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 ≥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. © 2009 Movement Disorder Society