Effect of Rifampicin on the Pharmacokinetics of Valemetostat and Its Primary Metabolite: A Phase 1 Study in Healthy Participants

ABSTRACT Valemetostat tosylate (valemetostat) is a dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, approved in Japan for the treatment of relapsed or refractory peripheral T‐cell lymphoma, including adult T‐cell leukemia/lymphoma, and globally under investigation for the treatment of non‐Hodgkin lymphomas and solid tumors. Valemetostat is a substrate of cytochrome P450 3A (CYP3A) and P‐glycoprotein (P‐gp) in vitro. This phase 1, open‐label, single‐sequence crossover study assessed the effect of repeated oral doses of rifampicin, a strong CYP3A and P‐gp inducer, on the pharmacokinetics (PK) of valemetostat in healthy Japanese participants. In this trial, 20 participants received two doses of valemetostat 200 mg, once alone and once after repeated daily doses of rifampicin 600 mg. Coadministration with rifampicin decreased the maximum plasma concentration ( C max ) and area under the plasma concentration–time curve extrapolated to infinity (AUC inf ) of total valemetostat. The geometric least‐squares mean ratios (GMR, test/reference) for C max and AUC inf were 0.417 [90% confidence interval (CI), 0.319–0.545] and 0.286 [90% CI, 0.225–0.364], respectively. C max of CALZ‐1809a (a major valemetostat oxidative metabolite) increased (GMR, 1.287 [90% CI, 1.036–1.600]), while the AUC inf decreased (GMR, 0.713 [90% CI, 0.573–0.886]). No treatment‐related or Grade ≥ 2 adverse events were reported. These results showed that valemetostat exposure was reduced upon coadministration of rifampicin, suggesting that concomitant use of valemetostat with strong CYP3A and P‐gp inducers should be avoided. Trial Registration: Japan Registry: jRCT2080225242