Evidence-Based Exploration of Exposure-Matched Candidate Pirfenidone Dose for East Asian Populations based on Population Pharmacokinetic Modeling and Simulation Approach

Purpose The approved maximum daily dose of pirfenidone for idiopathic pulmonary fibrosis (IPF) differs between East Asian (1,800 mg) and non-East Asian (2,400 mg) populations. This study aimed to explore exposure-matched candidate doses for East Asian populations by using population pharmacokinetic (popPK) modeling and simulations to compare the systemic exposure. Methods A popPK model for East Asians was developed using data from 50 healthy subjects. The East Asian model and a non-East Asian reference model from a U.S. Food and Drug Administration (FDA) review document were used in simulation studies to estimate exposure-matched candidate doses for East Asian populations under both healthy-subject condition and IPF-patient assumption. Findings A two-compartment popPK model for East Asians was developed with first-order absorption and elimination kinetics, incorporating body weight as a covariate on the volume of distribution for the central compartment. Under the healthy-subject condition, median-based candidate doses were 519 mg and 531 mg per administration based on area under the concentration-time curve of the dosing interval ( AUC tau,ss ) and peak concentrations ( C max,ss ), respectively. Under the IPF-patient assumption, the corresponding doses were 470 mg and 503 mg, respectively. Both conditions yielded candidate doses lower than the approved maximum practical dose of 600 mg per administration for East Asians. Implications To achieve systemic exposure comparable to that of the maximum practical dose in non-East Asians, East Asian patients with IPF may require a lower dose than is currently approved. These findings provide a quantitative rationale for the prospective evaluation of lower-dose pirfenidone regimens in East Asian patients.