PII-040 - PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELLING OF VALEMETOSTAT TO INFORM DOSE RECOMMENDATIONS WHEN CO-ADMINISTERED WITH CYP3A/P-GP MODULATORS.

A. Watanabe¹, N. Okudaira², M. Tachibana¹, T. Shimizu¹, Y. Lau³; ¹Daiichi Sankyo, Tokyo, Japan, ²Certara, Tokyo, Japan, ³Daiichi Sankyo, Basking Ridge, NJ, USA.

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. From in vitro and the clinical studies, valemetostat is assumed to be pre-systematically metabolized by CYP3A in gut and excreted into bile and urine via P-gp as an unchanged form and oxidative metabolites. A physiologically based pharmacokinetic (PBPK) model was developed for valemetostat to assess the impact of CYP3A/P-gp modulators.

Methods: The valemetostat PBPK model was developed in Simcyp V19. The contributions of CYP3A and P-gp in both gut and liver were incorporated in the model based on in vitro data and optimized using clinical data including a drug-drug interaction (DDI) study with fluconazole (a moderate CYP3A inhibitor). The model was validated by clinical DDI studies with itraconazole (a P-gp and strong CYP3A inhibitor) and rifampicin (a P-gp and strong CYP3A inducer). and then applied to predict the effect of CYP3A/P-gp modulators on the valemetostat PK.

Results: The developed model well characterized the valemetostat PK and recovered the DDIs with itraconazole (the observed AUCinf ratio: 4.19) and rifampicin (the observed AUCinf ratio: 0.286). The model predicted the valemetostat AUCinf increases to 2.67-fold when co-administered with a strong CYP3A inhibitor and 2.58-fold when the elimination route via P-gp is assumed to be completely inhibited. The effect of repeated dosing of efavirenz (a moderate CYP3A inducer) was also predicted to decrease the valemetostat AUCinf by 42.5%.

Conclusion: Valemetostat dose should be reduced when a strong CYP3A or P-gp inhibitor is co-administered. The concomitant use of moderate CYP3A inducers should be avoided.