Analysis of pramipexole dose–response relationships in Parkinson's disease

Introduction

Pramipexole (PPX), a non-ergot dopamine receptor agonist (DA), is prescribed as initial monotherapy for early Parkinson’s disease (PD) and adjuvant treatment for advanced PD. PPX has neuroprotective effects in vitro and in vivo, which manifest, especially in early PD, as delayed development of levodopa-induced motor complications.^1–3 Researchers postulated that DAs with a longer half-life than levodopa provide continuous activation of presynaptic dopaminergic receptors and/or intracellular kinase, which in turn reduces dopamine turnover and apoptosis and consequently the risk of motor complications.⁴ Initial PPX therapy reduced the risks of motor complications compared with levodopa⁵ and indicated a slower rate of dopamine neuron loss reflected by a surrogate biomarker.² In addition, PPX can not only control motor symptoms and delay motor complications but also improve depressive symptoms in patients with PD.^6,7

Currently, immediate-release (IR) PPX is administered orally three times daily. Sustained-release (SR) formulations of PPX, the same formulation with extended-release PPX, showed similar pharmacokinetics and tolerability as equivalent dose IR PPX.^8,9 In clinical trials, PPX SR has demonstrated similar therapeutic efficacy and safety profile as PPX IR, both in early and advanced PD.^9–16 In patients with previous PPX IR treatment, the success rates of switching from IR to SR and pseudo SR to SR were 86.2% and 83.8%, respectively.¹⁵ Moreover, 4 and 8 weeks after overnight switching from the IR to the SR formulation, patients’ adherence and motor symptoms (Unified Parkinson’s Disease Rating Scale [UPDRS] part III) improved without severe adverse effects; such improvement in efficacy might be attributable to a significantly higher adherence to the SR formulation than to the triple-dose formulation.^17,18

While initiating PPX treatment, doses should be increased gradually from a starting dose of 0.375 mg/d and then increased every 5–7 days.¹⁹ Provided patients do not experience intolerable or undesirable side effects, the doses should be titrated to achieve a maximal therapeutic effect. Individual doses should range between 0.375 and 4.5 mg/d.¹⁹ Studies have shown that patients already taking PPX tablets may be switched to PPX SR tablets overnight at the same daily dose.²⁰ During dose escalation in pivotal studies, both in early and advanced PD, efficacy was observed starting at a daily dose of 1.5 mg. As a preceding dose-escalation phase usually aids in achieving maximally tolerated doses in PD patients, the dose-dependent effects of PPX have not been fully explored. It is unclear whether the differences in different tolerated doses between patients indicate dose-dependent differences in benefit-to-risk ratios and/or risk profiles. In the present study, we retrospectively analyzed the raw data from a randomized clinical trial (ClinicalTrials.gov Identifier: NCT01191944) conducted in Chinese patients with early and advanced PD. In this study, patients received different dosages of PPX in maintenance period (0.375, 0.75, 1.5, 2.25, 3.0, 3.75, or 4.5 mg/d), and patient number is not enough to conduct statistical analysis between each dosage group. Patients received PPX at doses (mean dose in mg/d: SR, 1.5 and IR, 1.6) lower than those recommended by the Chinese PD consensus (usual PPX effective clinical dose: 1.5–2.25 mg/d, up to a maximum dosage of 4.5 mg/d).²¹ Accordingly, 1.5 mg/d was regarded as the critical dose level in this study to determine whether differences in the efficacy and tolerability of PPX in the Chinese population are dose dependent.

Methods

Patients and study design (heterogeneous participants)

Data from all patients included in the aforementioned Chinese study were analyzed in this retrospective analysis.¹⁶ Briefly, Chinese patients diagnosed with an idiopathic PD of >2 years’ duration were enrolled, including those with early- or advanced-stage PD and those with or without motor fluctuation. In addition, patients treated with stable doses of common anti-PD medications for >4 weeks prior to enrollment were included. After enrollment, the patients were randomized to receive PPX IR or PPX SR for 18 weeks, with no changes to the doses of the other combination anti-PD drugs. The optimal doses of PPX were up-titrated in the initial 7 weeks and maintained for 11 weeks thereafter. After completion of the study, the study drug was gradually withdrawn over 1 week. IR and SR PPX were administered at doses ranging between 0.375 and 4.5 mg/d. The study received ethical approval by the Ethics Committee of Ruijin Hospital, Shanghai, People’s Republic of China, and written informed consent was obtained for experimentation with human subjects.

