PII-098 - PBPK MODELING TO ASSESS DRUG-DRUG INTERACTION POTENTIAL OF VENGLUSTAT WITH CYP3A INHIBITORS.

J. Sharma¹, L. Li², S. Macha¹, C. Xu¹, J. Sahi³, y. Zhang²; ¹Sanofi, Bridgewater, NJ, USA, ²Sanofi, Shanghai, China, ³Sanofi, Cambridge, MA, USA.

Background: Venglustat is an oral glucosylceramide synthase inhibitor under development for treatment of Fabry disease, Gaucher’s Type 3 (GD3) disease, and second monosialic ganglioside (GM2) gangliosidosis. Venglustat is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6. The objective of this analysis is to develop and validate a physiologically based pharmacokinetic (PBPK) model to assess the effect of CYP3A inhibitors on venglustat PK.

Methods: Physicochemical, in vitro, and in vivo PK data of venglustat were used to develop a PBPK model with first order absorption, minimal distribution with single adjusting compartment, and enzyme kinetics and renal excretion for elimination. The model was validated by comparing predicted to observed PK from clinical studies of venglustat including a drug-drug interaction (DDI) study with itraconazole, a strong CYP3A inhibitor. Finally, the model was used to predict DDI potential of venglustat with moderate and weak CYP3A inhibitors.

Results: The model performance was confirmed by predicted to observed venglustat exposure ratios of 0.93 to 1.2 after single or repeated oral doses and 1.1 to 1.3 for venglustat alone or when co-administered with itraconazole. Venglustat exposure following co-administration with moderate (fluconazole, and fluvoxamine with CYP2D6 inhibition turned off) and weak (cimetidine with CYP2D6 inhibition turned off) CYP3A inhibitors were predicted to be 1.52-, 1.08-, and 1.08-fold higher compared to venglustat alone, respectively.

Conclusion: Venglustat PBPK model was successfully developed and validated. The validated PBPK model was used to predict DDI of venglustat with moderate and weak CYP3A inhibitors.