Objective: The pharmacokinetics of solifenacin succinate (YM905; Vesicare), a new, bladder-selective, muscarinic receptor antagonist for the treatment of overactive bladder in young/middle-aged and elderly subjects were compared.
Material: Solifenacin.
Methods: 47 healthy adults (24 young/middle-aged: mean age 35; and 23 elderly: mean age 68; 12 males in each age group) were enrolled in a single-center, multi-dose, open-label, crossover trial. Solifenacin, 5 or 10 mg, was administered once daily during two 14-day study periods separated by a washout period. Subjects were randomized to one dose in the first period and the other dose in the second period. Primary outcome variables were maximum plasma concentration (C(max)) and area under the curve from time 0 - 24 hours (AUC(0-24)). Secondary parameters included terminal elimination half-life (t1/2), time to C(max) (t(max)), fraction unbound, renal clearance, amount/percent of dose excreted in urine as solifenacin and its metabolites, and trough plasma metabolite concentrations. Adverse events and other safety parameters were also evaluated.
Results: Mean C(max) and AUC(0-24) were 16% (90% confidence interval 0.973 - 1.373) and 20% (1.003 - 1.435) higher, respectively, in elderly subjects. Mean t(max) and t1/2 were higher in elderly subjects. In both elderly and younger subjects, increasing the dose from 5 to 10 mg dose proportionally increased C(max), AUC(0- 24), and the amount excreted in urine. As expected, t(max) and t1/2 were not affected. Plasma concentrations and amounts of metabolites excreted in urine also increased dose proportionally. Solifenacin was highly bound to plasma proteins (fraction of the drug unbound in plasma was approximately 0.02), but there was no clear effect of gender or age. Solifenacin 5 or 10 mg once daily for 14 days was well tolerated by all subjects.
Conclusion: Although C(max) and AUC(0-24) were higher in elderly subjects than in younger subjects and there was a tendency toward longer t(max) and t1/2, these differences were small and not considered clinically relevant. In this study, no consistent safety/tolerability issues were associated with these pharmacokinetic differences and the administration of solifenacin 5 or 10 mg once daily was well tolerated. The number of adverse events in elderly subjects was similar to that in younger subjects, indicating that no age-related dose adjustments are needed with this agent.