Abstract
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.
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Change history
05 March 2024
A Correction to this paper has been published: https://doi.org/10.1007/s00280-024-04657-5
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Gu H, Sechaud R, Hanna I, Pelis R, Einolf H (manuscript in preparation) Physiologically based pharmacokinetic modeling of midostaurin and metabolites at steady state to bridge drug interaction scenarios in lieu of clinical trials
Acknowledgements
The authors thank all the investigators, trial site staff, and volunteers who participated in the trials. The authors thank Vennila Dharman MBBS (Novartis Healthcare Pvt. Ltd. India) for providing medical writing support in accordance with Good Publication Practice (GPP4) guidelines.
Funding
The studies were funded by Novartis.
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RS, HG, GR, AT, OC, GKS, AB, and HDM performed conception and design, data review and interpretation, drafting the manuscript, critical revision of the manuscript for important intellectual content, and final approval of the manuscript.
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R Sechaud, G Rahmanzadeh, and H Menssen are employees of Novartis Pharma AG, Switzerland. H Gu, A Taylor, O Chiparus, are employees of Novartis Pharmaceuticals Corporation, USA. GK Sharma is an employee of Novartis Healthcare Pvt. Ltd., India. A Breitschaft is an employee of Parexel International GmbH, Germany.
Ethical approval and informed consent
Both the studies were performed in accordance with the ethical principles, which have their origin in the Declaration of Helsinki and are consistent with Good Clinical Practice and applicable regulatory requirements. All participants of the study provided written informed consent according to international standards. Both studies were conducted at the Early Phase Clinical Unit of PAREXEL International GmbH in Berlin, Germany. The study protocols were reviewed and approved by the State Office of Health and Social Affairs Ethics Committee of Berlin (Landesamt für Gesundheitund Soziales Ethik-Kommission des Landes Berlin) for PAREXEL International GmbH. Study 1 with CYP substrates and Study 2 with oral contraceptives were registered under EudraCT number: 2018-002786-19 and EudraCT number: 2018-002867-25, respectively, and both obtained a favorable opinion from the IEC. The study participants were informed about the study procedures, risks, and benefits of their participation. Informed consent was documented by the investigator.
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Sechaud, R., Gu, H., Rahmanzadeh, G. et al. Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants. Cancer Chemother Pharmacol 93, 439–453 (2024). https://doi.org/10.1007/s00280-023-04635-3
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DOI: https://doi.org/10.1007/s00280-023-04635-3