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Antiparkinsonian dopaminergic drug.
Pharmacology: Pharmacodynamics: According to current understanding, the symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Dopamine does not cross the blood-brain barrier. Levodopa, the precursor of dopamine, crosses the blood-brain barrier and relieves the symptoms of the disease. As levodopa is extensively metabolised in the periphery, only a small portion of a given dose reaches the central nervous system when levodopa is administered without metabolic enzyme inhibitors.
Carbidopa and benserazide are peripheral dopa decarboxylase (DDC) inhibitors which reduce the peripheral metabolism of levodopa to dopamine, resulting in an increase in the amount of levodopa available to the brain. When decarboxylation of levodopa is reduced with the co-administration of a DDC inhibitor, a lower dose of levodopa can be used and the incidence of undesirable effects eg, nausea is reduced.
With the inhibition of the decarboxylase by a DDC inhibitor, catechol O-methyltransferase (COMT) becomes the major peripheral metabolic pathway catalyzing the conversion of levodopa to 3-O-methyldopa (3-OMD), a potentially harmful metabolite of levodopa. Entacapone is a reversible, specific and mainly peripherally acting COMT inhibitor designed for concomitant administration with levodopa. Entacapone slows the clearance of levodopa from the bloodstream resulting in an increased area under the curve (AUC) in the pharmacokinetic profile of levodopa. Consequently the clinical response to each dose of levodopa is enhanced and prolonged.
The evidence of the therapeutic effects of Stalevo is based on 2 phase III double-blind studies, in which 376 Parkinson's disease patients with end-of-dose motor fluctuations received either entacapone or placebo with each levodopa/DDC inhibitor dose. Daily ON time with and without entacapone was recorded in home-diaries by patients. In the 1st study, entacapone increased the mean daily ON time by 1 hr 20 min (CI95% 45 min, 1 hr 56 min) from baseline. This corresponded to an 8.3% increase in the proportion of daily ON time. Correspondingly, the decrease in daily OFF time was 24% in the entacapone group and 0% in the placebo group. In the 2nd study, the mean proportion of daily ON time increased by 4.5% (CI95% 0.93%, 7.97%) from baseline. This is translated to a mean increase of 35 min in the daily ON time. Correspondingly, the daily OFF time decreased by 18% on entacapone and by 5% on placebo. Because the effects of Stalevo tablets are equivalent with entacapone 200-mg tab administered concomitantly with the commercially available standard release carbidopa/levodopa preparations in corresponding doses these results are applicable to describe the effects of Stalevo as well.
Pharmacokinetics: General Characteristics of the Active Substances: Absorption/Distribution: There are substantial inter- and intraindividual variations in the absorption of levodopa, carbidopa and entacapone. Both levodopa and entacapone are rapidly absorbed and eliminated. Carbidopa is absorbed and eliminated slightly more slowly than levodopa. When given separately without the other 2 active substances, the bioavailability of levodopa is 15-33%, that of carbidopa 40-70% and that of entacapone 35% after a 200-mg oral dose. Meals rich in large neutral amino acids may delay and reduce the absorption of levodopa. Food does not significantly affect the absorption of entacapone. The distribution volume of both levodopa (Vd 0.36-1.6 L/kg) and entacapone (Vdss 0.27 L/kg) is moderately small; no data are available for carbidopa.
Levodopa is bound to plasma proteins only to a minor extent (about 10-30%), while carbidopa is bound approximately 36%, and while entacapone is extensively bound (about 98%), mainly to serum albumin. At therapeutic concentrations, entacapone does not displace other extensively bound active substances (eg, warfarin, salicylic acid, phenylbutazone or diazepam), nor is it displaced to any significant extent by any of these substances at therapeutic or higher concentrations.
Metabolism and Elimination: Levodopa is extensively metabolised to various metabolites, decarboxylation by DDC and O-methylation by catechol-O-methyltransferase (COMT) being the most important pathways.
Carbidopa is metabolised to 2 main metabolites which are excreted in the urine as glucuronides and unconjugated compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.
Entacapone is almost completely metabolised prior to excretion via urine (10-20%) and bile/faeces (80-90%). The main metabolic pathway is glucuronidation of entacapone and its active metabolite, the cis-isomer, which accounts for about 5% of the total amount in plasma.
Total clearance of levodopa is in the range of 0.55-1.38 L/kg/hr and that of entacapone is in the range of 0.7 L/kg/hr. The elimination-half life (t½) is 0.6-1.3 hrs for levodopa, 2-3 hrs for carbidopa and 0.4-0.7 hrs for entacapone, each given separately.
Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs on repeated administration.
Data from in vitro studies using human liver microsomal preparations indicate that entacapone inhibits cytochrome P-450 2C9 (IC50~4 micromole). Entacapone showed little or no inhibition of other types of P-450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19) (see Interactions).
Toxicology: Preclinical Safety Data: Preclinical data for levodopa, carbidopa and entacapone tested alone or in combination revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. In repeated dose toxicity studies with entacapone, anaemia, most probably due to iron chelating properties of entacapone, was observed. Regarding reproduction toxicity of entacapone, decreased foetal weight and a slightly delayed bone development were noticed in rabbits treated at systemic exposure levels in the therapeutic range. Both levodopa and combinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits.
