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European Journal of Drug Metabolism and Pharmacokinetics

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Open Access 09-03-2023 | Overactive Bladder | Original Research Article

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

Authors: Yamato Sano, Satoshi Shoji, Mohamed Shahin, Kevin Sweeney, Amanda Darekar, Bimal K Malhotra

Published in: European Journal of Drug Metabolism and Pharmacokinetics | Issue 3/2023

Abstract

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

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Title: Population Pharmacokinetic and Pharmacodynamic Modeling of Fesoterodine in Pediatric Patients with Neurogenic Detrusor Overactivity
Authors: Yamato Sano
Satoshi Shoji
Mohamed Shahin
Kevin Sweeney
Amanda Darekar
Bimal K Malhotra
Publication date: 09-03-2023
Publisher: Springer International Publishing
Keywords: Overactive Bladder
Fesoterodine
Published in: European Journal of Drug Metabolism and Pharmacokinetics / Issue 3/2023
Print ISSN: 0378-7966
Electronic ISSN: 2107-0180
DOI: https://doi.org/10.1007/s13318-023-00818-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background and Objective

Methods

Results

Conclusions

Clinical Trial Numbers

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background and Objective

Methods

Results

Conclusions

Clinical Trial Numbers

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