Pharmacokinetic-pharmacodynamic crossover comparison of two levodopa extension strategies

Controlled-release carbidopa and levodopa (CL-CR) and the combination of carbidopa, levodopa, and entacapone (CLE) are used for extending levodopa (L-dopa) effects. In a randomized, open-label crossover study of 17 PD subjects with wearing-off responses, we compared 8-hour L-dopa pharmacokinetics (PK) and clinical effects after two doses of CL-CR (50 and 200 mg, respectively) and CLE (37.7, 150, 200 mg, respectively). PK analysis revealed the anticipated near-equivalent mean L-dopa area-under-the-concentration-curve values (639,490 ng min/mL for two doses of CLE, and 662,577 for CL-CR, P = 0.86). The mean hourly fluctuation index for L-dopa concentration was 235% for CLE and 196% for CL-CR (P = 0.004). The mean maximal concentration for the first CLE dose was 1,926 +/- 760 ng/mL and for CL-CR, 1,840 +/- 889 (P = 0.33). During the PK studies, the mean time that L-dopa concentration was > or =1,000 ng/mL for CLE was 291 +/- 88 minutes and for CL-CR, 306 +/- 86 (P = 0.33). The mean percent-time in "off" state was 18% for CLE and 28% for CL-CR (P = 0.017), "on state without dyskinesia" was 64% for CLE and 65% for CL-CR (P = 0.803), and "on state with nontroublesome dyskinesia" was 18% for CLE and 7% for CL-CR (P = 0.03). Despite less "off" time with CLE, both formulations demonstrated similar mean PK values and marked intersubject PK variability.