Clinical assessment

Patients’ and treatment responses were assessed as previously described.¹⁶ Briefly, patients were assessed using the modified Hoehn and Yahr Scale. PD symptoms and primary treatment responses were assessed using UPDRS parts II and III. A treatment response was defined as a ≥20% decrease in UPDRS scores from the baseline. In addition, patients were evaluated using the Mini-Mental State Examination, and subjects’ self-reported likelihood of dosing was assessed using the Epworth Sleepiness Scale. The general status of patients was assessed using the Clinical Global Impressions of Improvement and the Patient Global Impression of Improvement scales.

Adverse events

Adverse events (AEs) were recorded as previously described.¹⁶ In brief, the occurrence, frequency, and severity of AEs were recorded throughout the trial. On the basis of severity, AEs were classified as mild if they were easily tolerated, moderate if they interfered with daily activities, and severe if these prevented patients from performing their daily activities or worse. AEs were considered serious if they resulted in death, were immediately life threatening, resulted in persistent or significant disability/incapacity, required or prolonged patient hospitalization, were a congenital anomaly/birth defect, or were deemed serious for any other reason.

Statistical analysis

Sample size estimation and different data sets have been described previously.¹⁶ The full analysis set (FAS) included patients who received at least 1 dose of the study drug and provided both a baseline and a post-baseline assessment of primary endpoints. Baseline refers to the last recorded measurements before administration of the study drug. Efficacy was analyzed using the FAS, and the last observation carried forward approach was used for missing data during follow-up. Because both PPX SR and IR improved symptoms in patients with early or advanced PD and showed similar efficacy and safety in this Chinese study, all patients were categorized into 2 subgroups based on the PPX maintenance dose (PPX <1.5 or ≥1.5 mg/d), PD stage (early or advanced), combined levodopa dose at baseline (low dose, 0–<400 mg/d or high dose, ≥400 mg/d), and the level of contribution of tremor to the sum score of Activities of Daily Living (part II) and Motor Examination (III) of the UPDRS score (UPDRS II+III score) at baseline (tremor scores/UPDRS II+III scores, <20% or ≥20%) for an exploratory analysis of the effects of these variables on efficacy. An analysis of covariance model was used to evaluate the improvement in UPDRS II+III scores in each of these subgroups based on the FAS. Formulation (IR or SR) and center were included as fixed effects, whereas baseline UPDRS II+III total scores formed a linear covariate. The incidence of AEs was presented for all treated patients who received PPX at a dose of ≥1.5 or <1.5 mg/d.

Results

Baseline characteristics

Patients who showed a comparable use of the 2 PPX formulations were regrouped by PPX dose, PD stage, levodopa dose, and contribution of tremor to UPDRS at baseline. The patients were almost equally distributed by disease stage (early and advanced) and levodopa dose (0–400 and ≥400 mg/d). Approximately two-third of patients were up-titrated to ≥1.5 mg/d in this trial. Approximately one-fourth of patients had a tremor contribution of ≥20% to the UPDRS II+III scores at baseline (Table 1).

Table 1 Patients’ distribution in subgroups (FAS) Abbreviations: FAS, full analysis set; IR, immediate release; PD, Parkinson’s disease; PPX, pramipexole; SR, sustained release.

Dose-related efficacy

After 18 weeks of PPX treatment, patients receiving PPX ≥1.5 mg/d showed a greater reduction in UPDRS II+III scores compared with those receiving PPX <1.5 mg/d (14.83 vs 10.69, respectively). The adjusted difference between the PPX ≥1.5 and PPX <1.5 mg/d subgroups was 3.21 (95% CI [confidence interval], 1.14–5.28; P=0.0025; Figure 1 and Table 2).

Table 2 Reduction in UPDRS II+III scores after 18 weeks of PPX treatment Note: *P<0.01 compared with other arm in the same group. Abbreviations: PD, Parkinson’s disease; PPX, pramipexole; SE, standard error; UPDRS, Unified Parkinson’s Disease Rating Scale.

Figure 1 Differences in efficacy between the PPX dose groups with individual PPX IR and SR formulations. Notes: Forest plot of adjusted mean differences between the PPX ≥1.5 and PPX <1.5 mg/d subgroups for PPX IR, SR, and all patients. Abbreviations: CI, confidence interval; IR, immediate release; PPX, pramipexole; SR, sustained release.

