Comparative multiple-dose pharmacokinetics of controlled-release levodopa products.
The multiple-dose (200 mg levodopa t.i.d.) pharmacokinetic profile of two controlled-release products of levodopa (Madopar HBS and Sinemet CR) was compared to conventional Madopar capsules in 18 healthy volunteers in a cross-over, randomized design. A pronounced controlled-release profile of the Madopar HBS and Sinemet CR product was demonstrated compared to conventional Madopar capsules with a significant (p < 0.001) decrease (-40 and -55%) in Cmax and a significant (p < 0.001) increase (+237 and +256%) in morning Cmin for the 200 mg t.i.d. dosage schedule. Almost equivalent bioavailability (85-90%) of levodopa was demonstrated for the controlled-release formulations relative to that of conventional Madopar capsules. The Madopar HBS formulation was bioequivalent with Sinemet CR with respect to levodopa, but it exhibited a moderately higher fluctuation index compared to Sinemet CR as a result of somewhat higher Cmax and lower Cmin values for the Madopar HBS formulation. 3-OMD (a metabolite of levodopa) levels were significantly (p < 0.05) higher for Madopar HBS and Madopar compared to Sinemet CR. The higher 3-OMD levels for the levodopa/benserazide combinations are consistent with a more potent decarboxylase inhibitory activity of benserazide as compared to carbidopa. The number of adverse events was highest for conventional Madopar (n = 18) compared to the controlled-release formulations (n = 12 for Sinemet CR and only 2 for Madopar HBS). A more efficient inhibition of dopamine formation from levodopa (resulting in higher 3-OMD levels) by Madopar HBS was consistent with the superior tolerability (especially for initial nausea) observed for the Madopar HBS formulation as compared to Sinemet CR.
Grahnén
A
A
Pharmaco Medical Consultants, PMC AB, Uppsala, Sweden.
Eckernäs
S A
SA
Collin
C
C
Ling-Andersson
A
A
Tiger
G
G
Nilsson
M
M
D000328:Adult; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002230:Carbidopa / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008750:Methyldopa / Q000493:pharmacokinetics; D009460:Neurologic Examination / Q000187:drug effects; D010300:Parkinson Disease / Q000097:blood / Q000188:drug therapy*
D000978:Antiparkinson Agents; D003692:Delayed-Action Preparations; D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D008750:Methyldopa; D002230:Carbidopa