Dosing of Ropinirole Prolonged Release in Parkinson's Disease
Dosing of Ropinirole Prolonged Release in Parkinson's Disease
RPR is a once daily oral dopamine agonist for PD. In general, it is prescribed as a once daily regimen. When patients switched from once-daily to twice-daily or twice-daily to once-daily, however, their mean mUPDRS, H&Y, ESS, sleep quality and AEs were not statistically different. Despite the different dosing frequency, these findings indicate the same dose of RPR had a similar efficacy without an increase in AEs and was not inferior.
To check for bias of the sequence effect, we analyzed the outcomes based on the order. When the once-daily regimen was administered first (sequence 1 → 2), 51.79% (15/29) of the patients preferred the twice-daily regimen. The proportion of subjects who preferred the twice-daily regimen more was 50% (16/32) when the twice-daily regimen was administered first (sequence 2 → 1). Thus there was no sequence effect. We also did not find a sequence effect in the secondary outcome analysis.
For PGI-I, 50 patients reported improvement after RPR over the IR form of agonists. Admittedly, the dose was increased from 9.1 ± 5.0 mg of the IR form of agonists to 10.7 ± 6.2 mg of RPR. It is to be noted that we tried to optimize the medication with the available IR form of agonists balancing many factors such as motor fluctuation, dyskinesia and adverse effects. Therefore, it is definitely a benefit of RPR when the condition of patients' improved even with the increased mean daily dose being within tolerance.
In our study, PD patients preferred the twice-daily regimen to the once-daily regimen (51% vs. 28%). In patients who preferred the twice-daily regimen, their main reasons were decreased severity of off symptoms or dyskinesia and decreased AEs. Especially for wearing-off duration, the PGI-I was significantly higher in twice-daily regimen. Thus, we should consider the twice daily regimen with its reduced severity of symptoms or decreased intolerable AEs for antiparkinsonian medications.
When patients chose the once-daily regimen, their main reason was improved on quality and decreased off symptoms or dyskinesia. Thus, we should consider the once daily regimen preferentially for young patients who are active workers in the daytime or have diphasic dyskinesia.
We expected changes in sleep quality and daytime sleepiness between the two regimens. However, there were no significant differences between the once-daily and twice-daily regimens.
As can be seen in the time window of the ropinirole level from Tompson et al., the nocturnal concentration may be lower in the once daily RPR than the three times daily RIR. The down sloping of the ropinirole level was designed taking into consideration natural dopaminergic stimulation and improvement in nocturnal side effects including insomnia and hallucinations. Additionally, the reason was not fully explained by the time window of the ropinirole level in the steady state. However, multiple dosing of RPR may provide even better control in some patients.
Although patients showed no differences in their mean mUPDRS, H&Y, ESS, sleep quality and AEs, more patients preferred the twice-daily regimen and their main reason was more tolerable off-symptoms. Three of our study patients preferred the twice-daily regimen due to psychological stability, and decreased anxiety due to reduced off symptoms. This finding shows that psychological factors may explain the preference. Patients in this study previously maintained dopaminergic therapy with multiple dosing. They endured off symptoms and have fear of them. Therefore, as an ostensible reason of preference, they chose "more tolerable off-symptoms", however the real reason would be "decreased anxiety due to reduced off symptoms."
In antiparkinsonian medication, once daily dosing may improve compliance and achieve the desired outcome. Four patients chose the once daily regimen due to convenience. However, almost all PD patients are taking multiple antiparkinsonian medications many times a day. Thus, compliance may not be a big issue especially for advanced PD patients.
Discussion
RPR is a once daily oral dopamine agonist for PD. In general, it is prescribed as a once daily regimen. When patients switched from once-daily to twice-daily or twice-daily to once-daily, however, their mean mUPDRS, H&Y, ESS, sleep quality and AEs were not statistically different. Despite the different dosing frequency, these findings indicate the same dose of RPR had a similar efficacy without an increase in AEs and was not inferior.
To check for bias of the sequence effect, we analyzed the outcomes based on the order. When the once-daily regimen was administered first (sequence 1 → 2), 51.79% (15/29) of the patients preferred the twice-daily regimen. The proportion of subjects who preferred the twice-daily regimen more was 50% (16/32) when the twice-daily regimen was administered first (sequence 2 → 1). Thus there was no sequence effect. We also did not find a sequence effect in the secondary outcome analysis.
For PGI-I, 50 patients reported improvement after RPR over the IR form of agonists. Admittedly, the dose was increased from 9.1 ± 5.0 mg of the IR form of agonists to 10.7 ± 6.2 mg of RPR. It is to be noted that we tried to optimize the medication with the available IR form of agonists balancing many factors such as motor fluctuation, dyskinesia and adverse effects. Therefore, it is definitely a benefit of RPR when the condition of patients' improved even with the increased mean daily dose being within tolerance.
In our study, PD patients preferred the twice-daily regimen to the once-daily regimen (51% vs. 28%). In patients who preferred the twice-daily regimen, their main reasons were decreased severity of off symptoms or dyskinesia and decreased AEs. Especially for wearing-off duration, the PGI-I was significantly higher in twice-daily regimen. Thus, we should consider the twice daily regimen with its reduced severity of symptoms or decreased intolerable AEs for antiparkinsonian medications.
When patients chose the once-daily regimen, their main reason was improved on quality and decreased off symptoms or dyskinesia. Thus, we should consider the once daily regimen preferentially for young patients who are active workers in the daytime or have diphasic dyskinesia.
We expected changes in sleep quality and daytime sleepiness between the two regimens. However, there were no significant differences between the once-daily and twice-daily regimens.
As can be seen in the time window of the ropinirole level from Tompson et al., the nocturnal concentration may be lower in the once daily RPR than the three times daily RIR. The down sloping of the ropinirole level was designed taking into consideration natural dopaminergic stimulation and improvement in nocturnal side effects including insomnia and hallucinations. Additionally, the reason was not fully explained by the time window of the ropinirole level in the steady state. However, multiple dosing of RPR may provide even better control in some patients.
Although patients showed no differences in their mean mUPDRS, H&Y, ESS, sleep quality and AEs, more patients preferred the twice-daily regimen and their main reason was more tolerable off-symptoms. Three of our study patients preferred the twice-daily regimen due to psychological stability, and decreased anxiety due to reduced off symptoms. This finding shows that psychological factors may explain the preference. Patients in this study previously maintained dopaminergic therapy with multiple dosing. They endured off symptoms and have fear of them. Therefore, as an ostensible reason of preference, they chose "more tolerable off-symptoms", however the real reason would be "decreased anxiety due to reduced off symptoms."
In antiparkinsonian medication, once daily dosing may improve compliance and achieve the desired outcome. Four patients chose the once daily regimen due to convenience. However, almost all PD patients are taking multiple antiparkinsonian medications many times a day. Thus, compliance may not be a big issue especially for advanced PD patients.
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