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Sinemet: factors affecting variability - gastric emptying

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Sage et al 1994 summarily present factors which affect availability of levodopa.

Roos et al 1993 compare C/L levels after empty-stomach ingestion with C/L levels after C/L has been ingested with a meal.

Chen et al 2012 describe a newer form of controlled release Sinemet: gastric-retentive extended-release formulations.

1. Pharmacokinetics of continuous-release carbidopa/levodopa.

Review article.

Sage JI, et al. Clin Neuropharmacol. 1994.


This article reviews the pharmacokinetics of Sinemet CR, a controlled-release (CR) levodopa preparation. The main influences on the kinetic profile are as follows: absorption, which depends on the dissolution characteristics of the tablet, the pattern of gastric emptying, and the rate of uptake in the small intestine; distribution, which is determined by rates of levodopa transport from gut to blood and from blood to brain; and biotransformation, which is affected peripherally by L-aromatic amino acid decarboxylase (LAAAD) and catechol-O-methyl transferase (COMT), and centrally by LAAAD, COMT, and monoamine oxidase. The kinetics of Sinemet CR are limited by rates of absorption (which depend on the dose administered), the conformation of the tablet, and daily variations in the patterns of gastric emptying (influenced by the presence or absence of food). Levodopa must also compete with food-derived amino acids for transport across the gut-blood and blood-brain barriers; this competition effectively limits the drug's rate of distribution. Finally, biotransformation is limited by the activity of LAAAD and COMT in the periphery. Plasma profiles of levodopa after administration of Sinemet CR can vary, depending on the age of the patient and the time of day when the drug is administered. Nevertheless, the pharmacokinetic profile of the preparation has a number of advantages over that of Sinemet, in that it offers a steadier climb to peak plasma concentrations that are less extreme and of greater duration.

PMID: 9358189

2. The influence of a standard meal on Sinemet CR absorption in patients with Parkinson's disease.

Roos RA, et al. Clin Neurol Neurosurg. 1993.


We studied the influence of dietary protein intake on the plasma level profile of levodopa, carbidopa, and 3-O-methyldopa and clinical efficacy in 12 patients with idiopathic Parkinson's disease after intake of one levodopa-carbidopa 200/50 controlled release tablet (Sinemet CR; LC-CR). The tablet was given 1 h before the protein rich meal on one day (fasted) and together with the meal on an other day (non-fasted). Higher levodopa and carbidopa concentrations were reached when the LC-CR was taken 1 h before the meal, but the plasma level profile for levodopa was flatter in the non-fasted state. The area under the curve for levodopa was slightly higher in the fasted condition. For the clinical variables walking and tapping slightly better clinical results (P = 0.08) were found in the fasted condition with the higher levodopa levels. If the patient on levodopa is in a clinically satisfactory condition, then non-fasted condition could be preferred because of the smooth plasma level profile demonstrated. However, if the initial levodopa concentrations are not in the critical range to be effective for the patient, the advice should be to take the drug in a fasted condition.

PMID: 8242964.

3. Pharmacokinetics of levodopa/carbidopa delivered from gastric-retentive extended-release formulations in patients with Parkinson's disease.

Randomized controlled trial.

Chen C, et al. J Clin Pharmacol. 2012.


The investigators conducted a single-dose pharmacokinetic (PK) study of levodopa/carbidopa delivered from novel gastric-retentive extended-release (ER) tablets versus a comparator ER tablet (M-ER) in patients with Parkinson's disease. Two levodopa/carbidopa (200 mg/50 mg) gastric-retentive ER formulations (4 hours and 6 hours) and M-ER were administered orally with food. Blood samples were collected for up to 24 hours post dose to determine levodopa and carbidopa concentrations. Tolerability was assessed by monitoring adverse events and measuring vital signs. PK modeling was conducted to estimate the release characteristics for future gastric-retentive ER formulations to achieve a less fluctuating plasma concentration profiles. Compared with M-ER, both gastric-retentive ER formulations exhibited a longer time to reach a lower maximal plasma concentration for levodopa and carbidopa. The 4-hour formulation demonstrated a similar area under the concentration-time curve compared with M-ER, whereas the 6-hour formulation demonstrated a lower area under the concentration-time curve. All formulations were well tolerated. Modeling suggests that a gastric-retentive ER formulation with a longer release duration administered twice daily may achieve a less fluctuating levodopa concentration profile than M-ER administered 3 times daily. This study demonstrates that gastric-retentive ER dosage forms may reduce dose frequency while minimizing the plasma peak-to-trough fluctuation and consequently reduce motor fluctuation in patients with Parkinson's disease.

PMID: 21610205.

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I am currently experimenting with a combination of IR and CR Sinemet. I will try taking a 50/25 IR with morning coffee and a 100/50 CR with my nuts/muesli/fresh fruit breakfast to go for a smoother profile. Its very hit and miss at low dosage - could do with an app to measure my tremor!

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