The pharmacokinetic profile of fesoterodine: similarities and differences to tolterodine.
BACKGROUND
Fesoterodine is a new antimuscarinic agent developed for the treatment of overactive bladder. Fesoterodine itself is inactive and is rapidly and extensively converted by ubiquitous esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is formed via biotransformation of both fesoterodine and tolterodine, albeit by different metabolising enzymes, viz. esterases and CYP2D6 respectively. Tolterodine is a potent muscarinic receptor antagonist and has been used for the treatment of overactive bladder for over ten years. The objective of this study was to establish the pharmacokinetic profile of fesoterodine and to highlight ist potential pharmacokinetic advantages over tolterodine.


METHODS
Single-centre, open-label, randomised, 4-way crossover study in a total of 24 healthy male volunteers. Single oral doses of 4, 8, or 12 mg fesoterodine were administered after an overnight fast. In addition, the 8 mg dose was also administered after a standard high-fat and high-calorie breakfast. Blood and urine samples for the analysis of 5-HMT were collected before and multiple times after drug administration for pharmacokinetic analysis.


RESULTS
The mean peak plasma concentration (Cmax) of 5-HMT and the mean area under the time versus concentration curve (AUC) increased proportionally with the fesoterodine dose. These two parameters were some 2-fold higher in CYP2D6 poor metabolisers, whereas the time to peak plasma concentration (tmax) and half life (t1/2) were not influenced by the dose or the CYP2D6 metaboliser status. If fesoterodine was taken following a high-fat breakfast, we observed small increases in Cmax and AUC. In spite of these modest genetic influences and food effects on the pharmacokinetics of fesoterodine, the overall interindividual variability in Cmax levels was relatively little compared to previously published reports using tolterodine.


CONCLUSIONS
Due to the esterase-mediated cytochrome P450-independent formation of 5-HMT and involvement of multiple metabolic and renal excretion pathways in the elimination of 5-HMT, the effects of patient-intrinsic and -extrinsic factors on the pharmacokinetics of fesoterodine are only modest, with some 2-fold higher 5-HMT exposure. Therefore, in contrast to tolterodine, no reduction of fesoterodine dosage is required under conditions of reduced elimination. In most cases of drug interaction or renal/hepatic impairment, the fesoterodine dose may be increased to 8 mg/day based on individual patients' response, or patients may be required to remain at the initial recommended dose of 4 mg/day.
Simon
Hans-Uwe
HU
Institute of Pharmacology, University of Bern, Bern, Switzerland. hus@pki.unibe.ch
Malhotra
Bimal
B
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D003408:Cresols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010665:Phenylpropanolamine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012016:Reference Values; D000068737:Tolterodine Tartrate; D053201:Urinary Bladder, Overactive / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D055815:Young Adult
D001559:Benzhydryl Compounds; D003408:Cresols; D018727:Muscarinic Antagonists; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C526675:fesoterodine