Population Pharmacokinetic and Pharmacodynamic Modeling of Fesoterodine in Pediatric Patients with Neurogenic Detrusor Overactivity

Background and Objective Fesoterodine is a muscarinic receptor antagonist approved for the treatment of overactive bladder (OAB) in adults and neurogenic detrusor overactivity (NDO) in pediatric patients. This work aimed to characterize the population pharmacokinetics of 5-hydroxymethyl tolterodine (5-HMT, the active metabolite of fesoterodine) and its pharmacokinetic/pharmacodynamic relationship in pediatric patients with OAB or NDO following administration of fesoterodine. Methods 5-HMT plasma concentrations from 142 participants of age ≥ 6 years were analyzed, and a nonlinear mixed-effects model was developed. Weight-based simulations of 5-HMT exposure and maximum cystometric capacity (MCC) were conducted using the final models. Results A one-compartment model with first-order absorption and a lag time, which included the effects of body weight, sex, cytochrome (CYP) 2D6 metabolizer status and fesoterodine formulation on pharmacokinetic parameters, best described the 5-HMT pharmacokinetics. An E max model described the exposure–response relationship adequately. The median maximum concentration at steady state for pediatric patients weighing 25–35 kg and receiving 8 mg once daily (QD) was estimated to be 2.45 times greater than that in adults receiving 8 mg QD. Furthermore, simulation results showed dosing with fesoterodine 4 mg QD to pediatric patients weighing 25–35 kg and 8 mg QD to pediatric patients weighing >35 kg would achieve adequate exposure to demonstrate a clinically meaningful change from baseline (CFB) MCC. Conclusions Population models were developed for 5-HMT and MCC in pediatric patients. Weight-based simulations indicated that 4 mg QD for pediatric patients weighing 25–35 kg and 8 mg QD for those weighing > 35 kg provided similar exposures to those in adults following 8 mg QD and a clinically meaningful CFB MCC. Clinical Trial Numbers NCT00857896, NCT01557244