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2.243 Ropinirole 24-hour prolonged release improves mood and quality of life in patients with advanced Parkinson's disease as adjunctive therapy
Poster Presentations: Therapeutical Interventions: Pharmacotherapy Cmin] were collected at selected times over the 24-hour dosing interval. For part A, PK parameters were normalized to a dose of 1 mg. Results: Exposure, based on dose-normalized AUC(0−24) and Cmin, was similar for once-daily ropinirole PR and three-times-daily ropinirole IR (dosing interval = 8 hours). Dose-normalized Cmax was slightly lower for ropinirole PR (~12%; not considered clinically relevant). Unlike ropinirole IR, ropinirole PR is not associated with multiple fluctuations in plasma concentrations over 24 hours. Cmax was slightly higher (15%) and tmax was slightly delayed (2 hours) in the fed versus fasted state. Both AUC(0−24) and Cmin were similar in the fed and fasted states with 90% CI intervals of the ratio fed : fasted within the limits generally associated with bioequivalence (0.80−1.25). Conclusion: Ropinirole PR provides a steady rate of absorption with a smooth 24-hour plasma concentration–time profile. Patients may switch overnight from ropinirole IR to a similar daily dose of ropinirole PR while maintaining similar average daily exposure. There was no clinically relevant effect of food on oral absorption of ropinirole PR.
2.241 Relationship between awake time spent “off” and systemic exposure of ropinirole 24-hour prolonged release in patients with advanced Parkinson’s disease D. Tompson1° , R. Pahwa United Kingdom
1 Harlow,
Objective: The pharmacokinetic–pharmacodynamic (PK−PD) relationship between systemic exposure to ropinirole 24-hour and awake time “off ” was evaluated in patients with advanced Parkinson’s disease. Method: In the EASE-PD Adjunct study (protocol 101468/169), patients with advanced Parkinson’s disease not optimally controlled with L-dopa were randomized to adjunctive ropinirole 24-hour (n = 202) or placebo (n = 191), once daily, and titrated to a maximum dose of 24.0 mg/day. Once titrated to 8.0 mg/day, L-dopa dose reduction was required. Sparse blood samples were collected for population PK analysis. The relationship between ropinirole systemic exposure [AUC(0−24ss)] and change from baseline in awake time “off ” (hours) at Weeks 12, 16, 20 and 24 was investigated. A logistic regression analysis was conducted between ropinirole AUC(0−24ss) and the probability of response (defined as >20% decrease in awake time “off ” from baseline). Results: The change from baseline in daily “off ” time versus AUC(0−24ss) values showed a median decrease of ~40−50% in time “off ” for ropinirole PR (n = 162) compared with a median ~10% decrease for placebo. The proportion of time “off ” was similar over the ropinirole AUC(0−24ss) range studied, although there was evidence of a greater decrease in time “off ” within the 80–100 percentile of AUC(0−24ss) values. The logistic regression showed that the probability of a patient experiencing >20% decrease in “off ” time from baseline was approximately 0.4 for placebo and increased to a near total response rate at the higher systemic exposures to ropinirole. Conclusion: The PK−PD analysis indicates that in patients with advanced stage Parkinson’s disease a ~50% decrease in time “off ” was observed over the exposure range studied and the probability of achieving a >20% decrease in time “off ” increased with increasing exposures to ropinirole (and reductions in L-dopa dose) to a near total response rate at higher systemic exposures to ropinirole.
