Levodopa Other names: L-dopa L-3,4-dihydroxyphenylalanine

Levodopa is a precursor of dopamine, and is given as dopamine replacement therapy in Parkinson's disease.

Absorption

The pharmacokinetics of levodopa 66 mg (2 x 33 mg capsules) and carbidopa/levodopa 25 mg/100 mg immediate release tablets was evaluated in 24 healthy volunteers in a fasted state receiving a total of 50 mg carbidopa every 8 hours.

The median time to maximal plasma concentration of levodopa was 30 minutes after a dose of levodopa 66 mg (2 x 33 mg capsules) compared to 45 minutes after a dose of carbidopa/levodopa 25 mg/100 mg immediate release tablets. The dose-normalised relative bioavailability of a single 66 mg emitted dose of levodopa was 88.0% (90% CI: 80.3, 96.4) when compared to a single oral carbidopa/levodopa 25 mg/100 mg dose.

The mean maximal plasma concentration at 10 minutes (C_10min) and at peak concentration (C_max) of levodopa following administration of levodopa 66 mg (2 x 33 mg capsules) was 418 ng/mL and 696 ng/mL, respectively, with exposure over 4 hours (AUC_0-4h) of 1,280 ng●h/mL.

Distribution

Apparent volume of distribution (V_z/F) was 168 L for levodopa 66 mg (2 x 33 mg capsules).

Biotransformation

Levodopa is extensively metabolised to various metabolites. The two major metabolic pathways are decarboxylation by L-aromatic amino acid decarboxylase and O-methylation by catechol-O-methyltransferase (COMT).

The pharmacokinetics of the major levodopa metabolites 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were studied following administration of a single inhaled dose of levodopa and a single oral carbidopa/levodopa 25 mg/100 mg immediate release tablet. The metabolite profile following levodopa inhalation was not substantially different than that observed following oral carbidopa/levodopa administration. The peak metabolite concentrations and total exposure achieved after levodopa administration did not exceed those observed following an oral carbidopa/levodopa dose.

The impact of the amount of circulating dopa-decarboxylase at the end of an oral carbidopa/levodopa dosing interval on the efficacy of levodopa was not studied.

Elimination

In the presence of carbidopa, the apparent terminal elimination half-life (t_1/2) of levodopa following a single administration of levodopa 66 mg (2 x 33 mg capsules) was 2.3 hours and comparable to that following an oral dose of carbidopa/levodopa 25 mg/100 mg immediate release tablets of 1.9 hours.

Linearity/non-linearity

Levodopa shows dose proportional pharmacokinetics of levodopa from 13 mg to 122 mg.

Renal impairment

Levodopa has not specifically been studied in patients with renal impairment. It is recommended to administer this medicinal product cautiously to patients with severe renal disease.

Hepatic impairment

Levodopa has not specifically been studied in patients with hepatic impairment. It is recommended to administer this medicinal product cautiously to patients with severe hepatic impairment.

Gender

A clinical study was performed with levodopa 66 mg (2 x 33 mg capsules) in 24 healthy subjects (13 men and 11 women). After administration of levodopa the C_max and AUC_0-24h for women were 42.2% higher and 48.8% higher than for men, respectively. After correcting the parameters for body weight, the gender difference after each treatment was no longer significant: the body-weight adjusted C_max and AUC_0-24h after a dose of levodopa in women were 9.7% and 15.1% higher than men. Most of the gender difference is accounted for by differences in body weight. No dose adjustment is required based on gender.

Smoking

A clinical study was performed with levodopa 66 mg (2 x 33 mg capsules) administered to 56 healthy subjects (31 non-smokers and 25 smokers). After administration of levodopa the C_max and AUC_0-24h was 11% to 12% higher for smokers than for non-smokers. No dose adjustment is required based on smoking status.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Reproductive toxicity

Levodopa has caused visceral and skeletal malformations in rabbits. No effects were seen on male or female reproductive organs in repeat dose toxicology studies in mice, rats or monkeys with levodopa alone.