Pharmacokinetic Interactions Between Isavuconazole and the Drug Transporter Substrates Atorvastatin, Digoxin, Metformin, and Methotrexate in Healthy Subjects.
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.
Astellas Pharma Global Development, Northbrook, IL, USA.
Takao
T
Yamazaki
Astellas Pharma Global Development, Northbrook, IL, USA.
Amit
A
Desai
PAREXEL, Baltimore, MD, USA.
Ronald
R
Goldwater
PAREXEL, Los Angeles, CA, USA.
David
D
Han
Clinical Pharmacology of Miami, Inc, Miami, FL, USA.
Kenneth C
KC
Lasseter
Astellas Pharma Global Development, Northbrook, IL, USA.
Corrie
C
Howieson
Astellas Pharma Global Development, Northbrook, IL, USA.
Shahzad
S
Akhtar
Astellas Pharma Global Development, Northbrook, IL, USA.
Donna
D
Kowalski
Astellas Pharma Global Development, Northbrook, IL, USA.
Christopher
C
Lademacher
Randstad Pharma, Deerfield, IL, USA.
Diane
D
Rammelsberg
Astellas Pharma Global Development, Northbrook, IL, USA.
Robert
R
Townsend
D000328:Adult; D019540:Area Under Curve; D000069059:Atorvastatin / Q000008:administration & dosage*; D004077:Digoxin / Q000008:administration & dosage*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008687:Metformin / Q000008:administration & dosage*; D008727:Methotrexate / Q000008:administration & dosage*; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D026901:Membrane Transport Proteins; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole; D004077:Digoxin; D008687:Metformin; D000069059:Atorvastatin; D008727:Methotrexate
atorvastatin; digoxin; isavuconazole; metformin; methotrexate