Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-parkinson drugs, dopa and dopa derivatives, ATC code: N04BA03.
According to the 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 DDC inhibitors which reduce the peripheral metabolism of levodopa to dopamine, and thus, more levodopa is 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 adverse reactions such as nausea is reduced.
With 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 two 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 first study, entacapone increased the mean daily ON time by 1 h 20 min (CI 95% 45 min, 1 h 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 second 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 tablet 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.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

General characteristics of the active substances
Absorption/distribution
There are substantial inter- and intra-individual variations in the absorption of levodopa, carbidopa and entacapone. Both levodopa and entacapone are rapidly absorbed and eliminated. Carbidopa is absorbed and eliminated slightly slower compared with levodopa. When given separately without the two other active substances, the bioavailability of levodopa is 15-33 %, for carbidopa 40-70 % and for 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 while no data for carbidopa are available.
Levodopa is bound to plasma protein only to a minor extent (about 10-30%) and carbidopa is bound approximately 36%, while entacapone is extensively bound to plasma proteins (about 98%), mainly to serum albumin. At therapeutic concentrations, entacapone does not displace other extensively bound active substances (e.g. warfarin, salicylic acid, phenylbutazone, or diazepam), nor is it displaced to any significant extent by any of these substances at therapeutic or higher concentrations.

Biotransformation and elimination
Levodopa is extensively metabolised to various metabolites: decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase (COMT) being the most important pathways.
Carbidopa is metabolized to two 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 metabolized prior to excretion via urine (10 to 20%) and bile/faeces (80 to 90%). The main metabolic pathway is glucuronidation of entacapone and its active metabolite, the cis- isomer, which accounts for about 5% of plasma total amount.
Total clearance for levodopa is in the range of 0.55-1.38 l/kg/h and for entacapone is in the range of 0.70 l/kg/h. The elimination-half life (t1/2) is 0.6-1.3 hours for levodopa, 2-3 hours for carbidopa and 0.4-0.7 hours 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 P450 2C9 (IC50 ~ 4 µM). Entacapone showed little or no inhibition of other types of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19); (see section 4.5).

Characteristics in patients

Elderly
When given without carbidopa and entacapone, the absorption of levodopa is greater and elimination is slower in elderly than in young people. However, after combination of carbidopa with levodopa, the absorption of levodopa is similar between the elderly and the young people, but the AUC is still 1.5 fold greater in the elderly due to decreased DDC activity and lower clearance caused by aging. There are no significant differences in the AUC of carbidopa or entacapone between younger (45–64 years) and elderly subjects (65–75 years).

Gender
Bioavailability of levodopa is significantly higher in women than in men. In the pharmacokinetic studies with Stalevo the bioavailability of levodopa is higher in women than in men, primarily due to the difference in body weight, while there is no gender difference with carbidopa and 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 both in the absorption and elimination phases (see sections 4.2 and 4.3). No particular studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment are reported, however, it is advised that Stalevo should be administered cautiously to patients with mild or moderate hepatic impairment.

Renal impairment
Renal impairment does not affect the pharmacokinetics of entacapone. No particular studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment. However, a longer dosing interval of Stalevo may be considered for patients who are receiving dialysis therapy (see section 4.2).