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

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.

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.

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.

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.

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.