PI-010 - A DDI STUDY TO EVALUATE THE EFFECT OF MULTIPLE ORAL ADMINISTRATION OF RIFAMPICIN ON THE PHARMACOKINETICS OF VALEMETOSTAT IN HEALTHY PARTICIPANTS.

A. Kurata¹, S. Matsuki², M. Fukae¹, S. Shinohara¹, M. Tachibana¹, T. Shimizu¹; ¹Daiichi Sankyo, Tokyo, Japan, ²ITA-MED Co., Fukuoka, Japan.

Background: Valemetostat is an orally administered dual inhibitor of enhancer of zeste homolog (EZH) 1 and EZH2 being investigated for the treatment of various types of cancers, including non-Hodgkin lymphomas and solid tumors. Valemetostat is identified as a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp) in vitro. This study assessed valemetostat pharmacokinetics when co-administered with rifampicin (a P-gp and strong CYP3A inducer) in healthy participants.

Methods: This phase 1, open-label, single-sequence crossover study enrolled 20 healthy participants. Participants received valemetostat 200 mg under fasted conditions on day 1. Participants received rifampicin 600 mg once daily on days 8-22. On day 16, participants received valemetostat 200 mg under fasted conditions, 2 hours after administration of rifampicin. Blood samples were collected, and plasma concentrations of valemetostat and its metabolite, CALZ-1809a, were measured by a validated LC-MS/MS method.

Results: The geometric least-squares mean (LSM) ratios (90% CIs) for valemetostat Cmax and AUCinf were 0.417 (0.319, 0.545) and 0.286 (0.225, 0.364) when co-administered with rifampicin vs alone, respectively. The mean t1/2 of valemetostat was 22.6 h after administration of valemetostat alone and 18.3 h after co-administration with rifampicin. For CALZ-1809a, a major metabolite formed by CYP3A, the geometric LSM ratios (90% CIs) for Cmax and AUCinf were 1.287 (1.036,1.600) and 0.713 (0.573, 0.886), respectively. No grade ≥2 treatment-emergent adverse events were reported in the study.

Conclusion: Multiple doses of rifampicin decreased valemetostat Cmax and AUCinf by approximately 60% and 70%, respectively. Therefore, concomitant use of valemetostat and strong CYP3A inducers should be avoided.