Pharmacokinetic Evaluation of CYP3A4-Mediated Drug-Drug Interactions of Isavuconazole With Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults
Robert Townsend,Albert J. Dietz,Christine Hale,Shahzad Akhtar,Donna Kowalski,Christopher Lademacher,Kenneth C. Lasseter,Helene Pearlman,Diane Rammelsberg,Anne Schmitt-Hoffmann,Takao Yamazaki,Amit Desai +11 more
TLDR
The phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and its effects on CYP3A 4‐mediated metabolism in healthy adults indicate that isavunazole is a sensitive substrate and moderate inhibitor of CYP4.Abstract:
This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazole's effects on CYP3A4-mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUCτ ) during a dosing interval by 90% and maximum concentration (Cmax ) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC0-∞ ) and Cmax by 422% and 9%, respectively. Isavuconazole was coadministered (200 mg 3 times daily for 2 days, then 200 mg once daily) with single doses of oral midazolam (3 mg; CYP3A4 substrate) or ethinyl estradiol/norethindrone (35 μg/1 mg; CYP3A4 substrate). Following coadministration, AUC0-∞ increased 103% for midazolam, 8% for ethinyl estradiol, and 16% for norethindrone; Cmax increased by 72%, 14%, and 6%, respectively. Most adverse events were mild to moderate in intensity; there were no deaths, and serious adverse events and adverse events leading to study discontinuation were rare. These results indicate that isavuconazole is a sensitive substrate and moderate inhibitor of CYP3A4.read more
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Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients.
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Pharmacokinetic Assessment of Drug‐Drug Interactions of Isavuconazole With the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults
Andreas H. Groll,Amit Desai,David Han,Corrie Howieson,Kota Kato,Shahzad Akhtar,Donna Kowalski,Christopher Lademacher,William Lewis,Helene Pearlman,Debra Mandarino,Takao Yamazaki,Robert Townsend +12 more
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Isavuconazole Treatment for Mucormycosis: A Single-Arm Open-Label Trial and Case-Control Analysis
Francisco M. Marty,Luis Ostrosky-Zeichner,Oliver A. Cornely,Kathleen M. Mullane,John R. Perfect,George Richard Thompson,George J Alangaden,Janice M. Brown,David N. Fredricks,Werner J. Heinz,Raoul Herbrecht,Nikolai Klimko,Galina Klyasova,Johan Maertens,Sameer R. Melinkeri,Ilana Oren,Peter G. Pappas,Zdeněk Ráčil,Galia Rahav,Rodrigo Ribeiro dos Santos,Stefan Schwartz,Jörg Janne Vehreschild,Jo Anne H. Young,Ploenchan Chetchotisakd,Sutep Jaruratanasirikul,Souha S. Kanj,Marc Engelhardt,Achim Kaufhold,Masanori Ito,Misun Lee,Carolyn Sasse,Rochelle Maher,Bernhardt Zeiher,Maria J G T Vehreschild +33 more
TL;DR: Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B, and can be used for treatment of mucormYcosis and is well tolerated.
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Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent
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