based simulations showed that exposures for all investigated regimens remained below safety reference values. Food reduced the fraction of sorfequiline dose absorbed as M3, likely due to limited gut first-pass metabolism. The developed model provides an initial platform for future pharmacokinetic/pharmacodynamic analyses and simulation of both analytes' exposures under drug-drug interaction scenarios.

Abstract as published, via PubMed.