Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Anti-Parkinson drugs, dopa and dopa derivatives, ATC code: N04BA03 
Mechanism of action
Lecigon is a combination of levodopa, carbidopa monohydrate and entacapone (ratio 4:1:4) in a gel for continuous intestinal infusion in advanced Parkinson's disease with severe motor fluctuations and hyperkinesia/dyskinesia.

According to current knowledge, the symptoms of Parkinson's disease are related to the lack of dopamine in the corpus striatum. Dopamine does not cross the blood-brain barrier.

Levodopa, a metabolic precursor of dopamine, crosses the blood-brain barrier and relieves the symptoms of the disease. Since levodopa is extensively metabolised peripherally in tissues, only a small proportion of the given dose reaches the central nervous system when levodopa is administered without metabolic enzyme inhibitors.

Carbidopa is a peripheral DDC inhibitor which reduces the peripheral metabolism of levodopa to dopamine, thereby making more levodopa available to the brain. When decarboxylation of levodopa is reduced through co-administration of a DDC inhibitor, a lower dose of levodopa can be used and the incidence of adverse events such as nausea may be reduced.

When decarboxylase is inhibited with a DDC inhibitor, COMT becomes the dominant peripheral metabolic pathway. Entacapone is a reversible, specific and mainly peripherally-acting COMT inhibitor designed for co-administration with levodopa. Entacapone reduces clearance of levodopa from the blood, resulting in an increased AUC in the pharmacokinetic profile of levodopa.
Consequently, the clinical response of levodopa is prolonged.
Intestinal infusion of individually tested doses of Lecigon maintains the plasma concentration of levodopa at an even level within an individual therapeutic window.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Lecigon is administered via an inserted tube directly into the duodenum or upper jejunum. There are major inter- and intraindividual variations in the absorption of levodopa, carbidopa and entacapone.
Both levodopa and entacapone are absorbed and eliminated quickly. Carbidopa is absorbed and eliminated slightly slower that levodopa. Meals rich in large neutral amino acids can delay and reduce the absorption of levodopa. Food does not significantly affect the absorption of entacapone.

In an open-label, randomised clinical trial (n=11) with cross-over design, including Duodopa as a comparator, intestinal administration of Lecigon rapidly led to therapeutic plasma levels of levodopa.
Comparable levodopa levels were maintained during the infusion for both Lecigon and Duodopa, but a gradually increasing plasma levodopa concentration was observed during the day for Lecigon relative to Duodopa. Lecigon had a statistically significant higher bioavailability of levodopa compared to Duodopa calculated during the infusion, AUC014h /dose (ratio: 1.38; 95% confidence interval [CI]: 1.26–1.51). After completion of infusion, the levels of levodopa decreased rapidly. The variability of levodopa plasma concentrations in the individual was small (13.8%) within the 3 to 14 hours interval after the start of Lecigon infusion.

An example of the expected plasma concentration/time profile with a constant maintenance dose is shown in Figure 1. If necessary, it is possible to use multiple maintenance doses per day/24-hour period (described in section 4.2 Posology).



Figure 1: Example of levodopa plasma concentration/time profile for a total daily dose of 800 mg levodopa with morning dose (176 mg) and continuous maintenance dose (45 mg/h) over the day. (Simulation from a population PK model).


Distribution
The distribution volume for both levodopa (0.36–1.6 l/kg) and entacapone (0.27 l/kg) at steady state is relatively small, while data for carbidopa is not available.

Levodopa is bound to plasma proteins to a low extent (approximately 10–30%) and carbidopa is bound to approximately 36%, while entacapone is highly bound (approximately 98%) –mainly to serum albumin. At therapeutic concentrations, entacapone does not interfere with other highly protein-bound active substances (e.g. warfarin, salicylic acid, phenylbutazone or diazepam), nor is it significantly impaired by any of these drugs at therapeutic or higher concentrations.
Biotransformation and elimination
Levodopa is largely metabolised to different metabolites: decarboxylation with dopadecarboxylase (DDC) and O-methylation with COMT are the major metabolic pathways.

Carbidopa is metabolised to two main metabolites that are primarily eliminated in the urine as glucuronides or unconjugated compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.

Entacapone is almost completely metabolised, and the metabolites are excreted via urine (10–20%) and bile/faeces (80–90%). The primary metabolic pathway is glucuronidation of entacapone and its active metabolite, cis-isomer. The cis-isomer accounts for approximately 5% of the total amount in plasma.

Total clearance is within the range 0.55–1.38 l/kg/hour for levodopa and approximately 0.70 l/kg/hour for entacapone. The half-life is 0.6–1.3 hours for levodopa, 2–3 hours for carbidopa, and 0.4–0.7 hours for entacapone when given separately. The mean estimated half-life for levodopa during treatment with Lecigon was 2.0 hours.

Data from in vitro studies with human liver microsome preparations indicates that entacapone inhibits cytochrome P450 2C9 (IC50 ~ 4 µM). Entacapone showed little or no inhibition of other types of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19).

Special populations

Elderly
When levodopa is administered without carbidopa and entacapone, the absorption of levodopa is higher and elimination slower in the elderly than in younger subjects. However, following administration of levodopa in combination with carbidopa, the absorption of levodopa is similar between elderly and younger subjects, but the AUC is still 1.5 times higher in elderly due to age- related decrease in DDC activity and clearance. There are no significant AUC differences for carbidopa or entacapone between younger (45–64 years) and elderly (65–75 years) subjects.

Gender
The bioavailability of levodopa is significantly higher in women than in men, even in the presence of entacapone. This difference is mainly due to the difference in body weight. There is no difference between gender with regard to the bioavailability of carbidopa or entacapone.

Hepatic impairment
The metabolism of entacapone is slowed in patients with mild to moderate hepatic impairment (Child- Pugh Class A and B), leading to an increased plasma concentration of entacapone in both the absorption and elimination phases (see sections 4.2, 4.3 and 4.4). There are no specific pharmacokinetic studies of levodopa and carbidopa in patients with hepatic impairment. However, it is recommended that Lecigon is administered with caution in patients with mild to moderate hepatic impairment. Lecigon should not be used in patients with severe hepatic impairment; see section 4.3.

Renal impairment
Renal impairment does not affect the pharmacokinetics of entacapone. There are no specific pharmacokinetic studies of levodopa and carbidopa in patients with renal impairment. It is therefore recommended that dose titration is made with caution in patients with severe renal impairment, including those receiving dialysis treatment (see section 4.2).