Pharmacokinetic Evaluation of CYP3A4-Mediated Drug-Drug Interactions of Isavuconazole With Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults.
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 Cmaxby 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; Cmaxincreased 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.
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Robert
R
Townsend
Spaulding Clinical Research, LLC, West Bend, WI, USA.
Albert
A
Dietz
Covance Clinical Research, Madison, WI, USA.
Christine
C
Hale
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Shahzad
S
Akhtar
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Donna
D
Kowalski
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Christopher
C
Lademacher
Clinical Pharmacology of Miami, Inc, Miami, FL, USA.
Kenneth
K
Lasseter
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Helene
H
Pearlman
Randstad Pharma, Deerfield, IL, USA.
Diane
D
Rammelsberg
Basilea Pharmaceutica International Ltd, Basel, Switzerland.
Anne
A
Schmitt-Hoffmann
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Takao
T
Yamazaki
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Amit
A
Desai
D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage*; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009640:Norethindrone / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage*; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D007654:Ketoconazole; D009640:Norethindrone; D012293:Rifampin
ethinyl estradiol/norethindrone; isavuconazole; ketoconazole; midazolam; rifampin
