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Pharmacology: Solifenacin is a competitive, specific cholinergic-receptor antagonist.
The urinary bladder is innervated by parasympathetic cholinergic nerves. Acetylcholine contracts the detrusor smooth muscle through muscarinic receptors of which the M3 subtype is predominantly involved. Solifenacin is a competitive inhibitor of the muscarinic M3 subtype receptor. In addition, Solifenacin showed to be a specific antagonist for muscarinic receptors by displaying low or no affinity for various other receptors and ion channels tested.
Pharmacokinetics: Absorption: After intake of Solifenacin, maximum Solifenacin plasma concentrations (Cmax) are reached after 3 to 8 hours. The tmax is independent of the dose. The Cmax and area under the curve (AUC) increase in proportion to the dose between 5 to 40 mg. Absolute bioavailability is approximately 90%.
Food intake does not affect the Cmax and AUC of Solifenacin.
Distribution: The apparent volume of distribution of Solifenacin following intravenous administration is about 600 L. Solifenacin is to a great extent (approximately 98%) bound to plasma proteins, primarily α1-acid glycoprotein.
Biotransformation: Solifenacin is extensively metabolized by the liver, primarily by cytochrome P450 3A4 (CYP3A4). However, alternative metabolic pathways exist, that can contribute to the metabolism of Solifenacin. The systemic clearance of Solifenacin is about 9.5 L/h and the terminal half life of Solifenacin is 45-68 hours. After oral dosing, one pharmacologically active (4R-hydroxy Solifenacin) and three inactive metabolites (N-glucuronide, N-oxide and 4R-hydroxy-N-oxide of Solifenacin) have been identified in plasma in addition to Solifenacin.
Elimination: After a single administration of 10 mg [14C-labelled]-Solifenacin, about 70% of the radioactivity was detected in urine and 23% in feces over 26 days. In urine, approximately 11% of the radioactivity is recovered as unchanged active substance; about 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide metabolite and 8% as the 4R-hydroxy metabolite (active metabolite).
Linearity/non-linearity: Pharmacokinetics are linear in the therapeutic dose range.
Other special populations: Elderly: No dosage adjustment based on patient age is required. It have been shown that the exposure to Solifenacin, expressed as the AUC, after administration of Solifenacin succinate (5 mg and 10 mg once daily) was similar in healthy elderly subjects (aged 65 through 80 years) and healthy young subjects (aged less than 55 years). The mean rate of absorption expressed as tmax was slightly slower in the elderly and the terminal half-life was approximately 20% longer in elderly subjects. These modest differences were considered not clinically significant.
Children and adolescents: The pharmacokinetics of Solifenacin have not been established on children and adolescents.
Gender: The pharmacokinetics of Solifenacin are not influence by gender.
Race: The pharmacokinetics of Solifenacin are not influence by race.
Renal impairment: The AUC and Cmax of Solifenacin in mild and moderate renally impaired patients, was not significantly different from that found in healthy volunteers. In patients with severe renal impairment (creatinine clearance ≤ 30 mL/min) exposure to Solifenacin was significantly greater than in the controls, with increases in Cmax of about 30%, AUC of more than 100% and t½ of more than 60%. A statistically significant relationship was observed between creatinine clearance and Solifenacin clearance.
Pharmacokinetics in patients undergoing hemodialysis have not been studied.
Hepatic impairment: In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) the Cmax is not affected, AUC increased with 60% and t½ doubled. Pharmacokinetics of Solifenacin in patients with severe hepatic impairment have not been studied.
