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Comparative multiple-dose pharmacokinetics of controlled-release levodopa products
A Grahnén1, S A Eckernäs, C Collin
1Pharmaco Medical Consultants, PMC AB, Uppsala, Sweden.
European Neurology
|January 1, 1992
Summary
Controlled-release levodopa formulations, Madopar HBS and Sinemet CR, show improved pharmacokinetic profiles and tolerability compared to conventional Madopar. Madopar HBS demonstrated superior tolerability, likely due to more efficient dopamine inhibition.
Area of Science:
- Pharmacology
- Drug Delivery Systems
- Clinical Pharmacokinetics
Background:
- Levodopa is a primary treatment for Parkinson's disease, but its short half-life necessitates frequent dosing and can lead to motor fluctuations.
- Controlled-release formulations aim to provide more stable plasma concentrations of levodopa, potentially improving therapeutic outcomes and reducing side effects.
- Understanding the pharmacokinetic and tolerability profiles of different controlled-release levodopa products is crucial for optimizing patient management.
Purpose of the Study:
- To compare the multiple-dose pharmacokinetic profiles of two controlled-release levodopa formulations (Madopar HBS and Sinemet CR) against conventional Madopar capsules.
- To evaluate the bioavailability, Cmax, Cmin, and fluctuation index of these formulations.
- To assess the tolerability and adverse event profiles associated with each formulation.
Main Methods:
- A randomized, cross-over study involving 18 healthy volunteers.
- Multiple-dose administration of 200 mg levodopa three times daily (t.i.d.) for each formulation.
- Pharmacokinetic parameters including Cmax, Cmin, and bioavailability were measured.
- Adverse events were systematically recorded and compared across formulations.
Main Results:
- Both Madopar HBS and Sinemet CR demonstrated a pronounced controlled-release profile, significantly reducing Cmax and increasing morning Cmin compared to conventional Madopar.
- Bioavailability of levodopa was nearly equivalent (85-90%) for both controlled-release formulations relative to conventional Madopar.
- Madopar HBS showed a higher fluctuation index than Sinemet CR but exhibited significantly fewer adverse events (n=2) compared to Sinemet CR (n=12) and conventional Madopar (n=18), particularly initial nausea.
- Higher 3-OMD levels were observed with Madopar HBS and conventional Madopar compared to Sinemet CR, suggesting more potent decarboxylase inhibition by benserazide.
Conclusions:
- Controlled-release levodopa formulations, Madopar HBS and Sinemet CR, offer significant pharmacokinetic advantages over conventional Madopar, with reduced peak concentrations and improved trough levels.
- Madopar HBS demonstrates superior tolerability, likely attributed to its enhanced inhibition of dopamine formation, leading to a more favorable side effect profile, especially concerning nausea.
- Both Madopar HBS and Sinemet CR are bioequivalent to conventional Madopar, providing comparable overall levodopa bioavailability with improved pharmacokinetic control.