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Pharmacokinetic-pharmacodynamic crossover comparison of two levodopa extension strategies


  • Potential conflict of interest: Drs. LeWitt, Jennings, Lyons, and Pahwa: received contractual payments from Novartis Pharmaceutical Corporation for the conduct of this study through their respective institutions, and each have also received compensation for other activities with Novartis, including scientific advisory roles, sponsored clinical trials, and lectures; Dr. Rabinowicz: a former employee of Novartis Pharmaceutical Corporation, is currently with Bayer HealthCare Pharmaceuticals, Wayne, NY; Dr. Hubble: a former employee of Novartis Pharmaceutical Corporation, is currently with Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT; Drs. Guarnieri and Wang: are employees of Novartis Pharmaceutical Corporation; Dr. Murck: is a former employee of Novartis Pharmaceutical Corporation, and is currently with Bristol-Myers Squibb Company, Plainsboro, NJ.


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

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