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.
LeWitt
Peter A
PA
Department of Neurology, Henry Ford Hospital and Wayne State University School of Medicine, Detroit, Michigan, USA. palewitt@ameritech.net
Jennings
Danna
D
Lyons
Kelly E
KE
Pahwa
Rajesh
R
Rabinowicz
Adrian L
AL
Wang
James
J
Guarnieri
Maria
M
Hubble
Jean P
JP
Murck
Harold
H
D000368:Aged; D000704:Analysis of Variance; D000978:Antiparkinson Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002230:Carbidopa / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002396:Catechols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018592:Cross-Over Studies; D004185:Disability Evaluation; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000145:classification / Q000379:methods; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007980:Levodopa / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010300:Parkinson Disease / Q000097:blood* / Q000188:drug therapy; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013997:Time Factors
D000978:Antiparkinson Agents; D002396:Catechols; D009570:Nitriles; D007980:Levodopa; C071192:entacapone; D002230:Carbidopa