Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2021 Publisher: Roche Products (New Zealand) Limited, PO Box 109113, Newmarket, Auckland 1149, NEW ZEALAND, Medical enquiries: 0800 276 243
Pharmacotherapeutic group: Anti-parkinson drugs
ATC code: N04BA02
Dopamine, which acts as a neurotransmitter in the brain, is not present in sufficient quantities in the basal ganglia of parkinsonian patients. Levodopa or L-DOPA (3,4-dihydroxy phenylalanine) is an intermediate in dopamine biosynthesis. Levodopa (dopamine precursor) is used as a prodrug to increase dopamine levels since it is able to cross the blood-brain barrier whereas dopamine itself cannot. Once levodopa has entered the central nervous system, it is metabolised to dopamine by aromatic L-amino acid decarboxylase After administration, levodopa is rapidly decarboxylated to dopamine in extracerebral as well as cerebral tissues. As a result, most of the levodopa administered is not available to the basal ganglia, and the dopamine produced peripherally frequently causes unwanted effects. It is therefore particularly desirable to inhibit extracerebral decarboxylation of levodopa. This can be achieved by simultaneous administration of levodopa and benserazide, a peripheral decarboxylase inhibitor.
Madopar is a combination of these two substances in a ratio of 4:1 – this ratio having proved optimal in clinical trials and therapeutic use – and is just as effective as large doses of levodopa given alone.
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Levodopa is mainly absorbed from the upper regions of the small intestine, and absorption there is independent of the site. Maximum plasma concentrations of levodopa are reached approximately one hour after ingestion of standard Madopar.
The maximum plasma concentration of levodopa and the extent of levodopa absorption (AUC) increase proportionally with dose (50-200 mg levodopa).
Food intake reduces the rate and extent of levodopa absorption. The peak levodopa plasma concentration is 30% lower and occurs later when standard Madopar is administered after a standard meal. The extent of levodopa absorption is reduced by 15%.
The pharmacokinetic profiles of levodopa following administration of Madopar dispersible in healthy volunteers and parkinsonian patients are very similar to those following administration of standard Madopar, but time to peak concentrations tends to be shorter after Madopar dispersible. There is less interindividual variability in absorption parameters for Madopar dispersible taken as a suspension.
The pharmacokinetic properties of Madopar HBS differ from those of standard Madopar (capsules) and dispersible form. The active ingredients are released slowly in the stomach. Maximum plasma concentrations of levodopa, which are 20-30% of those achieved with the standard dosage forms, are reached about 3 hours after administration. The plasma concentration-time curve shows a longer ‘half-value duration’ (time span during which plasma concentrations are equal to or exceed half the maximum concentration) than with standard Madopar, which indicates pronounced controlled-release properties. The bioavailability of Madopar HBS is 50-70% of that of standard Madopar and is not affected by food. Maximum plasma concentrations of levodopa are not affected by food, but occur later (5 hours) after postprandial administration of Madopar HBS.
Levodopa crosses the blood-brain barrier by a saturable transport system. It is not bound to plasma proteins, and its volume of distribution is 57 litres. The AUC of levodopa in cerebrospinal fluid is 12% of that in plasma.
In contrast to levodopa, benserazide does not penetrate the blood-brain barrier at therapeutic doses. It is concentrated mainly in the kidneys, lungs, small intestine and liver.
Levodopa is metabolised by two major pathways (decarboxylation and O-methylation) and two minor ones (transamination and oxidation).
Aromatic amino acid decarboxylase converts levodopa to dopamine. The major end-products of this pathway are homovanillic acid and dihydroxyphenylacetic acid. Catechol-Omethyltransferase methylates levodopa to 3-O-methyldopa. This major plasma metabolite has an elimination half-life of 15 hours, and it accumulates in patients who receive therapeutic doses of Madopar.
Decreased peripheral decarboxylation of levodopa when it is administered with benserazide is reflected in higher plasma levels of levodopa and 3-O-methyldopa and lower plasma levels of catecholamines (dopamine, noradrenaline) and phenolcarboxylic acids (homovanillic acid, dihydroxyphenylacetic acid).
Benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver. This metabolite is a potent inhibitor of the aromatic amino acid decarboxylase.
In the presence of peripherally inhibited levodopa decarboxylase the elimination half-life of levodopa is approximately 1.5 hours. The elimination half-life is slightly longer (approximately 25%) in elderly patients (65-78 years of age) with Parkinson’s disease (see Pharmacokinetics in special populations). The clearance of levodopa from plasma is about 430 mL/min.
Benserazide is almost entirely eliminated by metabolism. The metabolites are mainly excreted in the urine (64%) and to a smaller extent in faeces (24%).
No pharmacokinetic data are available in uraemic and hepatic patients.
In older Parkinsonian patients (65-78 years of age) both the elimination half-life and the AUC of levodopa is about 25% higher than in younger patients (34-64 years of age). The statistically significant age effect is clinically negligible and is of minor importance for the dosing schedule of any indication.
Carcinogenicity studies were not conducted with Madopar.
Madopar and its constituents (levodopa and benserazide) were not observed to be mutagenic in the Ames test. No further data are available.
No animal studies on fertility were performed with Madopar.
Teratogenicity studies showed no teratogenic effects or effects on skeletal development in mice (400 mg/kg; rats (600 mg/kg; 250 mg/kg), and rabbits (120 mg/kg; 150 mg/kg). At maternally toxic dose levels, intrauterine deaths increased (rabbits) and/or foetal weight decreased (rats).
General toxicological studies in rats have shown the possibility of disturbed foetal skeletal development.
No further animal data of relevance are available.
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