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.
OBJECTIVE
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.
Smulders
R A
RA
Astellas Pharma Europe B.V., Leiderdorp, the Netherlands. ronald.smulders@eu.astellas.com
Kuipers
M E
ME
Krauwinkel
W J J
WJ
D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D004077:Digoxin / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000032:analysis; D011812:Quinuclidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000032:analysis; D000069464:Solifenacin Succinate; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000032:analysis; D014859:Warfarin / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*
D000925:Anticoagulants; D002316:Cardiotonic Agents; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D044005:Tetrahydroisoquinolines; D014859:Warfarin; D004077:Digoxin; D000069464:Solifenacin Succinate