2.242 Relationship between Unified Parkinson’s disease Rating Scale total motor score and systemic exposure of ropinirole 24-hour prolonged release in patients with early stage Parkinson’s disease D. Tompson1° , F. Stocchi United Kingdom
1 Harlow,
Objective: The pharmacokinetic–pharmacodynamic (PK-PD) relationship between ropinirole systemic exposure and Unified Parkinson’s disease
S109
Rating Scale (UPDRS) total motor score was evaluated in patients with early Parkinson’s disease. Method: EASE-PD Monotherapy (protocol 101468/168), a noninferiority study comparing ropinirole 24-hour prolonged release (PR) with ropinirole immediate release (IR), randomized patients to one of four treatment sequences (IR−IR−PR, IR−PR−PR, PR−IR−IR or PR−PR−IR) for three 8-week maintenance periods (MP1, 2 and 3). At the end of MP1, half the patients were switched overnight to the nearest available total daily dose of the alternative ropinirole formulation; the remaining half of patients were switched at the end of MP2. Sparse blood samples were collected during MP1 and MP3 for population PK analysis. The relationship between ropinirole systemic exposure and change from baseline in UPDRS total motor score was investigated. Results: In total, 124 patients provided samples for PK-PD analysis, ~90% were receiving ropinirole IR or PR doses of 6 mg/day. For both ropinirole formulations, there was a median decrease in UPDRS total motor score of ~50% over the entire exposure range studied. A logistic regression analysis demonstrated that the probability of a patient experiencing a >30% decrease in UPDRS total motor score was ~70%, irrespective of formulation or systemic exposure to ropinirole. Plots of change from baseline in median UPDRS total motor score and median AUC(0−24ss) values by formulation in MP1 and MP3 showed that AUC(0−24ss) values associated with doses of 8−12 mg had similar efficacy to AUC(0−24ss) values associated with higher doses. Conclusion: Over the mean AUC (0−24ss) range observed in this study, the median change from baseline in UPDRS total motor score was similar for both formulations; results indicate that clinical benefit on the UPDRS total motor score may be achieved at doses of 8−12 mg/day for the majority of patients with early Parkinson’s disease. 2.243 Ropinirole 24-hour prolonged release improves mood and quality of life in patients with advanced Parkinson’s disease as adjunctive therapy F. Stocchi1° , S. Isaacson, H. Edin Italy
1 Rome,
Objective: Ropinirole 24-hour prolonged release offers a simple, oncedaily treatment for Parkinson’s disease (PD), potentially improving patient compliance and treatment outcomes. This study evaluated the effect of ropinirole 24-hour on improving mood and quality of life (QoL). Method: The EASE-PD Adjunct study (protocol 101468/169) randomized patients with PD not optimally controlled with L-dopa to once-daily ropinirole 24-hour (n = 202) or placebo (n = 191), for 24 weeks. Initial dose: 2.0 mg/day, titrated to a maximum of 24.0 mg/day. At 8.0 mg/day and subsequent increases, L-dopa dose reduction was required. Secondary endpoints included mean change from baseline in Beck Depression Inventory II (BDI-II) total score and PD Questionnaire-39 (PDQ-39) domains, a validated measure of QoL in PD. PDQ-39 summary index was analysed post-hoc. Primary endpoint: mean change from baseline in daily “off ” time at Week 24 last observation carried forward (LOCF). Results: Baseline mean BDI-II score was ~16 points in each treatment group, indicating mild depressive symptoms. Baseline PDQ-39 summary index scores were 30.6 and 31.9 in the ropinirole 24-hour and placebo groups, respectively. At Week 24 LOCF, ropinirole 24-hour significantly improved BDI-II total score versus placebo (adjusted mean change from baseline: −2.1 versus −0.5; adjusted mean treatment difference [AMTD]: −1.6; 95% CI: −2.9, −0.3; p = 0.0130). A significant difference in adjusted mean change from baseline in PDQ-39 summary index score was observed: ropinirole 24-hour, −2.6; placebo, 0.9 (AMTD: −3.4; 95% CI: −5.5, −1.4; p = 0.0010). Ropinirole 24-hour significantly reduced “off ” time, versus placebo at Week 24 LOCF (AMTD: −1.7 hours; 95% CI: −2.3, −1.1; p < 0.0001). Conclusion: In patients with PD not optimally controlled with L-dopa, once-daily ropinirole 24-hour prolonged release significantly reduces “off ” time, and provides significant improvements in mood and PD-related QoL versus placebo.
2.241 Relationship between awake time spent “off” and systemic exposure of ropinirole 24-hour prolonged release in patients with advanced Parkinson’s disease D. Tompson1° , R. Pahwa United Kingdom
1 Harlow,
Objective: The pharmacokinetic–pharmacodynamic (PK−PD) relationship between systemic exposure to ropinirole 24-hour and awake time “off ” was evaluated in patients with advanced Parkinson’s disease. Method: In the EASE-PD Adjunct study (protocol 101468/169), patients with advanced Parkinson’s disease not optimally controlled with L-dopa were randomized to adjunctive ropinirole 24-hour (n = 202) or placebo (n = 191), once daily, and titrated to a maximum dose of 24.0 mg/day. Once titrated to 8.0 mg/day, L-dopa dose reduction was required. Sparse blood samples were collected for population PK analysis. The relationship between ropinirole systemic exposure [AUC(0−24ss)] and change from baseline in awake time “off ” (hours) at Weeks 12, 16, 20 and 24 was investigated. A logistic regression analysis was conducted between ropinirole AUC(0−24ss) and the probability of response (defined as >20% decrease in awake time “off ” from baseline). Results: The change from baseline in daily “off ” time versus AUC(0−24ss) values showed a median decrease of ~40−50% in time “off ” for ropinirole PR (n = 162) compared with a median ~10% decrease for placebo. The proportion of time “off ” was similar over the ropinirole AUC(0−24ss) range studied, although there was evidence of a greater decrease in time “off ” within the 80–100 percentile of AUC(0−24ss) values. The logistic regression showed that the probability of a patient experiencing >20% decrease in “off ” time from baseline was approximately 0.4 for placebo and increased to a near total response rate at the higher systemic exposures to ropinirole. Conclusion: The PK−PD analysis indicates that in patients with advanced stage Parkinson’s disease a ~50% decrease in time “off ” was observed over the exposure range studied and the probability of achieving a >20% decrease in time “off ” increased with increasing exposures to ropinirole (and reductions in L-dopa dose) to a near total response rate at higher systemic exposures to ropinirole.
