Pharmacotherapeutic Group: Madopar is a combination of levodopa and the decarboxylase inhibitor benserazide. ATC Code: N04BA02.
Pharmacology: Pharmacodynamics: Mechanism of Action: Parkinson's disease: Dopamine, which acts as a neurotransmitter in the brain, is not present in sufficient quantities in the basal ganglia of parkinsonian patients. Levodopa (INN) of L-DOPA (3,4-dihydroxy L-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 (CNS), it is metabolized 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 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.
Pharmacokinetics: Absorption: Standard forms: 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.
Capsules and tablets of standard Madopar are bioequivalent.
The maximum plasma concentration of levodopa and the extent of levodopa absorption (AUC) increase proportionately 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%.
Dispersible form: 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.
Controlled release form: The pharmacokinetic properties of Madopar HBS differ from those of standard Madopar (capsules, tablets) 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 post-prandial administration of Madopar HBS.
Distribution: Levodopa crosses the gastric mucosa and the blood-brain barrier by a saturable transport system. It is not bound to plasma proteins and its volume of distribution is 57 liters. 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.
Metabolism: Levodopa is metabolized 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-O-methyltransferase 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 acids, dihydroxyphenylacetic acid).
Benserazide is hydroxylated into trihydroxybenzylhydrazine in the intestinal mucosa and the liver. This metabolite is a potent inhibitor of the aromatic amino acid decarboxylase.
Elimination: 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 geriatric patients (65-78 years of age) with Parkinson's disease (see Pharmacokinetics in Special Populations as follows). 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 feces (24%).
Pharmacokinetics in Special Populations: No pharmacokinetic data are available in uremic and hepatic patients.
Effect of age on pharmacokinetics of levodopa: 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.
Toxicology: Nonclinical Safety: Carcinogenicity: No carcinogenicity studies have been performed to establish the carcinogenic potential of Madopar.
Mutagenicity: Madopar and its constituents (levodopa and benserazide) were not observed to be mutagenic in the Ames test. No further data are available.
Impairment of Fertility: No fertility studies on animals have been performed to evaluate the effect of Madopar.
Reproductive toxicity: Animal studies have shown the possibility of disturbed fetal skeletal development.
General toxicity studies with benserazide in adult rats have shown the possibility of an interference with the epiphyses (growth plates) of bones. The skeletal growth plates of humans close at around the time of puberty, whilst those of rodents remain active into adulthood. There is thus a theoretical risk of disturbed fetal skeletal growth in the human child.
Teratogenicity studies showed no dysmorphic effects or effects on pre-natal skeletal development in mice (400 mg/kg) and rats (600 mg/kg; 250 mg/kg).
At maternally toxic dose levels, intrauterine deaths increased (rabbits) and/or fetal weight decreased (rats).
Other: General toxicological studies in rats have shown the possibility of disturbed skeletal development.