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Open-Label Assessment of the Effects of Itraconazole and Rifampicin on Balovaptan Pharmacokinetics in Healthy Volunteers

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Abstract

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.

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Acknowledgements

The authors would like to acknowledge and thank the participants in both studies described herein.

Funding

These studies and the journal’s Rapid Service Fee were funded by F. Hoffmann-La Roche Ltd.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Medical Writing and Editorial Assistance

Writing and editorial assistance for this article was provided by Clare Davis of ArticulateScience, UK. Support for this assistance was funded by F. Hoffmann-La Roche Ltd.

Prior Presentation

These studies have previously been presented at the INSAR 2020 Annual Meeting.

Disclosures

Michael G M Derks, Christoph Wandel, Annie Young and Stuart K Bolt are employees of F. Hoffmann-La Roche Ltd. Christoph Meyenberg is an employee of CRO KOEHLER eClinical, Freiburg, Germany, which is contracted to work on behalf of F. Hoffmann-La Roche Ltd.

Compliance with Ethics Guidelines

Each study was conducted in full accordance with the principles of the Declaration of Helsinki and Good Clinical Practice, and compliant with the European Union Clinical Trial Directive. Informed consent forms were reviewed and approved by the Dutch Independent Ethics Committee of the Foundation “Beoordeling Ethiek Biomedisch Onderzoek.” All subjects provided written informed consent before participation.

Data availability

Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

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Authors and Affiliations

  1. Roche Products Ltd, Welwyn Garden City, UK

    Michael G. M. Derks, Annie Young & Stuart K. Bolt

  2. F. Hoffmann-La Roche AG, Basel, Switzerland

    Christoph Wandel & Christoph Meyenberg

Authors
  1. Michael G. M. Derks
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  2. Christoph Wandel
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Corresponding author

Correspondence to Michael G. M. Derks.

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Derks, M.G.M., Wandel, C., Young, A. et al. Open-Label Assessment of the Effects of Itraconazole and Rifampicin on Balovaptan Pharmacokinetics in Healthy Volunteers. Adv Ther 37, 4720–4729 (2020). https://doi.org/10.1007/s12325-020-01491-y

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