Steady-state pharmacokinetic properties of a 24-hour prolonged-release formulation of ropinirole: results of two randomized studies in patients with Parkinson's disease

Abstract

Background: Ropinirole 24-hour prolonged release is a new once-daily formulation of ropinirole that provides continuous delivery of ropinirole over 24 hours.

Objective: The studies described here were conducted to characterize the steady-state pharmacokinetics of ropinirole 24-hour prolonged release in patients with Parkinson's disease.

Methods: Study 164 was a 2-part study; Part A employed a crossover design to assess the relative bioavailability of steady-state ropinirole 24-hour prolonged release 8 mg QD and ropinirole immediate release 2.5 mg TID, and Part B evaluated the effect of food intake on the rate and extent of ropinirole absorption from ropinirole 24-hour prolonged release 8 mg QD. Study 165 assessed the dose proportionality of ropinirole 24-hour prolonged release 2-, 4-, and 8-mg tablets and the dose-strength equivalence of four 2-mg tablets compared with one 8-mg tablet. Intensive pharmacokinetic blood sampling was performed over 24 hours. Steady-state C(max), C(min), AUC from time zero to 24 hours after dosing (AUC(0-24)), and T(max) were determined by noncompartmental methods.

Results: Twenty-three patients (91% white; mean age, 67 years [range, 34-80 years] mean weight, 84.5 kg [range, 57-103 kg]) were randomized to treatment in Study 164. Twenty-eight patients (86% white; mean age, 67 years [range, 47-87 years] mean weight, 84.6 kg [range, 49-128 kg]) were randomized to treatment in Study 165. Compared with ropinirole immediate release, ropinirole 24-hour prolonged release had a smooth plasma concentration-time profile over 24 hours. AUC(0-24) and C(min) values, normalized to a 1-mg dose, were similar for ropinirole 24-hour prolonged release and ropinirole immediate release. Dose-normalized C(max) was slightly lower (approximately 12%) for ropinirole 24-hour prolonged release than for ropinirole immediate release. The AUC(0-24) and C(min) were similar in the fed and fasted states. The pharmacokinetics of ropinirole 24-hour prolonged release were dose proportional, as indicated by the estimated slopes for AUC(0-24) and C(max) being close to unity, along with the 90% CIs being contained within the predefined dose-range-adjusted limits. For C(min), the slope was close to unity (1.04), but the upper end of the 90% CI fell marginally outside the predefined range. Statistical analysis indicated that the dose strengths were equivalent when a single pharmacokinetic outlier was excluded from the analysis.

Conclusions: Ropinirole 24-hour prolonged release provided continuous delivery of ropinirole over 24 hours, resulting in a smooth plasma concentration-time profile, and food had no significant effect on absorption. Dose-normalized AUC(0-24) and C(min) were similar for both formulations, and dose-normalized C(max) was slightly lower for ropinirole 24-hour prolonged release. These relative bioavailability data indicated that patients may switch overnight from ropinirole immediate release to ropinirole 24-hour prolonged release while maintaining similar daily exposure. The pharmacokinetics of ropinirole were dose proportional over the range from 2 to 8 mg. The dose strengths of four 2-mg tablets and one 8-mg tablet of ropinirole 24-hour prolonged release were found to be equivalent.