Urinary antispasmodics. ATC code:
Pharmacology: Pharmacodynamics: Mechanism of action:
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. In vitro
and in vivo
pharmacological studies indicate that 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.
Treatment with Vesicare in doses of 5 mg and 10 mg daily was studied in several doubleblind, randomised, controlled clinical trials in men and women with overactive bladder.
As shown in the table as follows, both the 5 mg and 10 mg doses of Vesicare produced statistically significant improvements in the primary and secondary endpoints compared with placebo. Efficacy was observed within one week of starting treatment and stabilizes over a period of 12 weeks. A long-term, open-label study demonstrated that efficacy was maintained for at least 12 months. After 12 weeks of treatment, approximately 50% of patients suffering from incontinence before treatment were free of incontinence episodes, and in addition 35% of patients achieved a micturition frequency of less than 8 micturitions per day. Treatment of the symptoms of overactive bladder also results in a benefit on a number of Quality of Life measures, such as general health perception, incontinence impact, role limitations, physical limitations, social limitations, emotions, symptom severity, severity measures and sleep/energy. (See Table 1.)
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Clinical QT Interval Data:
Two dedicated QT studies have been performed with solifenacin.
The first study was an open label, multiple dose escalating study in 60 healthy subjects. In this study solifenacin was administered starting at a dose of 10 mg once daily for 2 weeks and proceeded in 10 mg increments for 2 weeks at each dose level. The highest tolerated dose was 40 mg. The results are presented in the table as follows. There was no significant change in QTc interval using the Bazett as well as the Friderica method for the 10 mg solifenacin compared to baseline. Depending on the method applied, some prolongation was seen for the 20 mg and 30 mg doses, which are higher than the recommended therapeutic dose. However, both methods suggest no prolongation for the 40 mg dose, which is four times the highest recommended therapeutic dose. (See Table 2.)
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There were no QTc intervals > 500 msec; increases of >60 msec occurred in 1 subject (on 30 mg), while change <60 msec but >30 msec occurred in 34 subjects (11 changes on 10 mg, 20 changes on 20 mg, 27 changes on 30 mg, 9 changes on 40 mg).
The second study was a double blind, multiple dose, placebo and positive controlled (moxifloxacin 400 mg) study in 76 female volunteers aged 19 to 79 years. This second QT study was a dedicated thorough QT study with the subjects randomized to one of two treatment groups after receiving placebo and moxifloxacin sequentially. One group (n=51) went on to complete 3 additional sequential periods of dosing with solifenacin 10, 20, and 30 mg, while the second group (n=25) in parallel completed a sequence of placebo and moxifloxacin. The 30 mg dose of solifenacin succinate (three times the highest recommended dose) was chosen for use in this study because this dose results in a solifenacin exposure that covers the exposure observed upon co-administration of 10 mg Vesicare with potent CYP3A4 inhibitors (e.g. ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline ECG measurements were separated from the final QT assessment (of the 30 mg dose level) by 33 days.
The median difference from baseline in heart rate associated with the 10 and 30 mg doses of solifenacin succinate compared to placebo was -2 and 0 beats/minute, respectively. Because a significant period effect on QTc was observed, the QTc effects were analyzed utilizing the parallel placebo control arm rather than the pre-specified intra-patient analysis (Fridericia method). Representative results for solifenacin are shown in the table as follows. (See Table 3.)
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Moxifloxacin was included as a positive control in this study and, given the length of the study, its effect on the QT interval was evaluated in 3 different sessions.
The placebo subtracted mean changes (90% Confidence Interval) in QTcF for moxifloxacin in the three sessions were 11 msec (7, 14), 12 msec (8,17) and 16 msec (12, 21), respectively.
There were no subjects with a mean QTc > 500 msec. Four subjects experienced increases in mean QTcF that were greater than 60 msec from the time-matched baseline. Three subjects received 30 mg solifenacin and the fourth received 400 mg moxifloxacin.
A change in QTc of < 60 msec but > 30 msec occurred in 29 subjects on 10 mg and in 31 subjects during 30 mg solifenacin treatment.
The QT interval prolonging effect appeared to be greater for the 30 mg compared to the 10 mg dose of solifenacin. Although the effect of the highest solifenacin dose (three times the maximum therapeutic dose) studied did not appear as large as that of the positive control moxifloxacin at its therapeutic dose, the confidence intervals overlapped. This study was not designed to draw direct statistical conclusions between the drugs or the dose levels.
Across the four controlled phase 3 studies, QTc interval prolongation was seen of approximately up to 5 msec, along with PR interval prolongation. There were 12 patients with a change in QTc from baseline of > 60 msec and 6 patients with QTc > 500 msec at any time point on solifenacin. There were no reports of VT or VF or association between these QT changes and death, syncope, dizziness or ventricular arrhythmias.
After intake of Vesicare tablets, 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.
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.
Solifenacin is extensively metabolised 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
-oxide and 4R
-oxide of solifenacin) have been identified in plasma in addition to solifenacin.
After a single administration of 10 mg [14C-labelled]-solifenacin, about 70% of the radioactivity was detected in urine and 23% in faeces 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
-oxide metabolite and 8% as the 4R
-hydroxy metabolite (active metabolite).
Pharmacokinetics are linear in the therapeutic dose range.
Other special populations:
Elderly: No dosage adjustment based on patient age is required. Studies in the elderly have 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.
The pharmacokinetics of solifenacin have not been established in children and adolescents.
The pharmacokinetics of solifenacin are not influenced by gender.
The pharmacokinetics of solifenacin are not influenced 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 haemodialysis 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.
Toxicology: Preclinical safety data:
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, fertility, embryofetal development, genotoxicity, and carcinogenic potential. In the pre- and postnatal development study in mice, solifenacin treatment of the mother during lactation caused dose-dependent lower postpartum survival rate, decreased pup weight and slower physical development at clinically relevant levels. Dose related increased mortality without preceding clinical signs occurred in juvenile mice treated from day 10 or 21 after birth with doses that achieved a pharmacological effect and both groups had higher mortality compared to adult mice. In juvenile mice treated from postnatal day 10, plasma exposure was higher than in adult mice; from postnatal day 21 onwards, the systemic exposure was comparable to adult mice. The clinical implications of the increased mortality in juvenile mice are not known.