Drug-drug interaction study with itraconazole supplemented with physiologically based pharmacokinetic modelling to characterize the effect of CYP3A inhibitors on venglustat pharmacokinetics

Aims: Venglustat is an oral glucosylceramide synthase inhibitor under clinical investigation to treat various lysosomal storage diseases. Metabolism is a main pathway for its elimination in humans with CYP3A being the major contributor. This study aims to evaluate effect of CYP3A inhibition (using itraconazole) on venglustat exposure and to develop and validate a physiologically based pharmacokinetic (PBPK) model to assess effects of additional CYP3A inhibitors of varying potencies on venglustat pharmacokinetics. Methods: An open-label, single-sequence, 2-period drug-drug interaction (DDI) study was conducted in healthy subjects with coadministration of multiple twice daily oral doses of 100 mg itraconazole against a single dose of 15 mg venglustat. A minimal PBPK model was developed using available physicochemical, in vitro and in vivo pharmacokinetic data and validated using data from relevant venglustat clinical studies including the itraconazole DDI study. Effects of additional CYP3A inhibitors on venglustat exposure were predicted. Results: Coadministration with itraconazole increased venglustat area under the concentration-time curve by 2.03-fold (90% confidence interval [90%CI]: 1.81-2.27). Venglustat steady-state area under the concentration-time curve during a dosing interval following coadministration with strong (clarithromycin), moderate (fluconazole) and weak (fluvoxamine and cimetidine; with CYP2D6 inhibition turned off) CYP3A inhibitors is predicted to increase by 1.74- (5th-95th centile, 1.30-2.49), 1.52- (1.23-1.88), 1.08- (1.03-1.15) and 1.08-fold (1.04-1.12), respectively. Conclusion: The effect of itraconazole on venglustat exposure was quantified clinically, and a minimal PBPK model was successfully developed, validated and applied to assess DDI effect of additional CYP3A inhibitors on venglustat. The results help to further understand the DDI potential with venglustat and will inform dose recommendations with comedications.