CLINICAL PHARMACOLOGY
Mechanism of Action
Levodopa
Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease because it does not cross the blood-brain barrier. However, levodopa the metabolic precursor of dopamine, does cross the blood-brain barrier, and is presumably converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves the symptoms of Parkinson's disease.
Carbidopa
When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for delivery to the brain.
Entacapone
Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).
COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include DOPA, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. When decarboxylation of levodopa is prevented by carbidopa, COMT becomes the major metabolizing enzyme for levodopa, catalyzing its metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD).
Pharmacokinetics
The pharmacokinetics of Stalevo tablets has been studied in healthy subjects (age 45 years to 75 years). Overall, following administration of corresponding doses of levodopa, carbidopa and entacapone as Stalevo or as carbidopa and levodopa product plus Comtan (entacapone) tablets, the mean plasma concentrations of levodopa, carbidopa, and entacapone are comparable.
Absorption and Distribution
Both levodopa and entacapone are rapidly absorbed and eliminated, and their distribution volume is moderately small. Carbidopa is absorbed and eliminated slightly more slowly compared with levodopa and entacapone. There are substantial inter- and intra-individual variations in the absorption of levodopa, carbidopa and entacapone, particularly concerning its Cmax.
The food-effect on the Stalevo tablet has not been evaluated. Because levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients after eating a high protein meal. Meals rich in large neutral amino acids may delay and reduce the absorption of levodopa [see Patient Counseling Information
].
Levodopa
The pharmacokinetic properties of levodopa following the administration of single-dose Stalevo (carbidopa, levodopa and entacapone) tablets are summarized in Table 3.
Table 3: Pharmacokinetic Characteristics of Levodopa with Different Tablet Strengths of Stalevo (mean ± SD)
|
AUC0-∞
|
Cmax
|
Tmax
|
Tablet Strength |
(nanogram∙h per mL) |
(nanogram per mL) |
(h) |
12.5 mg per 50 mg per 200 mg |
1,040 ± 314 |
470 ± 154 |
1.1 ± 0.5 |
25 mg per 100 mg per 200 mg |
2,910 ± 715 |
975 ± 247 |
1.4 ± 0.6 |
37.5 mg per 150 mg per 200 mg |
3,770 ± 1,120 |
1,270 ± 329 |
1.5 ± 0.9 |
50 mg per 200 mg per 200 mg |
6,115 ± 1,536 |
1,859 ± 455 |
1.76 ± 0.7 |
Levodopa is bound to plasma protein only to a minor extent (about 10% to 30%).
Carbidopa
Following administration of Stalevo as a single dose to healthy male and female subjects, the peak concentration of carbidopa was reached within 2.5 hours to 3.4 hours on average. The mean Cmax ranged from about 40 nanogram per mL to 225 nanogram per mL and the mean AUC from 170 nanogram∙h per mL to 1,200 nanogram∙h per mL, with different Stalevo strengths providing 12.5 mg, 25 mg, 37.5 mg, or 50 mg of carbidopa.
Carbidopa is approximately 36% bound to plasma protein.
Entacapone
Following administration of Stalevo as a single dose to healthy male and female subjects, the peak concentration of entacapone in plasma was reached within 0.8 hour to 1.2 hours on average. The mean Cmax of entacapone was about 1,200 nanogram per mL to 1,500 nanogram per mL and the AUC 1,250 nanogram∙h per mL to 1,750 nanagram∙h per mL after administration of different Stalevo strengths all providing 200 mg of entacapone.
The plasma protein binding of entacapone is 98% over the concentration range of 0.4 mcg per mL to 50 mcg per mL. Entacapone binds mainly to serum albumin.
Metabolism and Elimination
Levodopa
The elimination half-life of levodopa, the active moiety of antiparkinsonian activity, was 1.7 hours (range 1.1 hours to 3.2 hours).
Levodopa is extensively metabolized to various metabolites. Two major pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by COMT.
Carbidopa
The elimination half-life of carbidopa was on average 1.6 hours to 2 hours (range 0.7 hour to 4.0 hours).
Carbidopa is metabolized to two main metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid). These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion.
Entacapone
The elimination half-life of entacapone was on average 0.8 hour to 1 hour (0.3 hour to 4.5 hours).
Entacapone is almost completely metabolized prior to excretion with only a very small amount (0.2% of dose) found unchanged in urine. The main metabolic pathway is isomerization to the cis-isomer, the only active metabolite. Entacapone and the cis-isomer are eliminated in the urine as glucuronide conjugates. The glucuronides account for 95% of all urinary metabolites (70% as parent and 25% as cis-isomer glucuronides). The glucuronide conjugate of the cis-isomer is inactive. After oral administration of a 14C-labeled dose of entacapone, 10% of labeled parent and metabolite is excreted in urine and 90% in feces.
Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs when they are administered repeatedly.
Renal Impairment
Entacapone
The pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose in subjects with normal, moderate, and severely impaired renal functions, without levodopa and dopa decarboxylase inhibitor coadministration. No significant effects of renal function on the pharmacokinetics of entacapone were found.
