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

Abstract

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 (V_z /F), and terminal half-life (t_1/2 ) were higher in adolescents than in children, but median time to maximum plasma concentration (t_max ) 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.

Trial registration: ClinicalTrials.gov NCT01565707 NCT01565694 NCT01981954.

Keywords: nephrology - urology; pediatrics - children; pharmacokinetics.

FIGURE 1

Trial designs for the LION (OAB population; (A), MONKEY (NDO population; (B), and MARMOSET (NDO population; (C) trials. NDO, neurogenic detrusor overactivity; OAB, overactive bladder; PED, pediatric equivalent dose. Figure 1A reprinted from Eur Urol, 71, Newgreen D, Bosman B, Hollestein‐Havelaar A, Dahler E, Besuyen R, Sawyer W, et al. Solifenacin in children and adolescents with overactive bladder: results of a phase 3 randomised clinical trial, 483‐90, Copyright (2017), with permission from Elsevier. ²⁶ Figure 1B and Cadapted from Franco, et al. ^{30 a}Every 3 weeks, dose modification of trial drug could be performed to obtain doses of PED2.5, PED5, PED7.5, or PED10. ^bWeight‐adjusted starting dose was equivalent to 5 mg in adults. ^cThe fixed‐dose assessment period started when the optimal dose for the patient was reached and it ended at week 52. ^dWeight‐adjusted starting dose was equivalent to 2.5 or 5 mg in adults depending on patient age

FIGURE 2

Dose‐normalized concentration‐time profiles for the patients enrolled in the LION (OAB population), MONKEY (NDO population), and MARMOSET (NDO population) trials. NDO, neurogenic detrusor overactivity; OAB, overactive bladder; SD, standard deviation. Data shown are geometric means ± SD. The curves are calculated using the nominal times for the concentration samples

FIGURE 3

Dose‐normalized exposures according to age group for the patients enrolled in the LION (OAB population; (A), MONKEY (NDO population; (B), and MARMOSET (NDO population; (C) trials. AUC, area under the plasma concentration‐time curve; AUC/D, dose‐normalized area under the plasma concentration‐time curve; C_max, maximum plasma concentration; C_max/D, dose‐normalized maximum plasma concentration; NDO, neurogenic detrusor overactivity; OAB, overactive bladder. The circles represent the individual values for each patient. The line within each plot represents the geometric mean