Iñaki F. Trocóniz1,2, Tarja Naukkarinen 3,4, Mats O. Karlsson4
1School of Pharmacy, University of Navarra, 31080 Pamplona, Spain;2Dpt. of Pharmacology, University of Basque Country, Spain.3Orion Corporation, Orion Pharma, Finland.4Dept of Pharmacy, Uppsala University, Sweden
Nineteen parkinsonian patients (11F, 8M), with fluctuations in response were studied in five one-day occasions, each separated by one week, during a phase II randomised clinical trial with cross-over design. Placebo, or entacapone at 50, 100, 200, or 400 mg was given orally concomitantly with the patient’s individual levodopa/ decarboxylase inhibitor (l-dopa/DCI) dose, which was the same on each occasion within one patient. 8-11 plasma l-dopa concentration (C) and effect measurements were recorded for each patient/occasion. The severity of Parkinson’s disease, evaluated by using the Unified Parkinson’s Disease Rating Scale (UPDRS), was used as the measure of drug effect. All the UPDRS vs C data was fitted simultaneously using NONMEM. The following covariates were used: age, sex, weight, duration of Parkinson’s disease (DUP, years), duration of fluctuations, Hoehn and Yahr stage, DCI (benserazide (BZ), carbidopa (CB)), and the dose of entacapone given (DENT).
Results: The C vs time profiles were described using linear interpolation; the UPDRS vs C relationship was modelled linking C with Ce (l-dopa effect site concentrations) using a first order rate constant (keo), and describing the UPDRS vs Ce relationship with an inhibitory sigmoidal Emax model. DUP and DCI were found to be significant covariates for the baseline UPDRS value (E0), and C50 (the steady-state C eliciting half of the maximum effect (Emax)), respectively. No covariate effects of DENT were found, indicating that entacapone does not modify the pharmacodynamics of l-dopa. The estimates of the mean population parameters (estimate (CV(%))) were: keo (h-1) = 1.73 (13); E0 (score) = 53.2 (3.4) + 0.8 (25) *(DUP-13); C50 (ng/ml) = 954 (9) (CB), 1272 (42) (BZ); Emax (score) = 0.48*E0 (5.4); g (slope) = 2.94 (12). The estimates of the interindividual variability (IIV) expressed as CV(%) were 14, 18, and 21 for E0, C50, and g, respectively. IIV for keo was estimated much higher (94%). A high correlation (0.81) was found between keo and E0, suggesting a closer relationship between C and UPDRS as the disease progresses. Interoccasion variability was found significant only for C50 (21%) and keo (51%).
Reference: PAGE 6 (1997) Abstr 670 [www.page-meeting.org/?abstract=670]
Poster: poster