INTRODUCTION: Balovaptan, an investigational vasopressin 1a receptor antagonist 
that has been evaluated for improvement of social communication and interaction, 
is primarily metabolized by cytochrome P450 3A4 (CYP3A4).
METHODS: Two single-center, non-randomized, two-period, phase 1 studies assessed 
the effect of the strong CYP3A4 inhibitor itraconazole (study NCT03579719) or 
the strong CYP3A4 inducer rifampicin (study NCT03586726) at steady state on the 
pharmacokinetics (PK) of steady-state balovaptan in healthy volunteers. 
Participants received balovaptan (5 or 10 mg/day) alone for 10 days, or in 
combination with itraconazole (200 mg/day) for 15 days, or rifampicin 
(600 mg/day) for 10 days, following balovaptan washout and 
itraconazole/rifampicin pre-dosing. Geometric mean ratios (GMRs) and 90% 
confidence intervals (90% CIs) for the area under the concentration-time curve 
over the dosing interval (AUC) and maximum plasma concentration (Cmax) of 
balovaptan dosed with vs. without itraconazole/rifampicin were estimated from a 
mixed effects model.
RESULTS: Both studies comprised 15-16 healthy male and female volunteers. 
Itraconazole 200 mg/day elevated steady-state exposure to 5 mg/day balovaptan 
approximately 4.5-5.5-fold (Day 15 GMR [90% CI], 4.46 [4.06-4.90] for Cmax and 
5.57 [5.00-6.21] for AUC) and extended the time to steady state from ~ 5 days 
to ~ 13-14 days. Rifampicin 600 mg/day resulted in ~ 90% reductions in both the 
Cmax (Day 10 GMR [90% CI], 0.14 [0.12-0.15]) and AUC (0.07 [0.06-0.07]) of 
balovaptan 10 mg/day. Time to balovaptan steady state could not be determined 
with rifampicin. There were no clinically significant safety findings in either 
study.
CONCLUSIONS: Strong modulators of CYP3A4 activity will significantly alter the 
PK of balovaptan, with the effect of CYP3A4 induction greater than that of 
inhibition. Caution should be taken when concomitantly dosing balovaptan with 
moderate or strong CYP3A4 inducers or strong CYP3A4 inhibitors.
TRIAL REGISTRATION NUMBER: NCT03579719; NCT03586726.