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

Clin Pharmacol Drug Dev. 2017 Jan;6(1):66-75. doi: 10.1002/cpdd.280. Epub 2016 Jul 15.

Abstract

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.

Keywords: atorvastatin; digoxin; isavuconazole; metformin; methotrexate.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Area Under Curve
  • Atorvastatin / administration & dosage*
  • Digoxin / administration & dosage*
  • Female
  • Healthy Volunteers
  • Humans
  • Male
  • Membrane Transport Proteins / metabolism
  • Metformin / administration & dosage*
  • Methotrexate / administration & dosage*
  • Middle Aged
  • Nitriles / administration & dosage
  • Nitriles / pharmacokinetics*
  • Pyridines / administration & dosage
  • Pyridines / pharmacokinetics*
  • Triazoles / administration & dosage
  • Triazoles / pharmacokinetics*
  • Young Adult

Substances

  • Membrane Transport Proteins
  • Nitriles
  • Pyridines
  • Triazoles
  • isavuconazole
  • Digoxin
  • Metformin
  • Atorvastatin
  • Methotrexate