Sechaud, Romain, Gu, Helen, Rahmanzadeh, Gholamreza, Taylor, Amanda, Chiparus, Ovidiu, Sharma, Gopal Krishna, Breitschaft, Astrid and Menssen, Hans (2024) Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants. Cancer chemotherapy and pharmacology, 93 (5). pp. 439-453. ISSN 1432-0843

Abstract

Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants.Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2.In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported.Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.

Item Type:	Article
Keywords:	Humans Area Under Curve Bupropion Contraceptives, Oral Cytochrome P-450 CYP2B6 Cytochrome P-450 CYP2C8 Cytochrome P-450 CYP3A Drug Combinations Drug Interactions Ethinyl Estradiol Healthy Volunteers Levonorgestrel Midazolam Pioglitazone Staurosporine Male Female Adolescent Young Adult Adult Middle Aged
Date Deposited:	07 Jun 2024 00:46
Last Modified:	07 Jun 2024 00:46
URI:	https://oak.novartis.com/id/eprint/52028