A Pharmacokinetic, Safety, and Tolerability Trial of Palovarotene in Healthy Japanese and Non-Japanese Participants

Abstract

Background and ObjectivePalovarotene is an oral, selective retinoic acid receptor gamma agonist under investigation for fibrodysplasia ossificans progressiva (FOP). Palovarotene is primarily metabolized by cytochrome P450 (CYP) 3A4. Differences in CYP-mediated metabolism of CYP substrates have been observed between Japanese and non-Japanese individuals. This phase I trial (NCT04829786) compared the pharmacokinetic profile of palovarotene in healthy Japanese and non-Japanese participants and evaluated the safety of single doses. Methods Healthy Japanese and non-Japanese participants were matched individually (1:1) and randomized to receive a single oral dose of palovarotene 5 or 10 mg, followed by the alternate dose after a 5-day washout period. Maximum plasma drug concentration (C max ) and area under the plasma concentration-time curve (AUC) were assessed. Estimates of the geometric mean difference between dose and Japanese and non-Japanese groups were calculated for natural log-transformed C max and AUC parameters. Adverse events (AEs), serious AEs, and treatment-emergent AEs were recorded. Results Eight pairs of matched non-Japanese and Japanese individuals and two unmatched Japanese individuals participated. Mean plasma concentration-time profiles were similar between the two cohorts at both dose levels, demonstrating that palovarotene absorption and elimination are similar irrespective of dose level. The pharmacokinetic parameters of palovarotene were similar between groups at both dose levels. C max and AUC values were dose-proportional between doses in each group. Palovarotene was well tolerated; there were no deaths or AEs leading to treatment discontinuation. Conclusions Japanese and non-Japanese groups had similar pharmacokinetic profiles, indicating that palovarotene dose adjustments are not necessary for Japanese patients with FOP.

The Pharmacokinetic Profile of Palovarotene: An Open-Label Phase I Trial Investigating the Effect of Food and Potential for Drug–Drug Interaction in Healthy Participants

“…Generalizability may also be limited since this trial was conducted at a single center in the US. However, pharmacokinetic phase I trials are typically conducted at a single site, and an ethnic sensitivity trial found no differences in the pharmacokinetics and safety of palovarotene between healthy Japanese and non-Japanese participants [ 33 ].…”

Palovarotene approved as first treatment for fibrodysplasia ossificans progressiva (FOP)

“…The safety of palovarotene was assessed in a double-blind, randomized, crossover, single-dose phase I trial in Japan with both local and international healthy participants. The results showed that palovarotene was well tolerated and metabolized identically in both Japanese and non-Japanese individuals, indicating its potential for global effectiveness and applicability [9]. Two trials studied the efficacy of palovarotene in patients with FOP.…”