Pharmacokinetic and pharmacodynamic comparison of ropinirole 24-hour prolonged release and ropinirole immediate release in patients with Parkinson's disease.
OBJECTIVE
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.
Tompson
Debra
D
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK. debra.j.tompson@gsk.com
Oliver-Willwong
Ruth
R
D000328:Adult; D000978:Antiparkinson Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000097:blood / Q000188:drug therapy*; D011336:Probability; D012720:Severity of Illness Index; D013997:Time Factors
D000978:Antiparkinson Agents; D007211:Indoles; C046649:ropinirole