Multiple doses of the antimuscarinic agent solifenacin do not affect the pharmacodynamics or pharmacokinetics of warfarin or the steady-state pharmacokinetics of digoxin in healthy subjects

Abstract

Aims: Solifenacin succinate is used for the treatment of overactive bladder (OAB). The potential for pharmacokinetic and/or pharmacodynamic interactions between solifenacin and warfarin or digoxin was investigated.

Methods: The solifenacin-warfarin study was a two-period crossover trial conducted in healthy males. Subjects received warfarin on the 10th day of 16 days of dosing with either solifenacin or placebo. The solifenacin-digoxin study was an one-sequence crossover trial conducted in healthy males and females. Following a phase-in period for digoxin, solifenacin was administered concomitantly with the drug on days 9-18.

Results: The AUC(PT; 0-168 h) following a single dose of warfarin was unchanged in the presence of solifenacin [point estimate = 1.005; 90% confidence interval (CI) 0.98, 1.02)]. The AUC(0-infinity) values for both warfarin enantiomers were also unchanged. A small increase in the C(max) of digoxin was observed during treatment with solifenacin, but for AUC(ss,tau) and C(max) the 90% CI fell within the prespecified interval of 0.80-1.25. Combined administration of solifenacin and warfarin or digoxin was well tolerated.

Conclusions: Since the pharmacokinetics and pharmacodynamics of a single dose of warfarin and the steady-state pharmacokinetics of digoxin were not affected by coadministration of solifenacin in healthy subjects, the need for dosing adjustments for digoxin and/or warfarin does not seem warranted.

Figure 1

Mean plasma concentration. Warfarin with solifenacin (), warfarin without solifenacin (▪), and prothrombin time, warfarin with solifenacin (), warfarin without solifenacin (▴) vs. time profiles of R-warfarin in the absence and presence of solifenacin

Figure 2

Mean plasma concentration. Warfarin with solifenacin (), warfarin without solifenacin (), and prothrombin time, warfarin with solifenacin (♦), warfarin without solifenacin (▴) vs. profiles of S-warfarin in the absence and presence of solifenacin

Figure 3

Mean plasma concentration vs. time profiles of digoxin in the absence and presence of solifenacin. Digoxin without solifenacin (), digoxin with solifenacin ()