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

• DOI: 10.1007/s00280-024-04667-3
• Publication Date: 2024-04-21T03:04:17Z
• Authors: Claire Miller; Roberto Sommavilla; Cindy L. O’Bryant; Minal Barve; Afshin Dowlati; Jason J. Luke; Mahmuda Khatun; Thomas Morris; Marie Cullberg
• Keywords: Midazolam; CYP3A

Abstract Purpose Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials advanced breast and prostate cancer. This study the drug–drug interaction risk capivasertib with cytochrome P450 3A substrate midazolam previously treated adults solid tumors. Methods Patients received oral 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 off) starting day 2 cycle 1 (29 days) each 28-day thereafter. In only, patients (1 mg) (alone), 8 12 (3rd off 4th capivasertib, respectively). Midazolam pharmacokinetics were analyzed versus 1. or without standard-of-care treatment, was continued deemed likely to benefit. Safety exploratory efficacy analyses conducted. Results Capivasertib–midazolam coadministration increased exposure ( n = 21): geometric mean ratio (90% confidence interval) AUC inf C max 1.13 (0.97–1.32) 1.15 (0.99–1.33) for 1, 1.75 (1.50–2.05) 1.25 (1.08–1.46) The safety profile manageable when administered midazolam. Two had partial responses treatment. Conclusion up 1.75-fold increase indicates weak CYP3A at BID schedule. Capivasertib well tolerated; analysis demonstrated evidence clinical activity this heavily pre-treated population. ClinicalTrials.gov: NCT04958226.