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

• Published in: European journal of drug metabolism and pharmacokinetics 2023-05, Vol.48 (3), p.257-269
• Main Authors: Sano, Yamato, Shoji, Satoshi, Shahin, Mohamed, Sweeney, Kevin, Darekar, Amanda, Malhotra, Bimal K
• Format: Article
• Language: English
• Subjects: Adult; Biomedical and Life Sciences; Biomedicine; Child; Cytochrome P-450 CYP2D6; Human Physiology; Humans; Medical Biochemistry; Muscarinic Antagonists; NCT; NCT00857896; NCT01557244; Original; Original Research Article; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Urinary Bladder, Overactive - drug therapy
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/s13318-023-00818-8

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 Plain Language Summary Fesoterodine is a muscarinic receptor antagonist approved for the treatment of overactive bladder (OAB) in adults and neurogenic detrusor overactivity (NDO) in pediatric patients in the US. Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed for 5-HMT based on data from two pediatric clinical trials that included 142 patients of age ≥ 6 years with OAB or NDO. Weight-based simulations of 5-HMT exposure and maximum cystometric capacity were conducted using the final models to examine the impact of covariates on 5-HMT exposure an