The effect of food on the pharmacokinetics of multiple-dose terbinafine in young and elderly healthy subjects.
Pharmacokinetic (PK) parameters for terbinafine were assessed in 15 elderly and 15 young healthy subjects randomized to receive 250 mg Lamisil once daily for 15 d in a two-period, two-treatment, two-sequence, crossover (fed versus fasted) design within age groups. On each treatment day except days 8 and 15, subjects took Lamisil with food at 8:00 a.m. On days 8 and 15, subjects took the drug under either fed or fasting conditions according to treatment sequence, and 24 h PK profiles were obtained. Two analyses of the pharmacokinetic data were undertaken. In a noncompartmental analysis, AUC0-24h, Cmax, C0h, and tmax were computed for each subject on each of days 8 and 15, and the influences of food condition and age on these variables were assessed by analysis of variance. AUC0-24h and C0h were found to be larger (p < 0.5) among elderly subjects than young subjects on day 15, and tmax was prolonged (p < 0.05) under the fed condition on day 15. Similar trends on day 8, as well as generally higher exposures under the fed condition on both days, were not statistically significant. A three-compartment model fitted to the complete sequence of 33 terbinafine concentrations measured over 29 d for each subject separately permitted a within-subject assessment of the food effect that confirmed prolonged absorption and increased bioavailability (p < 0.05) under the fed condition. Across-subject comparisons of oral clearances estimated with the model also confirmed the increased exposures (lower clearances) among the elderly (p < 0.05). The drug was well tolerated in both age groups. In particular, greater drug exposure in the elderly did not result in greater toxicity, as indicated by the safety evaluations in the study.
Nedelman
J
J
Department of Drug Metabolism and Pharmacokinetics, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936, USA. jerry.nedelman@gwa.sandoz.com
Cramer
J A
JA
Robbins
B
B
Gibiansky
E
E
Chang
C T
CT
Gareffa
S
S
Cohen
A
A
Meligeni
J
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D005502:Food; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D015233:Models, Statistical; D009281:Naphthalenes / Q000009:adverse effects / Q000493:pharmacokinetics*; D012016:Reference Values; D000077291:Terbinafine
D000935:Antifungal Agents; D009281:Naphthalenes; D000077291:Terbinafine