Effects of nebicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity, and motor fluctuations in patients with Parkinson disease.
OBJECTIVE
To investigate the effects of nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor, on levodopa pharmacokinetics, COMT activity, and motor fluctuations in Parkinson disease in comparison to placebo and entacapone.


METHODS
Randomized, double-blind, placebo-controlled, 4-way crossover study consisting of 4 treatment periods (6-9 days duration each) in 19 patients (65.3 +/- 8.5 years) treated with carbidopa/levodopa 3 to 7 times per day. Nebicapone/entacapone/placebo and carbidopa/levodopa doses were administered concomitantly. At the end of each period, a levodopa test was performed, and levodopa and 3-O-methyldopa levels and COMT activity were assayed.


RESULTS
After 75 mg nebicapone, 150 mg nebicapone, and 200 mg entacapone, levodopa area under the plasma concentration time curve significantly increased 28.1, 48.4, and 33.3%, and 3-O-methyldopa area under the plasma concentration time curve significantly decreased 59.2, 70.8, and 59.1%, respectively. Peak COMT inhibition was similar between active treatments, but extent of COMT inhibition was more sustained with 75 and 150 mg nebicapone than with 200 mg entacapone. After the levodopa test doses, ON time significantly increased 29 minutes with 75 mg nebicapone, 45 minutes with 150 mg nebicapone, and 16 minutes with 200 mg entacapone. Patients' diaries showed a decrease in daily OFF time of 109 minutes with 75 mg nebicapone, 103 minutes with 150 mg nebicapone, and 71 minutes with 200 mg entacapone, and an increase in daily ON time of 74, 101, and 74 minutes, respectively. Treatments were generally well tolerated and safe; no relevant changes in liver function tests were reported.


CONCLUSIONS
Nebicapone, a new COMT inhibitor, significantly decreased COMT activity, increased systemic exposure to levodopa, and improved motor response. Nebicapone deserves further evaluation in larger samples of patients.
Ferreira
Joaquim J
JJ
Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal.
Almeida
Luis
L
Cunha
Luis
L
Ticmeanu
Marina
M
Rosa
Mário M
MM
Januário
Cristina
C
Mitu
Cristina-Elena
CE
Coelho
Miguel
M
Correia-Guedes
Leonor
L
Morgadinho
Ana
A
Nunes
Teresa
T
Wright
Lyndon C
LC
Falcão
Amílcar
A
Sampaio
Cristina
C
Soares-da-Silva
Patrício
P
D000098:Acetophenones / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000978:Antiparkinson Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D002230:Carbidopa / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D010300:Parkinson Disease / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D010919:Placebos
D000098:Acetophenones; D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D010919:Placebos; D007980:Levodopa; C071192:entacapone; D002230:Carbidopa; C433466:nebicapone