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1.
Cancer Chemother Pharmacol ; 93(5): 439-453, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38270613

RESUMO

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.


Assuntos
Bupropiona , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A , Interações Medicamentosas , Midazolam , Estaurosporina , Humanos , Área Sob a Curva , Bupropiona/farmacocinética , Bupropiona/administração & dosagem , Anticoncepcionais Orais/administração & dosagem , Anticoncepcionais Orais/farmacologia , Anticoncepcionais Orais/farmacocinética , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Combinação de Medicamentos , Etinilestradiol/farmacocinética , Etinilestradiol/administração & dosagem , Etinilestradiol/farmacologia , Voluntários Saudáveis , Levanogestrel/farmacocinética , Levanogestrel/administração & dosagem , Levanogestrel/farmacologia , Midazolam/farmacocinética , Midazolam/administração & dosagem , Pioglitazona/farmacologia , Pioglitazona/administração & dosagem , Pioglitazona/farmacocinética , Estaurosporina/análogos & derivados , Estaurosporina/farmacologia , Estaurosporina/farmacocinética , Estaurosporina/administração & dosagem , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade
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