Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: local anaesthetics, amides.
ATC code: N01 BB02.
Mechanism of action
Versatis® 700 mg has a dual mode of action: the pharmacological action of lidocaine diffusion and the mechanical action of the hydrogel plaster that protects the hypersensitive area.
The lidocaine contained in the Versatis® 700 mg plaster diffuses continuously into the skin, providing a local analgesic effect. The mechanism by which this occurs is due to stabilisation of neuronal membranes, which is thought to cause down regulation of sodium channels resulting in pain reduction.

Clinical efficacy

Pain management in PHN is difficult. There is evidence of efficacy with Versatis® 700 mg in the symptomatic relief from the allodynic component of PHN in some cases (see section 4.2).
Efficacy of Versatis® 700 mg has been shown in post-herpetic neuralgia studies.
There were two main controlled studies carried out to assess the efficacy of the lidocaine 5% medicated plaster.
In the first study, patients were recruited from a population who were already considered to respond to the product.
It was a cross over design of 14 days treatment with lidocaine 5% medicated plaster followed by placebo, or vice versa. The primary endpoint was the time to exit, where patients withdrew because their pain relief was two points lower than their normal response on a six point scale (ranging from worse to complete relief).
There were 32 patients, of whom 30 completed. The median time to exit for placebo was 4 days and for active was 14 days (p value  0.001); none of those on active discontinued during the two week treatment period.
In the second study 265 patients with post-herpetic neuralgia were recruited and allocated eight weeks of open label active treatment with lidocaine 5% medicated plaster. In this uncontrolled setting approximately 50% of patients responded to treatment as measured by at least four points on a six point scale (ranging from worse to complete relief). A total of 71 patients were randomised to receive either placebo or lidocaine 5% medicated plaster given for 2-14 days. The primary endpoint was defined as lack of efficacy on two consecutive days because their pain relief was two points lower than their normal response on a six point scale (ranging from worse to complete relief) leading to withdrawal of treatment. There were 9/36 patients on active and 16/35 patients on placebo who withdrew because of lack of treatment benefit.
Post hoc analyses of the second study showed that the initial response was independent of the duration of pre- existing PHN. However, the notion that patients with longer duration of PHN (> 12 months) do benefit more from active treatment is supported by the finding that this group of patients was more likely to drop out due to lack of efficacy when switched to placebo during the double-blind withdrawal part of this study.
In a controlled open-label study Versatis® 700 mg suggested comparable efficacy to pregabalin in 98 patients with PHN with a favourable safety profile.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
When lidocaine 5% medicated plaster is used according to the maximum recommended dose (3 plasters applied simultaneously for 12 h) about 3 ± 2% of the total applied lidocaine dose is systemically available and similar for single and multiple administrations.
A population kinetics analysis of the clinical efficacy studies in patients suffering from PHN revealed a mean maximum concentration for lidocaine of 45 ng/ml after application of 3 plasters simultaneously 12 h per day after repeated application for up to one year. This concentration is in accordance with the observation in pharmacokinetic studies in PHN patients (52 ng/ml) and in healthy volunteers (85 ng/ml and 125 ng/ml).
For lidocaine and its metabolites MEGX, GX, and 2,6-xylidine no tendency for accumulation was found, steady state concentrations were reached within the first four days.
The population kinetic analysis indicated that when increasing the number from 1 to 3 plasters worn simultaneously, the systemic exposure increased less than proportionally to the number of used plasters.

Distribution
After intravenous administration of lidocaine to healthy volunteers, the volume of distribution was found to be 1.3 ± 0.4 l/kg (mean ± S.D., n = 15). The lidocaine distribution volume showed no age-dependency, it is decreased in patients with congestive heart failure and increased in patients with liver disease.
At plasma concentrations produced by application of the plaster approximately 70 % of lidocaine is bound to plasma proteins. Lidocaine crosses the placental and blood brain barriers presumably by passive diffusion.

Biotransformation
Lidocaine is metabolised rapidly in the liver to a number of metabolites. The primary metabolic route for lidocaine is N-dealkylation to monoethylglycinexylidide (MEGX) and glycinexylidide (GX), both of which are less active than lidocaine and available in low concentrations. These are hydrolyzed to 2,6-xylidine, which is converted to conjugated 4-hydroxy-2,6-xylidine.
The metabolite, 2,6-xylidine, has unknown pharmacological activity but shows carcinogenic potential in rats (see section 5.3). A population kinetics analysis revealed a mean maximum concentration for 2,6-xylidine of 9 ng/ml after repeated daily applications for up to one year. This finding is confirmed by a phase I pharmacokinetic study.
Data on lidocaine metabolism in the skin are not available.
Elimination
Lidocaine and its metabolites are excreted by the kidneys. More than 85 % of the dose is found in the urine in the form of metabolites or active substance. Less than 10 % of the lidocaine dose is excreted unchanged.
The main metabolite in urine is a conjugate of 4-hydroxy-2,6-xylidine, accounting for about 70 to 80% of the dose excreted in the urine. 2,6-xylidine is excreted in the urine in man at a concentration of less than 1% of the dose.
The elimination half-life of lidocaine after plaster application in healthy volunteers is 7.6 hours. The excretion of lidocaine and its metabolites may be delayed in cardiac, renal or hepatic insufficiency.