N. Simon (1), A. Boulamery (1), JP. Azulay (2), R. Viallet (3), S. Arguillère (3), B. Bruguerolle (1)
(1) Division of clinical pharmacology, AP-HM, Aix-Marseille University, France (2) Division of Neurology, AP-HM, Aix-Marseille University, France (3) Division of Neurology, CH Pays d’Aix, France
Objectives: After several years of treatment with levodopa, patients with Parkinson’s disease often present movement disorders such as dyskinesia. This side effect is extremely limiting for these patients and efforts should be done to find how to avoid their occurrence. A first concern is to establish whether it’s possible to adapt treatment to obtain a satisfactory effect without dyskinesia. This approach requires not only a PK/PD model but a joint model of both effects. This study aimed to develop a PK/PD-PD joint model of motor effect and dyskinesia following administration of levodopa
Methods: Parkinsonian patients with dyskinesia were enrolled: after a wash-out period of 12 hours, they received a single 150% dose of their usual daily dosing of levodopa. Eight blood samples were taken before administration and at 0.5, 1, 1.5, 2, 3 and 5 hours following levodopa administration. Pharmacodynamic assessments used the Unified Parkinson Disease Rating Score (UPDRS) and the Goetz‘s dyskinesia scale. A PK/PD model for each effect was first established and then several joint models were investigated.
Results: Thirty patients were included in the study. A first compartment model described the PK data, the Ka was 1.86 1/h, the volume of distribution was 36.2L and the oral clearance 31.6L/h. The motor effect and the dyskinesia were best described by effect-compartment models. From different joint models tested, the best consisted of a single KE0, 1.54 1/h, with separate EC50, 1890µg/L and 6990µg/L for UPDRS and dyskinesia. A large interpatient variability was found to affect levodopa EC50 for UPDRS (CV 54%) as well as EC50 for dyskinesia (CV 80%).
Conclusions: The study describes the simultaneous occurrence of motor effect and dyskinesia with separate values of EC50. However, the wide inter-individual variability limits the ability to dissociate these effects even with individualizing the levodopa regimen.
Reference: PAGE 21 () Abstr 2366 [www.page-meeting.org/?abstract=2366]
Poster: Other Drug/Disease Modelling