Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

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 ( C max ), AUC from time 0 to the time of the last quantifiable concentration (AUC(0,last)), time to C max ( t max ), and half‐life ( t 1/2 ) for S‐ and R‐warfarin. Pharmacodynamic endpoints were area under the INR‐time curve (AUC INR ), maximum INR (INR max ), area under the PT‐time curve (AUC PT ) and maximum PT (PT max ). 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.