Assessment of the relative in vivo potency of the hydroxylated metabolite of darifenacin in its ability to decrease...

To describe the population pharmacokinetic-pharmacodynamic relationship between darifenacin (UK-88,525) and its hydroxylated metabolite (UK-148,993), and the reduction in salivary flow (SF, a M3-mediated response). This enabled an estimation of the in vivo potency of the metabolite to decrease SF relative to that of the parent drug.

A total of 262 individuals were pooled from 11 Phase 1 studies and one Phase 2 study. A comparison was made between a series of pharmacodynamic models (direct-effect, indirect-effect, link and binding model) using NONMEM.

The binding model yielded the best description of the decrease in SF by fully accounting for the time course of the pharmacodynamic effect. An internal validation exercise demonstrated the robustness of this model. Covariate analysis identified a circadian rhythm in SF. This model, with confidence intervals (CI) determined by likelihood profiling, indicated that the relative potency of the metabolite to darifenacin to reduce SF was 11.1% (95% CI 3.8, 19.6). This implied that the metabolite was ninefold less potent than darifenacin in vivo. Accounting for the unbound fraction of darifenacin (2%) and its metabolite (13%), the in vivo protein binding-corrected relative potency was estimated to be 2.1%, indicating that the metabolite was 50-fold less potent than the parent drug. The model supported the assumption that no other metabolites contributing to the impairment of the SF were formed during first-pass, and that the development of sensitization or tolerance was not evident over time. The validation process indicated that the i.v.-oral crossover study was necessary for the estimation of the relative potency.

Population modelling of darifenacin and its hydroxylated metabolite yielded individual pharmacokinetic predictions that could be used to assess the in vivo potency of the metabolite to decrease SF relative to that of the parent drug. The metabolite had a negligible effect on SF.