The prevalence of overactive bladder (OAB) is known to increase with advancing age . Antimuscarinics are considered first-line pharmacological treatment for OAB symptoms . Fesoterodine is a non-selective antimuscarinic agent that is approved for once daily oral administration at 4-mg and 8-mg doses for the treatment of OAB symptoms [3–5]. Fesoterodine is not detectable in plasma after oral administration , which reflects a rapid and extensive conversion to 5-hydroxymethyl tolterodine (5-HMT) by non-specific esterases . 5-HMT exhibits linear pharmacokinetics (PK) across a wide range of fesoterodine doses (4–28 mg), with maximum plasma concentrations achieved approximately 5 h after administration of fesoterodine . The elimination of 5-HMT is mediated by multiple pathways, including renal excretion and metabolism to form inactive metabolites via cytochrome P450 (CYP) isozymes, CYP3A4 and CYP2D6 [8, 9].
Because the prevalence of OAB increases with age , many individuals receiving fesoterodine for OAB will also be receiving medication for concomitant, non-OAB-related conditions. Controlled clinical trials are needed to assess the effects of fesoterodine on the PK and pharmacodynamic (PD) profiles of drugs commonly co-administered in the older individuals. Warfarin is a widely used anticoagulant administered to patients with atrial fibrillation as a prophylaxis against thrombosis . Warfarin is approved for administration as a 50:50 racemic mixture of two active enantiomers, S-warfarin and R-warfarin . Warfarin has a narrow therapeutic index and its anticoagulant response can be affected by drug interactions that interfere with its absorption or metabolic clearance . S-warfarin, the more pharmacologically active enantiomer, is primarily metabolized by CYP2C9, while the less active R-warfarin enantiomer is largely metabolized by CYP3A4 and CYP1A2 . Drug–drug interactions with warfarin are common with potentially harmful consequences; competitive inhibition of S-warfarin metabolism enhances anticoagulation effects, whereas agents that enhance rates of warfarin metabolism diminish anticoagulation effects .
Preclinical in vitro studies suggest that fesoterodine or 5-HMT are not likely to affect warfarin metabolism [3, 4]. Because of the narrow therapeutic index of warfarin, this clinical study was conducted to confirm the preclinical results that suggested the lack of an effect of fesoterodine or 5-HMT on CYP3A4, 1A2 and 2C9, the enzymes responsible for the metabolism of R- and S-warfarin. In warfarin drug interaction studies, warfarin is administered as a single large dose (e.g. 25 mg) in the absence or presence of steady-state treatment of the drug that has potential to interact with warfarin; the use of a higher single dose of warfarin allows greater potential to detect an interaction as well as reduces the exposure of healthy volunteers to a prolonged period of anticoagulation. In some published studies, the interaction of a drug with warfarin has been assessed by administration of a single lower (10–15 mg) oral dose of warfarin [13, 14]. A 7% decrease in S-warfarin AUC could be demonstrated after a single 10-mg dose of warfarin. However, this study did not show a PD effect on prothrombin time (PT) . Therefore, the lower therapeutic doses of warfarin, administered as single doses, may not be sufficient to demonstrate a PD interaction in a genetically heterogenous population. Consequently, a single 25-mg dose of warfarin was chosen to evaluate the effects of fesoterodine on the PK and PD of warfarin. The specific aims of this study were to determine (i) the PK of R- and S-warfarin, (ii) the PD (anticoagulant activity) and (iii) safety and tolerability in healthy subjects when a single supratherapeutic (25 mg) dose of warfarin is administered alone or concomitantly with fesoterodine 8 mg once daily at steady state.