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2.240 Steady-state pharmacokinetics of ropinirole 24-hour prolonged release: Relative bioavailability and food effect in patients with Parkinson's disease
S108
Tuesday, 11 December 2007
2.237 Ropinirole 24-hour prolonged release improves sleep disturbance, but does not increase daytime somnolence in patients with advanced Parkinson’s disease when administered as adjunctive therapy S. Isaacson1° , F. Stocchi, N. Earl Raton, FL, USA
1 Boca
Objective: A new formulation, ropinirole 24-hour prolonged release, allows a simple, once-daily, dose-titration regimen with potential for enhanced compliance and tolerability in the treatment of Parkinson’s disease (PD). The effect of ropinirole 24-hour adjunctive therapy on sleep and daytime somnolence is presented. Method: The EASE-PD Adjunct study (protocol 101468/169) randomized patients with PD not optimally controlled with L-dopa to ropinirole 24-hour (n = 202) or placebo (n = 191), once daily, for 24 weeks. Initial dose was 2.0 mg/day, titrated to a maximum of 24.0 mg/day. At 8.0 mg/day and at each subsequent increase, L-dopa dose reduction was required. Secondary endpoints included change in PD Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS) total scores. Primary endpoint was mean change from baseline in awake time spent “off ” at Week 24 last observation carried forward (LOCF). Results: Baseline PDSS and ESS total scores were similar between treatment groups. At Week 24 LOCF, patients’ sleep, as measured by PDSS total score, was statistically significantly improved with ropinirole 24-hour versus placebo; adjusted mean change from baseline: 1.3 versus −3.3 (adjusted mean treatment difference [AMTD]: 4.7; 95% confidence interval [CI]: 0.8, 8.6; p = 0.0196). No statistically significant nor clinically relevant change in daytime somnolence was observed between ropinirole 24-hour and placebo, as measured by ESS total score, at Week 24 LOCF (AMTD: 0.3; 95% CI: −0.4, 1.1; p = 0.3692). At Week 24 LOCF, ropinirole 24-hour significantly reduced “off ” time, compared with placebo (AMTD: −1.7 hours; 95% CI: −2.3, −1.1; p < 0.0001). Mean (standard deviation) dose of ropinirole 24-hour at last visit was 18.8 (6.26) mg/day. Conclusion: Once-daily ropinirole 24-hour prolonged release leads to statistically significant improvements in sleep without increased ESSmeasured daytime somnolence, compared with placebo, in patients with PD not optimally controlled with L-dopa. 2.238 Ropinirole 24-hour prolonged-release adjunctive therapy improves cardinal symptoms in patients with advanced Parkinson’s disease not optimally controlled with L-dopa S. Isaacson1° , R. Pahwa, N. Earl Raton, FL, USA
1 Boca
Objective: Ropinirole 24-hour prolonged-release is a new formulation that provides a steady rate of absorption and reduces plasma level fluctuations (data on file). It offers a simple and convenient, once-daily treatment option in Parkinson’s disease (PD). This study evaluated the efficacy of adjunctive ropinirole 24-hour on the cardinal symptoms of PD in patients with PD not optimally controlled with L-dopa. Method: The EASE-PD Adjunct study (protocol 101468/169) randomized patients with advanced PD not optimally controlled with L-dopa to adjunctive ropinirole 24-hour (n = 202) or placebo (n = 191), once daily for 24 weeks. The initial dose was 2 mg/day, titrated to a maximum of 24 mg/day. At 8 mg/day and each subsequent dose increase, L-dopa dose reduction was required. Primary endpoint was mean change in daily “off ” time at Week 24 last observation carried forward (LOCF). Post-hoc analyses assessed mean changes from baseline in the tremor, rigidity and bradykinesia components of the Unified PD Rating Scale. Results: At Week 24 LOCF, significantly greater improvements were seen with ropinirole 24-hour, versus placebo, for change from baseline in tremor (adjusted mean treatment difference [AMTD]: −0.9; 95% CI: −1.3, −0.4; p = 0.0001), rigidity (AMTD: −0.9; 95% CI: −1.4, −0.4; p = 0.0003) and bradykinesia scores (AMTD: −1.8; 95% CI: −2.5, −1.0; p < 0.0001). Ropinirole 24-hour significantly reduced daily “off ” time,
versus placebo, at Week 2 (AMTD: −0.7 hours; 95% CI: −1.1, −0.2; p = 0.0029) and all visits through to Week 24 LOCF (AMTD: −1.7 hours; 95% CI: −2.3, −1.1; p < 0.0001). Mean (standard deviation) dose of ropinirole 24-hour at Week 24 LOCF was 18.8 (6.3) mg/day. Conclusion: Once-daily ropinirole 24-hour prolonged release significantly reduces “off ” time, versus placebo, and provides significant improvements in the cardinal symptoms of tremor, rigidity and bradykinesia in patients with advanced PD not optimally controlled with L-dopa.
