Fesoterodine

Fesoterodine is a competitive, specific muscarinic receptor antagonist. It is rapidly and extensively hydrolysed by non-specific plasma esterases to the 5-hydroxymethyl derivative, its primary active metabolite, which is the main active pharmacological principle of fesoterodine.

Absorption

After oral administration, due to rapid and extensive hydrolysis by non-specific plasma esterases, fesoterodine was not detected in plasma.

Bioavailability of the active metabolite is 52%. After single or multiple-dose oral administration of fesoterodine in doses from 4 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the dose. Maximum plasma levels are reached after approximately 5 hours. Therapeutic plasma levels are achieved after the first administration of fesoterodine. No accumulation occurs after multiple-dose administration.

Distribution

Plasma protein binding of the active metabolite is low with approximately 50% bound to albumin and alpha-1-acid glycoprotein. The mean steady-state volume of distribution following intravenous infusion of the active metabolite is 169 l.

Biotransformation

After oral administration, fesoterodine is rapidly and extensively hydrolysed to its active metabolite. The active metabolite is further metabolised in the liver to its carboxy, carboxy-N-desisopropyl, and N-desisopropyl metabolite with involvement of CYP2D6 and CYP3A4. None of these metabolites contribute significantly to the antimuscarinic activity of fesoterodine. Mean C_max and AUC of the active metabolite are 1.7 and 2-fold higher, respectively, in CYP2D6 poor metabolisers as compared to extensive metabolisers.

Elimination

Hepatic metabolism and renal excretion contribute significantly to the elimination of the active metabolite. After oral administration of fesoterodine, approximately 70% of the administered dose was recovered in urine as the active metabolite (16%), carboxy metabolite (34%), carboxy-N-desisopropyl metabolite (18%), or N-desisopropyl metabolite (1%), and a smaller amount (7%) was recovered in faeces. The terminal half-life of the active metabolite following oral administration is approximately 7 hours and is absorption rate-limited.

Age and gender

No dose adjustment is recommended in these subpopulations. The pharmacokinetics of fesoterodine are not significantly influenced by age and gender.

Paediatric population

The pharmacokinetics of fesoterodine have not been evaluated in paediatric patients.

Renal impairment

In patients with mild or moderate renal impairment (GFR 30–80 ml/min), C_max and AUC of the active metabolite increased up to 1.5 and 1.8-fold, respectively, as compared to healthy subjects. In patients with severe renal impairment (GFR<30 ml/min), C_max and AUC are increased 2.0 and 2.3-fold, respectively.

Hepatic impairment

In patients with moderate hepatic impairment (Child Pugh B), C_max and AUC of the active metabolite increased 1.4 and 2.1-fold, respectively, as compared to healthy subjects. Pharmacokinetics of fesoterodine in patients with severe hepatic impairment have not been studied.

In non-clinical safety pharmacology, general toxicity, genotoxicity and carcinogenicity studies no clinically relevant effects have been observed, except those related to the pharmacological effect of the active substance.

Reproduction studies have shown minor embryotoxicity at doses close to maternally toxic ones (increased number of resorptions, pre-implantation and post-implantation losses).

Supratherapeutic concentrations of the active metabolite of fesoterodine, have been shown to inhibit K+ current in cloned human ether-à-go-go-related gene (hERG) channels and prolong action potential duration (70% and 90% repolarisation) in canine isolated Purkinje fibres. However in conscious dogs, the active metabolite had no effect on the QT interval and QTc interval at plas ma exposures at least 33-fold higher than mean peak free plasma concentration in human subjects who are extensive metabolisers and 21-fold higher than measured in subjects who are poor CYP2D6 metabolisers after fesoterodine 8 mg once daily.

In a study of fertility and early embryonic development in mice, fesoterodine had no effect on male reproductive function or fertility at doses up to 45 mg/kg/day. At 45 mg/kg/day, a lower number of corpora lutea, implantation sites and viable foetuses was observed in female mice administered fesoterodine for 2 weeks prior to mating and continuing through day 7 of gestation. The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day. Based on AUC, the systemic exposure was 0.6 to 1.5 times higher in mice than in humans at the MRHD, whereas based on peak plasma concentrations, the exposure in mice was 5 to 9 times higher.