Isavuconazole does not significantly affect the pharmacokinetics of p-glycoprotein substrate digoxin in healthy subjects

Desai A., Zadeikis N., Breese N., Yamazaki T., Kowalski D. and Townsend R.


BACKGROUND: Isavuconazonium sulfate, a water soluble prodrug developed for oral and intravenous administration, which is converted in plasma to the active drug Isavuconazole (ISA), a broad-spectrum triazole that inhibits sterol 14 α-demethylase, was shown in an in vitro study to be an inhibitor of P-glycoprotein (P-gp). Digoxin (Dig), a P-gp probe substrate is a cardiac glycoside used for the treatment of congestive heart failure and atrial dysrhythmias that has a narrow therapeutic window and long half life. Inhibitors of P-gp coadministered with Dig can increase Dig concentrations leading to toxicity, which can include anorexia, nausea, vomiting, hallucinations, visual disturbances, and arrhythmias. The objective of this study was to determine the inhibitory effect of ISA on the P-gp probe substrate, Dig.
Methods: This was a Phase I, single center, open-label, drug interaction study of 24 healthy male and female volunteers, aged 18 to 54 years. On Days 1 and 19 subjects received a single 0.5 mg dose of Dig under fasting conditions. On Days 15 and 16, subjects received ISA 200 mg three times daily, administered approximately 8 hours apart. On Days 17 through 26, subjects received ISA 200 mg once daily. Pharmacokinetic (PK) parameters of Dig were assessed in the presence and absence (Day 19 to day 1) of ISA.
Results: Of the 24 subjects enrolled, 21 subjects completed the study. One subject discontinued due to protocol violation, and the remaining 2 subjects discontinued due to mild adverse events (AEs) that were not related to study drug. The geometric mean ratio (%) and 90% confidence intervals (CI) of area under the plasma concentration time curve from time of dosing extrapolated to infinity (AUC∞) and maximum plasma concentration (Cmax) for Dig when given in combination with ISA vs. Dig alone were 125.21 (117.24, 133.74) and 133.06 (119.01, 148.77), respectively.
Conclusion: There was no significant change in the PK of Dig when co-administered with ISA. Co-administration of ISA and Dig was well tolerated.

    • ASCPT 2013