In the individual PPX IR and SR groups, efficacy differences between the PPX ≥1.5 and <1.5 mg/d subgroups were comparable (3.62 vs 2.77, P=0.2924; Figure 1). These differences were greater than the minimal clinically important change (MCIC) of 2.5, thus indicating their clinical significance.²² The more serious a symptom was at baseline, the greater the improvement observed after 18 weeks of PPX treatment. Note the more prominent slope in the PPX ≥1.5 mg/d subgroup than in the PPX <1.5 mg/d subgroup in Figure 2 (slope: −0.3223 vs −0.3021). Therefore, patients in the PPX ≥1.5 mg/d group would get more improvement in UPDRS II+III scores than that in the PPX <1.5 mg/d group consistently across different baseline UPDRS II+III scores.

Figure 2 Differences in efficacy slopes between the PPX dose groups. Notes: The more serious the symptom was at baseline, the greater the improvement achieved after 18 weeks of PPX treatment; the improvement was more prominent in the PPX ≥1.5 mg/d subgroup than in the PPX <1.5 mg/d subgroup consistently across different baseline UPDRS II+III scores. Abbreviations: PPX, pramipexole; UPDRS, Unified Parkinson’s Disease Rating Scale.

In patients with a tremor contribution of ≥20% (tremor contribution = tremor scores [sum of 16th, 20th, and 21st items of UPDRS]/UPDRS II+III scores), PPX treatment resulted in greater improvements in UPDRS II+III scores; after adjustment for baseline UPDRS II+III scores, the average difference was 3.42 (95% CI, 1.29–5.55; P=0.0017; Table 2). However, patients with early and advanced PD responded similar to PPX (P=0.6580) as did those who had received levodopa at doses of 0–400 and ≥400 mg/d at baseline (P=0.1786).

Table 3 shows a subgroup analysis of improvements in major motor function characteristics, including bradykinesia (sum of 23rd, 24th, 25th, 26th, and 31st UPDRS items), rigidity (22nd item), postural instability gait difficulty (PIGD; sum of 13th, 14th, 15th, 29th, and 30th items), and tremors (sum of 16th, 20th, and 21st items). Score reduction for these 4 core motor symptoms and the corresponding proportions of patients who showed ≥20% improvement was greater in the PPX ≥1.5 mg/d subgroup than in the PPX <1.5 mg/d subgroup (Table 3). However, differences of <1.5 points were observed between the early and advanced PD subgroups and between the 0–400 and ≥400 mg/d levodopa dose groups, which were far below the MCIC of 2.5. Patients with dominant tremors (tremor contribution ≥20%) tended to achieve greater score reductions compared with those with nondominant tremors; however, score reductions for bradykinesia, rigidity, and PIGD were comparable between these patient types.

Table 3 Improvements in 4 core motor symptoms Abbreviations: PD, Parkinson’s disease; PIGD, postural instability gait difficulty; UPDRS, Unified Parkinson’s Disease Rating Scale.

Dose-related AEs

The incidence of AEs was lower in the PPX ≥1.5 mg/d subgroup (68.6%) than in the PPX <1.5 mg/d subgroup (75.4%). The 3 most common AEs were somnolence (18.6% vs 18.0%), dizziness (16.2% vs 11.1%), and nausea (10.8% vs 6.2%). Withdrawal due to AEs (12.6% vs 0.7%) and the incidence of investigator-defined drug-related AEs (61.1% vs 46.1%) were higher in the PPX <1.5 mg/d subgroup than in the PPX ≥1.5 mg/d subgroup (Table 4).

Table 4 Incidence of AEs for different PPX dose groups Abbreviations: AEs, adverse events; PPX, pramipexole.

