PII-166 - DEVELOPMENT OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL FOR BALOVAPTAN AND ITS MAJOR METABOLITE TO EVALUATE THEIR CYP3A4-MEDIATED VICTIM DRUG-DRUG INTERACTION (DDI) LIABILITY

A. Olivares-Morales¹, Z. Barter², A. Amponsah², C. Bissantz¹, M. Derks¹; ¹Roche Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, ²Certara.

Background: Balovaptan is a potent and selective human vasopressin 1a (V1a) receptor antagonist under development for the treatment post-traumatic stress disorder (PTSD). Balovaptan is highly permeable, its oral bioavailability is complete, and it’s predominantly eliminated by CYP3A4-mediated metabolic clearance. The main metabolite of balovaptan (M3) has been shown also predominantly to be metabolized by CYP3A4

Methods: A fit for purpose PBPK model based on prior in vitro and in vivo information on the metabolism and PK of balovaptan and its M3 metabolite was developed in SimCYP v18 (Certara, UK). A combination of in vitro and clinical PK data obtained following administration of multiple oral 5 mg and 12 mg doses of balovaptan in healthy subjects were used to develop the PBPK model. The fmCYP3A4 of balovaptan and its M3 metabolite were optimized using the results of a human DDI study in the presence of itraconazole (a strong CYP3A inhibitor)

Results: The final model-predicted geometric mean (gmean) Cmax and AUC ratios of balovaptan were within 1.25-fold of the observed values of 4.46 and 5.57, whereas for the M3 metabolite the gmean Cmax and AUC ratios of M3 were within 1.28-fold of the observed values of 1.43 and 1.42, respectively. The final PBPK models were then verified by comparing predicted balovaptan and M3 Cmax and AUC values with observed values following multiple dosing of 40 mg QD balovaptan to healthy subjects and the predictions were within 1.5-fold of the reported values. Furthermore, the effect of the strong inducer rifampicin on the PK of balovaptan and its M3 metabolite were simulated using the PBPK model, and the predicted gmean ratios for balovaptan and M3 AUC were compared with reported values from a DDI study following co-administration of rifampicin with multiple doses of balovaptan (10 mg QD) and were within 1.33-fold. Finally, prospective PBPK simulations in the presence of moderate and weak CYP3A4 inhibitors and moderate inducers were conducted to assess intermediate DDI risks and presented in Table 1.

Conclusion: In conclusion, moderate (AUCr ≥ 2 and < 5) to no interactions (AUCr < 1.25) for both balovaptan and M3 were predicted for moderate and weak inhibitors, whereas moderate CYP3A4 inducers are expected to have moderate interactions for both balovaptan and M3.