2.239 Dose strength equivalence and dose proportionality demonstrated with ropinirole 24-hour prolonged release D. Vearer1° , D. Tompson United Kingdom
1 Harlow,
Objective: Evaluate dose proportionality and dose strength equivalence of ropinirole 24-hour prolonged release in patients with early Parkinson’s disease. Method: In an open-label, multicentre study (protocol 101468/165), patients received once-daily ropinirole 24-hour prolonged release at an initial dose of 2 mg/day, with weekly dose escalation of 2 mg up to 8 mg/day. To assess dose proportionality, steady-state pharmacokinetic evaluations were conducted at the 2, 4 and 8 mg dose levels. To assess steady-state dose strength equivalence, patients were randomized, at the 8 mg dose, to one of two once-daily treatment sequences: (1) ropinirole 24-hour 1 × 8 mg followed by 4× 2 mg; or (2) 4× 2 mg followed by 1 × 8 mg. To assess dose proportionality, estimated mean slopes and 90% CIs using the power model were constructed for AUC(0−24), Cmax and Cmin (primary endpoints). To assess dosage strength equivalence, point estimates and 90% CIs were constructed for AUC(0−24), Cmax and Cmin. Results: Dose proportionality was demonstrated for ropinirole 24-hour prolonged release based on estimated slopes for AUC(0−24) and Cmax, close to unity (1.07 and 1.05, respectively), and 90% CIs contained within dose-range-adjusted limits of 0.84−1.16. For Cmin, the slope was close to unity (1.04), but the upper end of the 90% CI fell marginally outside the pre-defined range. Dosage strength equivalence was demonstrated for Cmin, but for Cmax and AUC(0−24), the upper end of the 90% CI fell marginally outside the limit of 1.25. Bioequivalence was demonstrated for all three endpoints, however, when a single pharmacokinetic outlier was excluded from the statistical analysis. Conclusion: These data demonstrate that once-daily ropinirole 24-hour prolonged release provides a linear increase in systemic exposure to ropinirole over the tablet strength range of 2−8 mg. Patients taking multiple low strength tablets can switch to a single higher strength tablet and maintain similar systemic exposure.
2.240 Steady-state pharmacokinetics of ropinirole 24-hour prolonged release: Relative bioavailability and food effect in patients with Parkinson’s disease D. Vearer1° , D. Tompson United Kingdom
1 Harlow,
Objective: Assess the relative bioavailability of ropinirole 24-hour prolonged release (PR) and ropinirole immediate release (IR), and the effects of food using pharmacokinetic (PK) parameters in patients with Parkinson’s disease. Method: Protocol 101468/164 was an open-label, randomized, two-part study. Part A assessed relative bioavailability of steady-state ropinirole PR (8 mg once daily) versus ropinirole IR (2.5 mg three times daily). Patients were randomized to one of two treatment sequences (PR−IR or IR−PR) over two treatment periods; patients switched formulations at end of period 1. Part B evaluated effect of food intake on rate and extent of ropinirole PR absorption; patients receiving 8 mg ropinirole PR were compared in fed (high-fat breakfast 30mins before dosing) and fasted (overnight fast 10 hours) states. Blood samples for PK evaluation [AUC(0−24), Cmax,
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.
