Pharmacokinetic Interactions Between Isavuconazole and the Drug Transporter Substrates Atorvastatin, Digoxin, Metformin, and Methotrexate in Healthy Subjects

• Published in: Clinical pharmacology in drug development Vol. 6; no. 1; pp. 66 - 75
• Main Authors: Yamazaki, Takao, Desai, Amit, Goldwater, Ronald, Han, David, Lasseter, Kenneth C., Howieson, Corrie, Akhtar, Shahzad, Kowalski, Donna, Lademacher, Christopher, Rammelsberg, Diane, Townsend, Robert
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2017; John Wiley and Sons Inc
• Subjects: Adult; Area Under Curve; atorvastatin; Atorvastatin Calcium - administration & dosage; digoxin; Digoxin - administration & dosage; Drug dosages; Female; Healthy Volunteers; Humans; isavuconazole; Male; Membrane Transport Proteins - metabolism; metformin; Metformin - administration & dosage; methotrexate; Methotrexate - administration & dosage; Middle Aged; Nitriles - administration & dosage; Nitriles - pharmacokinetics; Original Manuscript; Pyridines - administration & dosage; Pyridines - pharmacokinetics; Triazoles - administration & dosage; Triazoles - pharmacokinetics; Young Adult; metformin; methotrexate; isavuconazole; digoxin; atorvastatin
• ISSN: 2160-763X; 2160-7648; 2160-7648
• DOI: 10.1002/cpdd.280

This article summarizes 4 phase 1 trials that explored interactions between the novel, triazole antifungal isavuconazole and substrates of the drug transporters breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein‐1 (MATE1), organic anion transporters 1/3 (OAT1/OAT3), organic anion‐transporting polypeptide 1B1 (OATP1B1), organic cation transporters 1/2 (OCT1/OCT2), and P‐glycoprotein (P‐gp). Healthy subjects received single doses of atorvastatin (20 mg; OATP1B1 and P‐gp substrate), digoxin (0.5 mg; P‐gp substrate), metformin (850 mg; OCT1, OCT2, and MATE1 substrate), or methotrexate (7.5 mg; BCRP, OAT1, and OAT3 substrate) in the presence and absence of clinical doses of isavuconazole (200 mg 3 times a day for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased mean area under the plasma concentration‐time curves (90% confidence interval) of atorvastatin, digoxin, and metformin to 137% (129, 145), 125% (117, 134),  and 152% (138, 168) and increased mean maximum plasma concentrations to 103% (88, 121), 133% (119, 149), and 123% (109, 140), respectively. Methotrexate parameters were unaffected by isavuconazole. There were no serious adverse events. These findings indicate that isavuconazole is a weak inhibitor of P‐gp, as well as OCT1, OCT2, MATE1, or a combination thereof but not of BCRP, OATP1B1, OAT1, or OAT3.