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

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.

Pharmacokinetic Interaction Between Isavuconazole and a Fixed‐Dose Combination of Lopinavir 400 mg/Ritonavir 100 mg in Healthy Subjects

“…[11][12][13] Ritonavir is also an inducer of UGT. 14 However, isavuconazole does not appear to be a substrate of these transporters in vitro (data on file) or in vivo, 6 and although isavuconazole undergoes secondary metabolism by UGT in vivo, it takes place only after metabolism by CYP3A4 and CYP3A5 (unpublished data). Together, these properties suggest that it is unlikely that interactions with P-gp, OATP1B1, OATP1B3, or UGT affected the metabolism of isavuconazole.…”

“…In vivo, isavuconazole is also a weak inducer of CYP2B6 5 and a weak inhibitor of uridine diphosphate glucuronosyltransferase (UGT) as well as the transporters P-glycoprotein (P-gp), organic cation transporters 1 and 2 (OCT 1 and OCT2), and multidrug and toxin extrusion protein 1 (MATE1). 6,7 In human liver microsomes in vitro, isavuconazole also has been shown to inhibit UGT (IC 50 for Lopinavir (400 mg)/ritonavir (100 mg) is a coformulated fixed-dose antiviral medication approved for the treatment of HIV infection in adults and children. Lopinavir and ritonavir are substrates of CYP3A, 7 and the combined drug is a strong inhibitor of these isoenzymes.…”

Pharmacokinetic Effects of Isavuconazole Coadministration With the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects

“…However, isavuconazole does not affect OATP1B1 activity in vitro (data on file) or in vivo,11 and so the lack of an effect of isavuconazole on repaglinide exposure can be interpreted to reflect the lack of an effect of isavuconazole on CYP2C8.…”

Drug‐drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4

“…The effect of isavuconazole on P‐gp is not as clear. Strong inhibition of NMQ transport (IC 50 , 3 μM) has been observed in vitro, but in vitro inhibition of digoxin transport is markedly less (IC 50 , 26 μM) . Furthermore, plasma exposure of digoxin in vivo was only increased by ~25% with co‐administration of the clinically recommended dose of isavuconazole, and a 37% increase in AUC 0‐∞ of the P‐gp substrate atorvastatin with co‐administered isavuconazole was mostly explicable in terms of its moderate inhibition of CYP3A4 .…”

“…Strong inhibition of NMQ transport (IC 50 , 3 μM) has been observed in vitro, but in vitro inhibition of digoxin transport is markedly less (IC 50 , 26 μM) . Furthermore, plasma exposure of digoxin in vivo was only increased by ~25% with co‐administration of the clinically recommended dose of isavuconazole, and a 37% increase in AUC 0‐∞ of the P‐gp substrate atorvastatin with co‐administered isavuconazole was mostly explicable in terms of its moderate inhibition of CYP3A4 . On the other hand, the increase in digoxin exposure was unlikely to result from inhibition of CYP3A4 as this enzyme has at most only a minor role in digoxin metabolism, and so some of the effect of isavuconazole on atorvastatin exposure may well have resulted from P‐gp inhibition.…”