Purpose: Isavuconazole (ISA), the active moiety of the water soluble prodrug isavuconazonium sulfate, is a novel triazole antifungal agent currently in phase 3 clinical development for the treatment of invasive fungal infections caused by Aspergillus, Candida, or rare mould species. ISA has been found to inhibit CYP3A4, and also to induce CYP2B6. Induction of CYP2B6 influences methadone metabolism and clearance, and alters plasma methadone concentrations. Methadone is normally administered as a racemic mixture of R- and S-methadone, but only R-methadone is pharmacologically active and responsible for most opioid activity. The primary objective of this study was to assess the effect of multiple doses of ISA on the pharmacokinetics (PK) of methadone after single dose administration.
Methods: This was a phase 1, single-center, open-label, drug-interaction study of twenty-three healthy male and female subjects, aged 18–55 years. On days 1 and 20, subjects received a single oral dose of 10 mg methadone. On days 16 and 17, subjects received oral loading doses of 200 mg ISA three times daily, followed by daily 200 mg ISA from days 18 through 28. PK parameters of R- and S-methadone were assessed in the presence/absence (day 20/day 1) of ISA using non-compartmental analysis.
Results: Twenty-two subjects completed the study. One subject, prior to receiving ISA, discontinued the study due a moderate adverse event (AE) of worsening toothache. All other AEs were mild in intensity. The geometric mean ratio (%) and 90% confidence intervals (CI) of area under the plasma concentration–time curve from time of dosing extrapolated to infinity (AUCinf) for Rmethadone and S-methadone when methadone was given in combination with ISA vs. methadone alone were 90 (84, 96) and 65 (59, 72), respectively. The geometric mean ratio (%) and 90% CI for maximum plasma concentration (Cmax) for R-methadone and S-methadone when given in combination with ISA vs. methadone alone were 104 (97, 111) and 101 (95, 108), respectively.
Conclusion: Coadministration of ISA and methadone was generally well tolerated. Exposure of R-methadone and S-methadone decreased by 10% and 35%, respectively, when given in combination with ISA, compared with methadone alone.
- AAPS 2013