Discussion

The optimal dose of PPX for individual PD patients should be titrated to achieve a balance between efficacy and tolerability. A Japanese study reported that the increase in plasma concentration of PPX was proportional to the gradual increase in dose; however, current clinical data are insufficient to confirm an improvement in efficacy and AEs with increasing PPX doses.⁹ Previous studies have shown that the efficacy and safety profiles of PPX SR and IR were comparable.^9,16 Therefore, we retrospectively analyzed the pooled raw data of PPX IR and SR groups from the Chinese study. Results of this analysis provide evidence for the existence of a critical dose level of PPX for PD patients, which in this case was 1.5 mg/d. Patients whose PPX doses could be titrated to ≥1.5 mg/d showed greater improvements in UPDRS II+III scores than those who received PPX at <1.5 mg/d at the end of the 18-week treatment period. In addition, patients in the PPX ≥1.5 mg/d subgroup reported fewer AEs, except for gastrointestinal disorders. Moreover, patients receiving PPX ≥1.5 mg/d showed greater improvements in motor function, particularly bradykinesia, rigidity, PIGD, and tremors. Both PPX IR and SR showed comparable efficacy improvement in terms of UPDRS II+III score reduction with increasing doses without any statistically significant differences. In the individual PPX IR and SR groups, and the IR + SR pooled groups, the differences between the ≥1.5 and <1.5 mg/d subgroups reached the MCIC of 2.5, which indicated superior efficacy of PPX at ≥1.5 mg/d.

In this study, tremor control contributed largely to the total UPDRS II+III score reduction. A large series of 100 patients with pathologically proven PD revealed tremor in 69% of patients at disease onset and in 75% during the disease course; in 9% of patients, tremors were lost late during the disease course.²³ Previous data have demonstrated that PPX demonstrates favorable efficacy in tremor control, even for patients with refractory tremors.²⁴ In this analysis, we observed that PPX improved the 4 core motor symptoms of PD, and this effect was more evident with increasing doses. Moreover, for patients with dominant tremor symptoms, improvements in UPDRS II+III and tremor scores were even more evident, which is consistent with previous data showing the superiority of PPX in improving tremor.

It remains unclear whether PD patients receiving PPX at different dose levels manifest different AE profiles. We observed a trend toward a marginally higher incidence of AEs in the <1.5 mg/d subgroup than in the ≥1.5 mg/d subgroup. However, these data are insufficient to draw concrete conclusions. Moreover, patients in the <1.5 mg/d subgroup had received low PPX doses, which might be related to poor tolerability; therefore, the incidence of AEs was higher in this subgroup than in the ≥1.5 mg/d subgroup. Accordingly, patients with better tolerability showed greater improvements in motor symptoms with PPX ≥1.5 mg/d without any significant increase in the incidence of AEs.

The retrospective analysis is a study limitation, and it is exploratory in nature. Furthermore, the comparisons were not based on a randomized sample although the analysis was adjusted for several important factors.

Conclusion

For PD patients receiving PPX treatment for 18 weeks, PPX at both dose levels can improve motor function and daily activities with comparable AE rates. However, compared with PPX <1.5 mg/d, administration of PPX ≥1.5 mg/d can result in further clinically significant efficacy improvements. Both IR and SR formulations displayed similar trends. Patients with dominant tremors tended to achieve greater improvements after PPX administration. PPX treatment can effectively improve patients’ symptoms regardless of the PD stage or dose of combined levodopa at baseline.

Acknowledgments

We thank Fei Liu and Paul Liu from Elsevier for linguistic assistance during the preparation of this manuscript, which was contracted and compensated by Boehringer Ingelheim (China) Investment Co., Ltd. Editorial assistance was provided by Cactus Communications and was funded by Boehringer Ingelheim. Boehringer Ingelheim (China) Investment Co., Ltd. was given the opportunity to review the manuscript content for medical and scientific accuracy and intellectual property considerations. In addition, we thank the Pramipexole SR Study Team for their help, and we thank Gang Cheng’s help.

Disclosure

Ying Wang has participated in clinical trials sponsored by GSK, Eisai, Lundbeck, and Novartis. Sheng-Gang Sun has participated in clinical trials sponsored by Novartis, Servier, Eisai, GSK, and Lundbeck. Sui-Qiang Zhu has participated in a clinical trial sponsored by UCB. Chun-Feng Liu has participated in clinical trials sponsored by Pfizer, UCB, and GSK. Yi-Ming Liu has participated in a clinical trial sponsored by UCB. Qing Di has participated in a clinical trial sponsored by Pfizer. Hui-Fang Shang has participated in clinical trials sponsored by GSK and UCB. Yan Ren reports no conflicts of interest in this work. Sheng-Di Chen has participated in clinical trials sponsored by Novartis, Lundbeck, Eisai, and Xian Janssen. All aforementioned authors served as investigators in this retrospective analysis sponsored by Boehringer Ingelheim (China) Investment Co., Ltd. Wei Xiang is employee of Boehringer Ingelheim (China) Investment Co., Ltd. The authors report no other conflicts of interest in this work.

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