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

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.

Steady-state pharmacokinetics of lamotrigine when converting from a twice-daily immediate-release to a once-daily extended-release formulation in subjects with epilepsy (The COMPASS Study).

PURPOSE: To compare the pharmacokinetics (PK) of lamotrigine (LTG) when converting from twice-daily immediate-release (LTG-IR) to once-daily extended-release (LTG-XR) in subjects with epilepsy. METHODS: An open-label, conversion study was conducted, consisting of a 2-week LTG-IR Baseline Phase, followed by a 2-week LTG-XR Treatment Phase and a 1-week LTG-IR Phase. Forty-four subjects (> or =13 years of age) were enrolled and grouped as metabolically neutral (15), induced (15), or inhibited (14) based on the effects of the concomitant antiepileptic drugs (AEDs) on the clearance of LTG. The primary outcome was LTG PK parameters upon conversion. Secondary outcomes included seizure frequency, adverse events, and subject's preference. RESULTS: LTG-XR and LTG-IR regimens were similar with respect to area under curve from 0 to 24 h (AUC (0-24)), apart from the induced group, where the AUC (0-24) of LTG-XR was on average 21% lower than for LTG-IR. A reduction in the LTG Cmax was observed for LTG-XR compared to LTG-IR resulting in a decrease in the peak-to-trough fluctuation in serum LTG concentrations. The steady-state, dose-normalized, trough concentrations for LTG-XR were similar to those of LTG-IR. The median time to peak concentration (Tmax) following administration of LTG-XR ranged from 4 to 6 h, 6 to 10 h, and 9 to 11 h in the induced, neutral, and inhibited groups, respectively. In comparison, the median Tmax following administration of LTG-IR was between 1 and 1.5 h. CONCLUSIONS: Trough concentrations of LTG can be maintained on conversion from twice-daily LTG-IR to once-daily LTG-XR at the same total daily dose.