Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Urinary antispasmodics, ATC code: G04B D08.

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.

Pharmacodynamic effects:
Treatment with Vesicare in doses of 5 mg and 10 mg daily was studied in several double blind, randomised, controlled clinical trials in men and women with overactive bladder.

As shown in the table below, 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 stabilises 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.



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Results (pooled data) of four controlled Phase 3 studies with a treatment duration of 12 weeks Placebo    Vesicare     Vesicare Tolterodine
5 mg o.d.      10 mg      2 mg b.i.d.
o.d.
No. of micturitions/24 h
Mean baseline                         11.9        12.1         11.9         12.1 Mean reduction from baseline          1.4         2.3          2.7          1.9 % change from baseline                (12%)       (19%)        (23%)        (16%) n                                     1138        552          1158         250 p-value*                                          <0.001       <0.001       0.004 No. of urgency episodes/24 h
Mean baseline                         6.3         5.9          6.2          5.4 Mean reduction from baseline          2.0         2.9          3.4          2.1 % change from baseline                (32%)       (49%)        (55%)        (39%) n                                     1124        548          1151         250 p-value*                                          <0.001       <0.001       0.031 No. of incontinence episodes/24 h
Mean baseline                         2.9         2.6          2.9          2.3 Mean reduction from baseline          1.1         1.5          1.8          1.1 % change from baseline                 (38%)      (58%)        (62%)        (48%) n                                     781         314          778          157 p-value*                                          <0.001       <0.001       0.009 No. of nocturia episodes/24 h
Mean baseline                         1.8         2.0          1.8          1.9 Mean reduction from baseline          0.4         0.6          0.6          0.5 % change from baseline                (22%)       (30%)         (33%)       (26%) n                                     1005        494          1035         232 p-value*                                          0.025        <0.001       0.199 Volume voided/micturition
Mean baseline                         166 ml      146 ml       163 ml       147 ml Mean increase from baseline           9 ml        32 ml        43 ml        24 ml % change from baseline                (5%)        (21%)        (26%)        (16%) n                                     1135        552          1156         250 p-value*                                          <0.001       <0.001       <0.001 No. of pads/24 h
Mean baseline                         3.0         2.8          2.7          2.7 Mean reduction from baseline          0.8         1.3          1.3          1.0 % change from baseline                (27%)       (46%)        (48%)        (37%) n                                     238         236          242          250 p-value*                                          <0.001       <0.001       0.010 Note: In 4 of the pivotal studies, Vesicare 10 mg and placebo were used. In 2 out of the 4 studies also Vesicare 5 mg was used and one of the studies included tolterodine 2 mg bid.
Not all parameters and treatment groups were evaluated in each individual study.
Therefore, the numbers of patients listed may deviate per parameter and treatment group.
*     P-value for the pair wise comparison to placebo



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Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
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.

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 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-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 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-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. Studies in 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.


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Gender
The pharmacokinetics of solifenacin are not influenced by gender.

Race
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 has 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 has not been studied.