2.242 Relationship between Unified Parkinson’s disease Rating Scale total motor score and systemic exposure of ropinirole 24-hour prolonged release in patients with early stage Parkinson’s disease D. Tompson1° , F. Stocchi United Kingdom
1 Harlow,
Objective: The pharmacokinetic–pharmacodynamic (PK-PD) relationship between ropinirole systemic exposure and Unified Parkinson’s disease
S109
Rating Scale (UPDRS) total motor score was evaluated in patients with early Parkinson’s disease. Method: EASE-PD Monotherapy (protocol 101468/168), a noninferiority study comparing ropinirole 24-hour prolonged release (PR) with ropinirole immediate release (IR), randomized patients to one of four treatment sequences (IR−IR−PR, IR−PR−PR, PR−IR−IR or PR−PR−IR) for three 8-week maintenance periods (MP1, 2 and 3). At the end of MP1, half the patients were switched overnight to the nearest available total daily dose of the alternative ropinirole formulation; the remaining half of patients were switched at the end of MP2. Sparse blood samples were collected during MP1 and MP3 for population PK analysis. The relationship between ropinirole systemic exposure and change from baseline in UPDRS total motor score was investigated. Results: In total, 124 patients provided samples for PK-PD analysis, ~90% were receiving ropinirole IR or PR doses of 6 mg/day. For both ropinirole formulations, there was a median decrease in UPDRS total motor score of ~50% over the entire exposure range studied. A logistic regression analysis demonstrated that the probability of a patient experiencing a >30% decrease in UPDRS total motor score was ~70%, irrespective of formulation or systemic exposure to ropinirole. Plots of change from baseline in median UPDRS total motor score and median AUC(0−24ss) values by formulation in MP1 and MP3 showed that AUC(0−24ss) values associated with doses of 8−12 mg had similar efficacy to AUC(0−24ss) values associated with higher doses. Conclusion: Over the mean AUC (0−24ss) range observed in this study, the median change from baseline in UPDRS total motor score was similar for both formulations; results indicate that clinical benefit on the UPDRS total motor score may be achieved at doses of 8−12 mg/day for the majority of patients with early Parkinson’s disease. 2.243 Ropinirole 24-hour prolonged release improves mood and quality of life in patients with advanced Parkinson’s disease as adjunctive therapy F. Stocchi1° , S. Isaacson, H. Edin Italy
1 Rome,
Objective: Ropinirole 24-hour prolonged release offers a simple, oncedaily treatment for Parkinson’s disease (PD), potentially improving patient compliance and treatment outcomes. This study evaluated the effect of ropinirole 24-hour on improving mood and quality of life (QoL). Method: The EASE-PD Adjunct study (protocol 101468/169) randomized patients with PD not optimally controlled with L-dopa to once-daily ropinirole 24-hour (n = 202) or placebo (n = 191), for 24 weeks. Initial dose: 2.0 mg/day, titrated to a maximum of 24.0 mg/day. At 8.0 mg/day and subsequent increases, L-dopa dose reduction was required. Secondary endpoints included mean change from baseline in Beck Depression Inventory II (BDI-II) total score and PD Questionnaire-39 (PDQ-39) domains, a validated measure of QoL in PD. PDQ-39 summary index was analysed post-hoc. Primary endpoint: mean change from baseline in daily “off ” time at Week 24 last observation carried forward (LOCF). Results: Baseline mean BDI-II score was ~16 points in each treatment group, indicating mild depressive symptoms. Baseline PDQ-39 summary index scores were 30.6 and 31.9 in the ropinirole 24-hour and placebo groups, respectively. At Week 24 LOCF, ropinirole 24-hour significantly improved BDI-II total score versus placebo (adjusted mean change from baseline: −2.1 versus −0.5; adjusted mean treatment difference [AMTD]: −1.6; 95% CI: −2.9, −0.3; p = 0.0130). A significant difference in adjusted mean change from baseline in PDQ-39 summary index score was observed: ropinirole 24-hour, −2.6; placebo, 0.9 (AMTD: −3.4; 95% CI: −5.5, −1.4; p = 0.0010). Ropinirole 24-hour significantly reduced “off ” time, versus placebo at Week 24 LOCF (AMTD: −1.7 hours; 95% CI: −2.3, −1.1; p < 0.0001). Conclusion: In patients with PD not optimally controlled with L-dopa, once-daily ropinirole 24-hour prolonged release significantly reduces “off ” time, and provides significant improvements in mood and PD-related QoL versus placebo.