Tuesday, 11 December 2007
2.237 Ropinirole 24-hour prolonged release improves sleep disturbance, but does not increase daytime somnolence in patients with advanced Parkinson’s disease when administered as adjunctive therapy S. Isaacson1° , F. Stocchi, N. Earl Raton, FL, USA
1 Boca
Objective: A new formulation, ropinirole 24-hour prolonged release, allows a simple, once-daily, dose-titration regimen with potential for enhanced compliance and tolerability in the treatment of Parkinson’s disease (PD). The effect of ropinirole 24-hour adjunctive therapy on sleep and daytime somnolence is presented. Method: The EASE-PD Adjunct study (protocol 101468/169) randomized patients with PD not optimally controlled with L-dopa to ropinirole 24-hour (n = 202) or placebo (n = 191), once daily, for 24 weeks. Initial dose was 2.0 mg/day, titrated to a maximum of 24.0 mg/day. At 8.0 mg/day and at each subsequent increase, L-dopa dose reduction was required. Secondary endpoints included change in PD Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS) total scores. Primary endpoint was mean change from baseline in awake time spent “off ” at Week 24 last observation carried forward (LOCF). Results: Baseline PDSS and ESS total scores were similar between treatment groups. At Week 24 LOCF, patients’ sleep, as measured by PDSS total score, was statistically significantly improved with ropinirole 24-hour versus placebo; adjusted mean change from baseline: 1.3 versus −3.3 (adjusted mean treatment difference [AMTD]: 4.7; 95% confidence interval [CI]: 0.8, 8.6; p = 0.0196). No statistically significant nor clinically relevant change in daytime somnolence was observed between ropinirole 24-hour and placebo, as measured by ESS total score, at Week 24 LOCF (AMTD: 0.3; 95% CI: −0.4, 1.1; p = 0.3692). At Week 24 LOCF, ropinirole 24-hour significantly reduced “off ” time, compared with placebo (AMTD: −1.7 hours; 95% CI: −2.3, −1.1; p < 0.0001). Mean (standard deviation) dose of ropinirole 24-hour at last visit was 18.8 (6.26) mg/day. Conclusion: Once-daily ropinirole 24-hour prolonged release leads to statistically significant improvements in sleep without increased ESSmeasured daytime somnolence, compared with placebo, in patients with PD not optimally controlled with L-dopa. 2.238 Ropinirole 24-hour prolonged-release adjunctive therapy improves cardinal symptoms in patients with advanced Parkinson’s disease not optimally controlled with L-dopa S. Isaacson1° , R. Pahwa, N. Earl Raton, FL, USA
1 Boca
Objective: Ropinirole 24-hour prolonged-release is a new formulation that provides a steady rate of absorption and reduces plasma level fluctuations (data on file). It offers a simple and convenient, once-daily treatment option in Parkinson’s disease (PD). This study evaluated the efficacy of adjunctive ropinirole 24-hour on the cardinal symptoms of PD in patients with PD not optimally controlled with L-dopa. Method: The EASE-PD Adjunct study (protocol 101468/169) randomized patients with advanced PD not optimally controlled with L-dopa to adjunctive ropinirole 24-hour (n = 202) or placebo (n = 191), once daily for 24 weeks. The initial dose was 2 mg/day, titrated to a maximum of 24 mg/day. At 8 mg/day and each subsequent dose increase, L-dopa dose reduction was required. Primary endpoint was mean change in daily “off ” time at Week 24 last observation carried forward (LOCF). Post-hoc analyses assessed mean changes from baseline in the tremor, rigidity and bradykinesia components of the Unified PD Rating Scale. Results: At Week 24 LOCF, significantly greater improvements were seen with ropinirole 24-hour, versus placebo, for change from baseline in tremor (adjusted mean treatment difference [AMTD]: −0.9; 95% CI: −1.3, −0.4; p = 0.0001), rigidity (AMTD: −0.9; 95% CI: −1.4, −0.4; p = 0.0003) and bradykinesia scores (AMTD: −1.8; 95% CI: −2.5, −1.0; p < 0.0001). Ropinirole 24-hour significantly reduced daily “off ” time,
versus placebo, at Week 2 (AMTD: −0.7 hours; 95% CI: −1.1, −0.2; p = 0.0029) and all visits through to Week 24 LOCF (AMTD: −1.7 hours; 95% CI: −2.3, −1.1; p < 0.0001). Mean (standard deviation) dose of ropinirole 24-hour at Week 24 LOCF was 18.8 (6.3) mg/day. Conclusion: Once-daily ropinirole 24-hour prolonged release significantly reduces “off ” time, versus placebo, and provides significant improvements in the cardinal symptoms of tremor, rigidity and bradykinesia in patients with advanced PD not optimally controlled with L-dopa.
