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Open Access 20-04-2024 | Midazolam | Original Article

Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors

Authors: Claire Miller, Roberto Sommavilla, Cindy L. O’Bryant, Minal Barve, Afshin Dowlati, Jason J. Luke, Mahmuda Khatun, Thomas Morris, Marie Cullberg

Published in: Cancer Chemotherapy and Pharmacology

Abstract

Purpose

Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials in advanced breast and prostate cancer. This study evaluated the drug–drug interaction risk of capivasertib with the cytochrome P450 3A substrate midazolam in previously treated adults with advanced solid tumors.

Methods

Patients received oral capivasertib 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 days off) starting on day 2 of cycle 1 (29 days) and on day 1 of each 28-day cycle thereafter. In cycle 1 only, patients received oral midazolam (1 mg) on day 1 (alone), and days 8 and 12 (3rd day off and 4th day on capivasertib, respectively). Midazolam pharmacokinetics on days 8 and 12 were analyzed versus day 1. Capivasertib, with or without standard-of-care treatment, was continued in patients deemed likely to benefit. Safety and exploratory efficacy analyses were conducted.

Results

Capivasertib–midazolam coadministration increased midazolam exposure (n = 21): geometric mean ratio (90% confidence interval) AUC_inf and C_max was 1.13 (0.97–1.32) and 1.15 (0.99–1.33) for day 8 versus day 1, and 1.75 (1.50–2.05) and 1.25 (1.08–1.46) for day 12 versus day 1. The capivasertib safety profile was manageable when administered with or without midazolam. Two patients had partial responses to treatment.

Conclusion

The up to 1.75-fold increase in midazolam exposure indicates capivasertib is a weak CYP3A inhibitor at 400 mg BID on an intermittent schedule. Capivasertib was well tolerated; exploratory efficacy analysis demonstrated evidence of clinical activity in this heavily pre-treated population.

ClinicalTrials.gov: NCT04958226.

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Title: Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors
Authors: Claire Miller
Roberto Sommavilla
Cindy L. O’Bryant
Minal Barve
Afshin Dowlati
Jason J. Luke
Mahmuda Khatun
Thomas Morris
Marie Cullberg
Publication date: 20-04-2024
Publisher: Springer Berlin Heidelberg
Keywords: Midazolam
Pharmacokinetics
Solid Tumor
Published in: Cancer Chemotherapy and Pharmacology
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-024-04667-3

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