Clinical pharmacokinetics and pharmacodynamics of solifenacin.
The succinate salt of solifenacin, a tertiary amine with anticholinergic properties, is used for symptomatic treatment of overactive bladder. Solifenacin peak plasma concentrations of 24.0 and 40.6 ng/mL are reached 3-8 hours after long-term oral administration of a 5 or 10 mg solifenacin dose, respectively. Studies in healthy adults have shown that the drug has high absolute bioavailability of about 90%, which does not decrease with concomitant food intake. Solifenacin has an apparent volume of distribution of 600 L, is 93-96% plasma protein bound, and probably crosses the blood-brain barrier. Solifenacin is eliminated mainly through hepatic metabolism via cytochrome P450 (CYP) 3A4, with about only 7% (3-13%) of the dose being excreted unchanged in the urine. Solifenacin metabolites are unlikely to contribute to clinical solifenacin effects. In healthy adults, total clearance of solifenacin amounts to 7-14 L/h. The terminal elimination half-life ranges from 33 to 85 hours, permitting once-daily administration. Urinary excretion plays a minor role in the elimination of solifenacin, resulting in renal clearance of 0.67-1.51 L/h. Solifenacin does not influence the activity of CYP1A1/2, 2C9, 2D6 and 3A4, and shows a weak inhibitory potential for CYP2C19 and P-glycoprotein in vitro; however, clinical drug-drug interactions with CYP2C19 and P-glycoprotein substrates are very unlikely. Exposure to solifenacin is increased about 1.2-fold in elderly subjects and about 2-fold in subjects with moderate hepatic and severe renal impairment, as well as by coadministration of the potent CYP3A4 inhibitor ketoconazole 200 mg/day. The full therapeutic effects of solifenacin occur after 2-4 weeks of treatment and are maintained upon long-term therapy. Although solifenacin pharmacokinetics display linearity at doses of 5-40 mg, no obvious dose dependency was observed in efficacy and tolerability studies. The efficacy of solifenacin (5 or 10 mg/day) is at least equal to that of extended-release (ER) tolterodine (4 mg/day) in reducing the mean number of micturitions per 24 hours and urgency episodes, and in increasing the volume voided per micturition. Solifenacin (5 mg/day) appears to be superior to ER tolterodine (4 mg/day) in reducing incontinence episodes (mean -1.30 vs -0.90, p = 0.018) and is superior to propiverine (20 mg/day) at the dose of 10 mg/day in reducing urgency (-2.30 vs -2.78, p = 0.012) and nocturia episodes. Based on withdrawal rates due to adverse effects during the 52-week treatment period, solifenacin appears to have better tolerability than immediate-release (IR) oxybutynin 10-15 mg/day and IR tolterodine 4 mg/day. With regard to the pharmacokinetics of solifenacin, and for safety reasons, doses exceeding 5 mg/day are not recommended for patients with moderate hepatic impairment (Child-Pugh score 7-9), patients with severe renal impairment (creatinine clearance <30 mL/min) and subjects undergoing concomitant therapy with CYP3A4 inhibitors.
Doroshyenko
Oxana
O
Department of Pharmacology, Clinical Pharmacology Unit, University of Cologne, Cologne, Germany.
Fuhr
Uwe
U
D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011812:Quinuclidines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D000069464:Solifenacin Succinate; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D014549:Urinary Incontinence / Q000188:drug therapy / Q000378:metabolism
D011812:Quinuclidines; D044005:Tetrahydroisoquinolines; D000069464:Solifenacin Succinate