PHARMACOKINETICS AND PHARMACODYNAMICS OF MULTIPLE-DOSE TERBINAFINE

Data from clinical trials of terbinafine for the treatment of onychomy cosis were analyzed with the following two objectives: 1) to identify demographic predictors of the duration and extent of systemic drug exp osure; and 2) to explore whether increased systemic exposure or demogr aphic predictors of increased exposure were associated with altered sa fety or efficacy. Demographic predictors of exposure were identified b y a model-free, nonparametric approach applied to the sparse pharmacok inetic data from the onychomycosis studies. Those covariates were then incorporated into a multicompartmental nonlinear mixed effects model. Post hoc parameter estimates from the nonlinear mixed effects model p rovided individual measures of exposure. Safety scores were derived fo r adverse events that were frequently attributed to drug exposure and for liver function tests. Terbinafine was found to have an average ter minal half-life (t(1/2)) Of approximately 3 weeks. That terminal elimi nation phase contributed so little to the total exposure, however, tha t average concentrations accumulated only approximately two-fold at st eady state with once daily dosing. Age and concomitant hypertension we re predictors of higher plasma concentrations of terbinafine; smokers had lower levels than nonsmokers. Although some statistically signific ant associations between adverse events and systemic exposure were fou nd, in all cases the actual frequency of the adverse events was low, a nd there were no trends in severity with respect to exposure. Above-no rmal levels of gammaglutamyl transferase were associated with exposure , but there was no trend in severity with respect to exposure. No othe r liver function test abnormalities were associated with exposure, nor were there any significant associations between adverse events or liv er-function abnormalities and demographic subgroups that differed with respect to exposure. Among patients taking the active drug there were no significant associations between exposure levels and efficacy, nor were there differences in efficacy between demographic subgroups that differed with respect to exposure.