Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers
Article first published online: 11 JUL 2011
© 2011 Pfizer Inc.. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society
British Journal of Clinical Pharmacology
Special Issue: Uropharmacology Themed Section
Volume 72, Issue 2, pages 257–262, August 2011
How to Cite
Malhotra, B., Alvey, C., Gong, J., Li, X., Duczynski, G. and Gandelman, K. (2011), Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. British Journal of Clinical Pharmacology, 72: 257–262. doi: 10.1111/j.1365-2125.2011.03989.x
- Issue published online: 11 JUL 2011
- Article first published online: 11 JUL 2011
- Accepted manuscript online: 15 APR 2011 10:00AM EST
- Received , 3 August 2010 , Accepted , 30 March 2011 , Accepted Article , 15 April 2011
- drug–drug interactions;
- overactive bladder;
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Drug–drug interactions with warfarin are common with potentially harmful consequences. Preclinical in vitro studies suggest that fesoterodine or 5-hydroxymethyl tolterodine are not likely to affect warfarin metabolism, but a lack of interaction has not been demonstrated in a clinical study.
WHAT THIS STUDY ADDS
• This study shows that the pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg, and that co-administration of warfarin 25 mg and fesoterodine 8 mg is safe and well tolerated.
AIMS To confirm the lack of an interaction of fesoterodine 8 mg with warfarin pharmacokinetics and pharmacodynamics in healthy adults.
METHODS In this open-label, two-treatment, crossover study, subjects (n= 14) aged 20–41 years with normal prothrombin time (PT) and International Normalized Ratio (INR) were randomized to receive a single dose of warfarin 25 mg alone in one period and fesoterodine 8 mg once daily on days 1–9 with a single dose of warfarin 25 mg co-administered on day 3 in the other period. There was a 10-day washout between treatments. Pharmacokinetic endpoints were area under the plasma concentration–time curve from time 0 to infinity (AUC(0,∞)), maximum plasma concentration (Cmax), AUC from time 0 to the time of the last quantifiable concentration (AUC(0,last)), time to Cmax (tmax), and half-life (t1/2) for S- and R-warfarin. Pharmacodynamic endpoints were area under the INR-time curve (AUCINR), maximum INR (INRmax), area under the PT-time curve (AUCPT) and maximum PT (PTmax).
RESULTS Across all pharmacokinetic and pharmacodynamic comparisons, the point estimates of treatment ratio (warfarin co-administered with fesoterodine vs. warfarin alone) were 92–100%. The 90% confidence intervals for the ratios of the adjusted geometric means were contained within (80%, 125%). There were no clinically relevant changes in laboratory tests, vital signs or ECG recordings.
CONCLUSIONS The pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg. Concomitant administration of fesoterodine and warfarin was well tolerated.