1. Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors.
- Author
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Miller C, Sommavilla R, O'Bryant CL, Barve M, Dowlati A, Luke JJ, Khatun M, Morris T, and Cullberg M
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Pyrroles pharmacokinetics, Pyrroles administration & dosage, Pyrroles adverse effects, Pyrimidines pharmacokinetics, Pyrimidines administration & dosage, Pyrimidines adverse effects, Aged, 80 and over, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Midazolam pharmacokinetics, Midazolam administration & dosage, Neoplasms drug therapy, Cytochrome P-450 CYP3A metabolism, Drug Interactions
- 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 Cmax 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., (© 2024. The Author(s).)- Published
- 2024
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