Open-Label Assessment of the Effects of Itraconazole and Rifampicin on Balovaptan Pharmacokinetics in Healthy Volunteers
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BRIEF REPORT
Open-Label Assessment of the Effects of Itraconazole and Rifampicin on Balovaptan Pharmacokinetics in Healthy Volunteers Michael G. M. Derks
. Christoph Wandel . Annie Young .
Stuart K. Bolt . Christoph Meyenberg
Received: July 17, 2020 / Accepted: August 28, 2020 Ó Springer Healthcare Ltd., part of Springer Nature 2020
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 preDigital Features To view digital features for this article go to https://doi.org/10.6084/m9.figshare.12888368. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12325020-01491-y) contains supplementary material, which is available to authorized users. M. G. M. Derks (&) A. Young S. K. Bolt Roche Products Ltd, Welwyn Garden City, UK e-mail: [email protected] C. Wandel C. Meyenberg F. Hoffmann-La Roche AG, Basel, Switzerland
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 4.5–5.5fold (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.
Adv Ther
Keywords: Autism spectrum disorder; Balovaptan; CYP3A4; Drug-drug interaction; Itraconazole; Pharmacokinetics; Rifampicin Key Summary Points Pharmacotherapeutic modulators of cytochrome P
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