Summary:
In healthy adult volunteers (Japanese n=20-21, non-Japanese n=20-21), single-dose cilofexor 100 mg or firsocostat 20 mg showed higher plasma exposure in Japanese participants: cilofexor AUCinf 1.24-fold higher, firsocostat AUCinf ~2-fold higher compared to non-Japanese participants, with both drugs well-tolerated in both populations, no dose adjustment required based on prior safety data.
| PICO | Description |
|---|---|
| Population | Healthy adult volunteers: Japanese (n=20-21) and non-Japanese (n=20-21). |
| Intervention | Single-dose cilofexor 100 mg or firsocostat 20 mg with intensive PK sampling. |
| Comparison | PK parameters compared between Japanese and non-Japanese participants. |
| Outcome | Higher exposure in Japanese (1.24-2x). Well-tolerated. No dose adjustment needed. |
Clinical Context
NASH drug development requires ethnic PK bridging studies. Cilofexor (FXR agonist) and firsocostat (ACC inhibitor) are being developed for NASH.
Clinical Pearls
1. Ethnic PK Differences Are Common: Factors include body weight, CYP enzyme polymorphisms, and transporter variations.
2. Higher Exposure Doesn’t Always Require Dose Adjustment: Prior trials established safety at much higher doses.
3. Safety Margin Concept: Ethnic differences fall within established safety ranges.
4. Healthy Volunteer Studies Inform Patient Trials: Results inform dosing for subsequent patient studies.
Practical Application
Standard doses can be used in Asian patients without ethnic-specific adjustments. Both drugs remain investigational for NASH.
Study Limitations
Single-dose study in healthy volunteers. Small sample sizes. Steady-state PK in NASH patients could differ.
Bottom Line
Japanese show 1.24-2x higher exposure for cilofexor/firsocostat vs non-Japanese. Well-tolerated, no dose adjustment needed.
Source: Younis IR, et al. “Pharmacokinetics and Safety of Cilofexor and Firsocostat in Healthy Japanese and Non-Japanese Participants.” J Clin Pharmacol. 2024. Read article