Pharmacokinetics of solifenacin in pediatric populations with overactive bladder or neurogenic detrusor overactivity.

The aim of this investigation was to characterize and compare the pharmacokinetics (PK) of the antimuscarinic drug solifenacin in pediatric patients with overactive bladder (OAB) or neurogenic detrusor overactivity (NDO) utilizing data from three phase III trials. LION was a placebo-controlled, 12-week trial in children (5-<12 years) and adolescents (12-<18 years) with OAB. MONKEY and MARMOSET were open-label, 52-week trials in children and adolescents or younger children (6 months-<5 years), respectively, with NDO. During the trials, solifenacin doses could be titrated to weight-adjusted pediatric equivalent doses (PEDs) of 2.5, 5, 7.5, or 10 mg day-1 . Nonlinear mixed effects modeling was used to develop population PK models to characterize the PK in patients with either OAB or NDO. Overall, 194 children and adolescents received solifenacin. At the time of PK sampling, the majority (119/164 [72.6%] patients) were receiving PED10 once daily. All population models included first-order oral absorption, a lag time, and interindividual variability. PK analysis showed that apparent clearance was similar in both patient populations. Mean apparent oral plasma clearance (CL/F), apparent volume of distribution during the terminal phase (Vz /F), and terminal half-life (t1/2 ) were higher in adolescents than in children, but median time to maximum plasma concentration (tmax ) was similar. Dose-normalized exposure results were similar for both younger and older patients with OAB or NDO. In conclusion, population PK modeling was used to successfully characterize solifenacin PK in pediatric patients with OAB or NDO. Similar solifenacin PK characteristics were observed in both populations.

Factors associated with antimuscarinic drug persistence and increasing drug persistence after switching to mirabegron for overactive bladder patients.

PURPOSE: To evaluate long-term antimuscarinic drug persistence and its associated characteristics in patients with overactive bladder (OAB) treated with antimuscarinic agents. We also assessed the efficacy and safety of switching from solifenacin to mirabegron in patients refractory to antimuscarinic therapy. METHODS: In this prospective, open-label, 48-month study, 416 patients (mean age, 70.6 ± 12.4 years) were enrolled. All patients completed the overactive bladder symptom score and urgency severity score questionnaires, along with initial and follow-up uroflowmetry. All patients received antimuscarinic solifenacin 5 mg daily. Mirabegron (25 mg daily) was suggested in patients that were refractory to antimuscarinic therapy or had intolerable side effects. RESULTS: The mean solifenacin persistence was 6.6 ± 8.1 months (range, 0.5-48 months). Only 81 (19.5%) patients had drug persistence of ≥12 months. Male sex, age, cerebral vascular accident, maximum flow rate, and post-void residual were associated with solifenacin persistence in the univariate analysis. Age (odds ratio [OR], 0.14; 95% CI, 0.08-0.21) was the only independent predictor in the multivariate logistic regression. Of the 416 patients, 171 (60.8%) changed from solifenacin to mirabegron for due to the persistence of OAB symptoms. The switch resulted in a significantly longer period of actual OAB pharmacotherapy (9.3 ± 9.2 vs 13.3 ± 9.3 months, p < 0.001). CONCLUSION: Long-term drug persistence of solifenacin was low during the 2-year follow-up. Age was an independent factor associated with longer drug persistence. Switching from solifenacin to mirabegron was an effective and safe alternative for OAB patients that were refractory to solifenacin treatment.

Donepezil Plus Solifenacin (CPC-201) Treatment for Alzheimer's Disease.

Available cholinergic drugs for treating Alzheimer's disease (AD) provide modest symptomatic benefit. We hypothesized that co-administration of a peripheral anticholinergic to reduce dose-limiting adverse effects (AEs) would enable the safe/tolerable use of higher cholinesterase inhibitor doses and thus improve their antidementia efficacy. A modified single-blind, ascending-dose, phase IIa study of donepezil plus solifenacin (CPC-201) lasting 26 weeks was conducted in 41 patients with probable AD of moderate severity. Entry criteria included the use of donepezil at a dose of 10 mg/day during the preceding 3 months. The primary outcome measure was the maximum tolerated dose (MTD) of donepezil achieved (to protocol limit of 40 mg/day) when administered with the anticholinergic solifenacin 15 mg/day. Secondary measures included assessments of cognitive and global function, as well as of AEs. The mean ± SD donepezil MTD increased to 38 ± 0.74 mg/day (median 40 mg/day; p < 0.001); 88% of the study population safely attained this dose at the end of titration. Markedly reduced donepezil AE frequency, especially gastrointestinal, allowed this dose increase. There were no drug-related serious AEs or clinically significant laboratory abnormalities. At 26 weeks, Alzheimer's Disease Assessment Scale Cognitive Component scores in the efficacy evaluable population improved by 0.35 ± 0.85 points over baseline (p < 0.05), an estimated 2.5 ± 0.84 points above 10 mg/day donepezil and 5.4 ± 0.84 points above historic placebo (both p < 0.05). Clinical Global Impression of Improvement scores improved by 0.94 ± 0.20 to 3.1 ± 0.20 points (p < 0.001). The findings suggest that limiting donepezil AEs by co-administration of solifenacin allows the safe administration of substantially higher cholinesterase inhibitors doses that may augment cognitive and global benefits in patients with AD.