2.239 Dose strength equivalence and dose proportionality demonstrated with ropinirole 24-hour prolonged release D. Vearer1° , D. Tompson United Kingdom
1 Harlow,
Objective: Evaluate dose proportionality and dose strength equivalence of ropinirole 24-hour prolonged release in patients with early Parkinson’s disease. Method: In an open-label, multicentre study (protocol 101468/165), patients received once-daily ropinirole 24-hour prolonged release at an initial dose of 2 mg/day, with weekly dose escalation of 2 mg up to 8 mg/day. To assess dose proportionality, steady-state pharmacokinetic evaluations were conducted at the 2, 4 and 8 mg dose levels. To assess steady-state dose strength equivalence, patients were randomized, at the 8 mg dose, to one of two once-daily treatment sequences: (1) ropinirole 24-hour 1 × 8 mg followed by 4× 2 mg; or (2) 4× 2 mg followed by 1 × 8 mg. To assess dose proportionality, estimated mean slopes and 90% CIs using the power model were constructed for AUC(0−24), Cmax and Cmin (primary endpoints). To assess dosage strength equivalence, point estimates and 90% CIs were constructed for AUC(0−24), Cmax and Cmin. Results: Dose proportionality was demonstrated for ropinirole 24-hour prolonged release based on estimated slopes for AUC(0−24) and Cmax, close to unity (1.07 and 1.05, respectively), and 90% CIs contained within dose-range-adjusted limits of 0.84−1.16. For Cmin, the slope was close to unity (1.04), but the upper end of the 90% CI fell marginally outside the pre-defined range. Dosage strength equivalence was demonstrated for Cmin, but for Cmax and AUC(0−24), the upper end of the 90% CI fell marginally outside the limit of 1.25. Bioequivalence was demonstrated for all three endpoints, however, when a single pharmacokinetic outlier was excluded from the statistical analysis. Conclusion: These data demonstrate that once-daily ropinirole 24-hour prolonged release provides a linear increase in systemic exposure to ropinirole over the tablet strength range of 2−8 mg. Patients taking multiple low strength tablets can switch to a single higher strength tablet and maintain similar systemic exposure.
2.240 Steady-state pharmacokinetics of ropinirole 24-hour prolonged release: Relative bioavailability and food effect in patients with Parkinson’s disease D. Vearer1° , D. Tompson United Kingdom
1 Harlow,
Objective: Assess the relative bioavailability of ropinirole 24-hour prolonged release (PR) and ropinirole immediate release (IR), and the effects of food using pharmacokinetic (PK) parameters in patients with Parkinson’s disease. Method: Protocol 101468/164 was an open-label, randomized, two-part study. Part A assessed relative bioavailability of steady-state ropinirole PR (8 mg once daily) versus ropinirole IR (2.5 mg three times daily). Patients were randomized to one of two treatment sequences (PR−IR or IR−PR) over two treatment periods; patients switched formulations at end of period 1. Part B evaluated effect of food intake on rate and extent of ropinirole PR absorption; patients receiving 8 mg ropinirole PR were compared in fed (high-fat breakfast 30mins before dosing) and fasted (overnight fast 10 hours) states. Blood samples for PK evaluation [AUC(0−24), Cmax,
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.