Levodopa and carbidopa
No studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment.
Hepatic Impairment
Entacapone
Hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone. A single 200 mg dose of entacapone, without levodopa and dopa decarboxylase inhibitor coadministration, showed approximately 2-fold higher AUC and Cmax values in patients with a history of alcoholism and hepatic impairment (n=10) compared to normal subjects (n=10). All patients had biopsy-proven liver cirrhosis caused by alcohol. According to Child-Pugh grading 7 patients with liver disease had mild hepatic impairment and 3 patients had moderate hepatic impairment. As only about 10% of the entacapone dose is excreted in urine, as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug. Stalevo should be administered with care to patients with biliary obstruction or hepatic disease.
Levodopa and carbidopa
There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with hepatic impairment.
Geriatric Use
In the pharmacokinetics studies conducted in healthy volunteers following a single dose of carbidopa-, levodopa- and entacapone (as Stalevo or as separate carbidopa/levodopa and Comtan tablets):
Levodopa
The AUC of levodopa is significantly (on average 10% to 20%) higher in elderly (60 years to 75 years) than younger subjects (45 years to 60 years). There is no significant difference in the Cmax of levodopa between younger (45 years to 60 years) and elderly subjects (60 years to 75 years).
Carbidopa
There is no significant difference in the Cmax and AUC of carbidopa, between younger (45 years to 60 years) and elderly subjects (60 years to 75 years).
Entacapone
The AUC of entacapone is significantly (on average, 15%) higher in elderly (60 years to 75 years) than younger subjects (45 years to 60 years). There is no significant difference in the Cmax of entacapone between younger (45 years to 60 years) and elderly subjects (60 years to 75 years).
Gender
Pharmacokinetics following a single dose of carbidopa, levodopa and entacapone together, either as Stalevo or as separate carbidopa/levodopa and Comtan tablets in healthy volunteers (age range 45 years to 74 years):
Levodopa
The plasma exposure (AUC and Cmax) of levodopa is significantly higher in females than males (on average, 40% for AUC and 30% for Cmax). These differences are primarily explained by body weight. Other published literature showed significant gender effect (higher concentrations in females) even after correction for body weight.
Carbidopa
There is no gender difference in the pharmacokinetics of carbidopa.
Entacapone
There is no gender difference in the pharmacokinetics of entacapone.
Drug Metabolized by COMT
When a single 400 mg dose of entacapone was given together with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa and dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and epinephrine, respectively.
Drugs known to be metabolized by COMT should be administered with caution in patients receiving entacapone regardless of the route of administration [see Drug Interactions
].
Drugs Metabolized via CYP2C9
Due to its affinity to CYP2C9 in vitro, entacapone may potentially interfere with medicinal products with metabolism dependent on this isoenzyme. In an interaction study in healthy volunteers, entacapone increased the AUC of R-warfarin on average by 18%, and the INR values increased on average by 13% [see Drug Interactions
].
Hormone Levels
Of the ingredients in Stalevo, levodopa is known to depress prolactin secretion and increase growth hormone levels.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In rats, oral administration of carbidopa-levodopa for 2 years resulted in no evidence of carcinogenicity at doses of approximately 2 times (carbidopa)-4 times (levodopa) the maximum recommended human dose (MRHD).
Two-year carcinogenicity studies of entacapone were conducted in mice and rats. Mice were treated once daily by oral gavage with doses of 20, 100, or 600 mg/kg/day (0.05, 0.3, or 2 times the MRHD on a mg/m2 basis). Because of a high incidence of premature mortality in mice receiving the highest dose of entacapone, the mouse study is not an adequate assessment of carcinogenicity. Rats were treated with entacapone at oral doses of 20, 90, or 400 mg/kg/day. An increased incidence of renal tubular adenomas and carcinomas was found in male rats treated with the highest dose of entacapone. Plasma exposures (AUC) associated with the highest dose not associated with increased renal tumors were approximately 5 times that in humans at the MRHD of entacapone.
The carcinogenic potential of entacapone administered in combination with carbidopa-levodopa has not been evaluated.
Mutagenesis
Carbidopa was mutagenic in the in vitro bacterial reverse mutation (Ames) assay in the presence and absence of metabolic activation, and in the in vitro mouse lymphoma thymidine kinase (tk) assay in the absence of metabolic activation. Carbidopa was negative in the in vivo mouse micronucleus assay.
Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the presence and absence of metabolic activation, and was clastogenic in cultured human lymphocytes in the presence of metabolic activation. Entacapone, either alone or in combination with carbidopa-levodopa, was negative in the in vivo mouse micronucleus and in the Ames assays.
Impairment of Fertility
In reproduction studies, no effects on fertility were found in rats receiving carbidopa-levodopa at doses of approximately 2 times (carbidopa)-4 times (levodopa) the MRHD.
In rats treated orally with entacapone (up to 700 mg/kg/day), no effects on fertility or general reproductive performance were observed. Plasma exposures (AUC) at the highest dose tested were approximately 30 times that in humans at the MRHD of entacapone. Delayed mating was evident in females at the highest dose tested.
|