Effect of Terbinafine on the Pharmacokinetics of Cyclosporin in Humans

Abstract

Cyclosporin is largely metabolized by hepatic cytochrome P450 enzymes, and azole drugs that inhibit cytochrome P450 may precipitate cyclosporin toxicity. The allylamine terbinafine binds to a small subfraction of hepatic cytochrome P450 in type I fashion, and has no effect upon hepatic metabolism of cyclosporin in vitro. The purpose of this study was to determine whether oral terbinafine alters the pharmacokinetics of oral cyclosporin in vivo.Twenty male volunteers (age 19–44 years), were randomly allocated to two groups. The first group received three single oral doses of cyclosporin 300mg at intervals of 21 d. The second and third doses of cyclosporin were preceded by a 6-d course of oral terbinafine 250mg each morning. A further 250mg of terbinafine was taken with the second and third doses of cyclosporin. Blood levels of cyclosporin and terbinafine were monitored for 36h after each dose. The second group received a 7-d course of terbinafine 250mg each morning. On the seventh day a single dose of cyclosporin 300mg was taken together with the terbinafine. Blood levels of both cyclosporin and terbinafine were monitored for 36kh. Two further single doses of cyclosporin 300mg were given at intervals of 2 weeks and the cyclosporin levels again monitored. In both groups each cyclosporin dose was preceded by an 8-h fast.The mean peak blood concentration of cyclosporin when taken alone was 958 μg/I, and 822 when taken with terbinafine. The mean area under the curve for cyclosporin was 4207 μg/l/h when taken alone and 3665 when taken with terbinafine. The mean absorption half-life for cyclosporin when taken alone was 0.29 h, and 0.33 when taken with terbinafine. The mean time of maximum concentration and elimination half-life of cyclosporin were unaltered by terbinafine. The results suggest that terbinafine is likely to prove a safe systemic anti-fungal treatment for patients who are taking cyclosporin