Population pharmacokinetics of the 5‐hydroxymethyl metabolite of tolterodine after administration of fesoterodine sustained release tablet in western and east Asian populations

Abstract

This analysis was conducted to investigate factors that affect 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics after administration of fesoterodine sustained release tablets to Westerners and East Asians. Ten pharmacokinetic studies and three efficacy/safety studies in overactive bladder (OAB) patients were pooled for the population pharmacokinetic analysis. The plasma 5-HMT concentration data were described by a 1-compartment model with first order absorption and a lag time. Creatinine clearance (CLCR), hepatic impairment, CYP2D6 genotype, and concomitant medication with CYP3A inhibitor/inducer were identified as influential covariates. It was estimated that decreasing of CLCR from 80 to 15 mL/min resulted in a 39.5% reduction in 5-HMT apparent oral clearance (CL/F). Hepatic impairment, CYP2D6 poor metabolizer, and CYP3A inhibitor were estimated to reduce CL/F by about 60%, 40%, and 50%, respectively. CYP3A inducer resulted in about fourfold increase in CL/F. Although sex and Japanese ethnicity were selected as covariates on CL/F, each resulted in only about 10% decrease and increase of CL/F, respectively. Of the influential covariates of 5-HMT CL/F, CLCR, hepatic impairment, CYP2D6 genotype, and concomitant medication with CYP3A inhibitor/inducer were of significance, whereas sex and Japanese ethnicity covariates were considered not to have clinically significant impact on exposures of 5-HMT.

Simultaneous usage of dementia medications and anticholinergics among Asians and Pacific Islanders

“…Additionally, the third most common anticholinergic medication was tolterodine, which is metabolized primarily by CYP2D6 and secondarily by CYP3A4 . Interestingly, a pharmacokinetic study comparing the metabolite for tolterodine in East Asian and Caucasian populations found that there was increased clearance in Japanese subjects, although there was no significant difference in exposure to the metabolite . We note that the most commonly used anticholinergics found in this study were not necessarily used less frequently in the Asian patients that received anticholinergics, but we hypothesize a decreased use of these medications in the Asian population in general compared to the Caucasian and Hawaiian populations.…”

Fesoterodine clinical efficacy and safety for the treatment of overactive bladder in relation to patient profiles: a systematic review

“…Based on a population pharmacokinetic analysis, renal impairment, hepatic impairment, CYP2D6 genotype, and concomitant CYP3A4 inhibitors/inducers were identified as factors impacting 5-HMT exposure after fesoterodine administration 27 . A large randomized, double-blind, placebo and active (moxifloxacin) controlled trial in healthy adults that evaluated the effects of fesoterodine on cardiac repolarization indicated that fesoterodine 4 mg (therapeutic dose) and 28 mg (supratherapeutic dose) administered once daily for 3 days did not prolong the Fridericia's corrected QT (QTc) interval from baseline versus placebo 28 . The positive QTc prolongation by moxifloxacin confirmed the sensitivity of the study.…”

“…The key results of the 15 retained articles [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] on the pharmacology of oral fesoterodine are summarized in Table 1. After single or multiple dosing of oral fesoterodine 4 mg to 28 mg once daily, plasma concentrations of the active metabolite 5-HMT are proportional to the dose 16,17 .…”

Randomized, open‐label, tolterodine‐controlled, comparative study of the novel antimuscarinic agent imidafenacin in patients with overactive bladder

“…A placebo‐controlled clinical trial demonstrated the efficacy and safety of imidafenacin for the treatment of OAB in Japanese patients. However, there is a lack of data for imidafenacin in the Caucasian population, and there might be differences in pharmacokinetics and behavioral habits between Western and East Asian patients …”

“…However, there is a lack of data for imidafenacin in the Caucasian population, and there might be differences in pharmacokinetics and behavioral habits between Western and East Asian patients. 8 This study aims to evaluate the efficacy and safety of imidafenacin compared with those of standard treatment with tolterodine in Caucasian patients with OAB.…”