Pharmacokinetic and pharmacodynamic comparison of ropinirole 24-hour prolonged release and ropinirole immediate release in patients with Parkinson's disease.

Author(s): Tompson D, Oliver-Willwong R

Affiliation(s): GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK. debra.j.tompson@gsk.com

Publication date & source: 2009-05, Clin Neuropharmacol., 32(3):140-8.

Publication type: Clinical Trial, Phase III; Comparative Study; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't

OBJECTIVES: To explore the pharmacokinetic-pharmacodynamic relationship between systemic exposure to ropinirole and the primary efficacy end points from two phase 3 studies. METHODS: Efficacy And Safety Evaluation in Parkinson's Disease (EASE-PD) Monotherapy (101468/168) compared ropinirole 24-hour prolonged release with ropinirole immediate release in patients with early Parkinson's disease (PD). Efficacy And Safety Evaluation in Parkinson's Disease Adjunct (101468/169) compared ropinirole 24-hour prolonged release or placebo in patients with advanced PD not optimally controlled with L-dopa. Sparse blood samples were collected for pharmacokinetic evaluations through population analysis. The relationship between ropinirole systemic exposure [steady-state area under the curve between time zero and 24 hours after dose, AUC(0-24,ss)] and change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) total motor score, and awake time spent off was investigated. RESULTS: In EASE-PD Monotherapy, the relationship between the decrease in UPDRS motor score and AUC(0-24,ss) was similar for both formulations, with a 60% to 80% probability of response for the exposure range studied. In patients with early PD, similar clinical benefit was achieved at AUC(0-24,ss) values associated with doses of 8 to 12 mg and higher doses (up to 24 mg). In EASE-PD Adjunct, the predicted probability of an off-time response for a patient on placebo was approximately 0.4, increasing to a near total probability of response rate (approximately 0.9) at higher systemic exposures of ropinirole 24-hour prolonged release. CONCLUSIONS: Characterization of the exposure-response relationship has identified that a dose range of 8 to 12 mg provides clinical benefit for the improvement in UPDRS total motor score in patients with early PD. Similarly, pharmacokinetic-pharmacodynamic analysis showed that, in patients with advanced PD, the probability of response increased with increasing exposures to ropinirole, indicating that doses more than 8 to 12 mg may lead to an improved benefit in parallel with reductions in L-dopa dose.