Bioavailability and pharmacokinetic profile of balovaptan, a selective, brain-penetrant vasopressin 1a receptor antagonist, in healthy volunteers

ABSTRACT

Background

Balovaptan is a potent, selective vasopressin 1a receptor antagonist. The early-phase pharmacokinetics (PK) of balovaptan are reported.

Research design and methods

Two Phase 1 studies (overall N = 93) assessed single- and multiple-dose balovaptan PK in healthy adults. One (N = 16) assessed absolute oral bioavailability (10 mg or 50 mg) vs a [¹³C]-balovaptan microdose. The other (N = 77) explored single- (0.5–76 mg) and multiple-dose (14 days; 12–52 mg/day) – randomized 6:2 balovaptan:placebo per dose – PK, dose proportionality, and the effect of food on single-dose (32 mg) C_max and AUC_inf.

Results

Absolute balovaptan bioavailability was high (103–116%). Steady-state (Day 14) balovaptan PK was approximately dose proportional with a half-life of 45–47 hours, but single-dose C_max increased more than dose proportionally and half-life was inversely dose-proportional – a discordance partially attributable to a dose-and-time-dependent volume of distribution. Accumulation (Day 1–Day 14) was inversely dose-proportional (~3.5 [12 mg] to ~1.8 [52 mg]). There was no relevant effect of a high-fat meal on single-dose balovaptan exposure. There were no safety signals: 2/93 subjects discontinued for adverse events.

Conclusions

Balovaptan was well tolerated at single (≤76 mg) and multiple (≤52 mg/day) doses, with a PK profile supportive of once-daily administration without food restrictions.

Trial registration

ClinicalTrials.gov NCT03764449; NCT01418963.

KEYWORDS:

• Balovaptan
• vasopressin 1a
• pharmacokinetics
• bioavailability
• healthy volunteers

Acknowledgments

Writing and editorial assistance was provided by Nick Fitch of Articulate Science, UK.

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Declaration of interest

All authors are employees of F. Hoffmann La-Roche Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Author contributions

MD was involved in the development of the study design, protocol, and clinical study report. HK wrote and signed the protocol and study report of the study. CW and PS were the safety physicians involved in development of the study protocol, safety monitoring, and reporting of the results. AG and SL-C were the clinical pharmacologists responsible for the PK analysis of the study. AP involved in the drug metabolism and PK scientist responsible for study design and the PK analysis of the study. LS was the statistician of the study. All authors reviewed, commented on, and approved the manuscript.

Supplementary material

Supplemental data for this article can be accessed here.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

These studies were funded by F. Hoffmann-La Roche Ltd.