The effect of different dosing regimens of levodopa/carbidopa/entacapone on plasma levodopa concentrations

• Published in: European journal of clinical pharmacology Vol. 68; no. 3; pp. 281 - 289
• Main Authors: Ingman, Kimmo, Naukkarinen, Tarja, Vahteristo, Mikko, Korpela, Irja, Kuoppamäki, Mikko, Ellmén, Juha
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.03.2012; Springer; Springer Nature B.V
• Subjects: Adult; Antiparkinson Agents - administration & dosage; Antiparkinson Agents - blood; Antiparkinson Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Carbidopa - administration & dosage; Catechols - administration & dosage; Clinical trials; Cross-Over Studies; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine Agents - administration & dosage; Dopamine Agents - blood; Dopamine Agents - pharmacokinetics; Drug Combinations; Drug Interactions; Drug therapy; Female; Humans; Kinetics; Levodopa - administration & dosage; Levodopa - blood; Levodopa - pharmacokinetics; Male; Medical sciences; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Nitriles - administration & dosage; Pharmacokinetics and Disposition; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Young Adult; Entacapone; Levodopa; Pharmacokinetics; Parkinson’s disease; Dyskinesia; Agonist; Parkinson's disease; Carbidopa; Parkinson disease; Catechol O-methyltransferase; Lyases; Posology; Involuntary movement; Carboxy-lyases; Degenerative disease; Neurological disorder; Human; Decarboxylase; Nervous system diseases; Enzyme; Transferases; Enzyme inhibitor; Antiparkinson agent; Motor control; Cerebral disorder; Carbon-carbon lyases; D2 Dopamine receptor; Methyltransferases; Central nervous system disease; Therapeutic protocol; Extrapyramidal syndrome
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-011-1121-5

Background Repeated dosing of levodopa/carbidopa/entacapone (LCE) has shown a favourable pharmacokinetic (PK) profile compared with levodopa/carbidopa (LC), but increases maximum plasma levodopa concentrations (C max ) during the day. High levodopa concentrations are associated with peak-dose dyskinesias. Purpose To determine whether administering LCE 75/18.5/200 and 125/31.5/200 mg (LCE 75 and LCE 125) following a morning dose of LCE 100/25/200 and 150/37.5/200 mg (LCE 100 and LCE 150), respectively, would avoid the increase in levodopa C max values observed during multiple dosing of LCE 100 and LCE 150. Methods This was an open, randomized, three-period, crossover PK trial in healthy volunteers ( n  = 19). Subjects were randomized to Group 1 or 2. Group 1 received in random sequence: LCE 150 followed by LCE 125 three times daily (tid); LCE 150 four times daily (qid); LC 150 qid. Group 2 received in random sequence: LCE 100 followed by LCE 75 tid; LCE 100 qid; LC 100 qid. Levodopa C max , minimum plasma concentration (C min ), area under the curve (AUC 0−14 ) and peak–trough fluctuation (PTF) were calculated up to 14 h after the first dose. Results Levodopa C max was not increased when the LCE dose was decreased by 25 mg after the morning dose. In comparison to LC, levodopa C min levels and AUC 0−14 values for LCE were significantly higher, while the levodopa PTF was significantly smaller. Conclusions Reducing the dose of LCE by 25 mg following the first morning dose results in a more consistent levodopa C max profile, avoiding levodopa accumulation while maintaining significantly higher C min levels and AUC 0−14 values compared with LC.