EFFECT OF TERBINAFINE ON THE PHARMACOKINETICS OF CYCLOSPORINE IN HUMANS

Cyclosporin is largely metabolized by hepatic cytochrome P450 enzymes, and azole drugs that inhibit cytochrome P450 may precipitate cyclospo rin toxicity. The allylamine terbinafine binds to a small subfraction of hepatic cytochrome P450 in type I fashion, and has no effect upon h epatic metabolism of cyclosporin in vitro. The purpose of this study w as to determine whether oral terbinafine alters the pharmacokinetics o f 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 300 mg at intervals of 21 d. The seco nd and third doses of cyclosporin were preceded by a 6-d course of ora l terbinafine 250 mg each morning. A further 250 mg of terbinafine was taken with the second and third doses of cyclosporin. Blood levels of cyclosporin and terbinafine were monitored for 36 h after each dose. The second group received a 7-d course of terbinafine 250 mg each morn ing. On the seventh day a single dose of cycle-sporin 300 mg was taken together with the terbinafine. Blood levels of both cyc!osporin and t erbinafine were monitored for 36 h. Two further single doses of cyclos porin 300 mg were given at intervals of 2 weeks and the cyclesporin le vels again monitored. In both groups each cyclesporin dose was precede d by an 8-h fast. The mean peak blood concentration of cyclosporin whe n taken alone was 958 mu g/l, and 822 when tal;en with terbinafine. Th e mean area under the curve for cyclosporin was 4207 mu ug/l/h when ta ken alone and 3665 when taken with terbinafine. The mean absorption ha lf-life for cyclosporin when taken alone was 0.29 h, and 0.33 when tak en with terbinafine. The mean time of maximum concentration and elimin ation half-life of cyclesporin were unaltered by terbinafine. The resu lts suggest that terbinafine is likely to prove a safe systemic anti-f ungal treatment for patients who are taking cyclosporin.