- 學位論文
台灣初期帕金森病患使用樂伯克速效劑型直接轉換至長效劑型之可行性評估: 開放性、交叉試驗
The Feasibility of Overnight Switching of Pramipexole from Immediate-release to Extended-release Formulation in Early Parkinson's Disease: An Open-labeled, Crossover Study in Taiwan
摘要
研究目的 帕金森病為國內常見老年慢性病之一，其為一錐體外多巴胺神經系統之慢性退化性疾病。非麥角固醇類多巴胺受體制效劑─樂伯克(pramipexole/MirapexR)被核准用於初期帕金森患者之單一藥物治療，以及晚期左多巴製劑之合併療法，具有降低左多巴劑量並降低長期使用所導致之併發症的效果。近期研究指出，樂伯克(MirapexR, Boehringer Ingelheim pharmaceutical company)亦有神經保護作用及抗憂鬱之效果。2010年FDA核准樂伯克之長效劑型用於帕金森患者的治療，並於同年八月於台灣衛生署核准上市。據先前研究顯示，樂伯克長效劑型相對於短效劑型有較穩定的血中濃度，且每日一次的給藥方式可提高病人的用藥順服性，並減少副作用(頭暈、嘔吐)的產生。在此一開放性交叉試驗中，評估在台灣的早期巴金森病人群中，將樂伯克之長效與速效劑型以相同日劑量做劑型轉換的可行性，以及兩劑型使用上對其動作功能、用藥順服性、用藥滿意度及安全性上是否有差異。 研究方法 此為一開放性、交叉性、上市後研究。納入條件為經UK brain bank Parkinson’s disease clinical diagnostic criteria診斷、疾病嚴重度為輕至中度(Hoehn and Yahr stage 1-3期) 之初期帕金森病人。允許穩定使用L-DOPA, selegiline, amantadine, anticholinergic等帕金森藥物至少四週納入試驗。排除條件為失智症(簡易智能狀態測驗 < 25且臨床失智評估量表 > 0.5)、次發性或非典型帕金森症狀、精神病或物質濫用。試驗前及過程中禁止使用抗精神病劑、急救性止吐劑、其他多巴胺致效劑及含卡瓦椒成份之藥品。其他排除條件包含低血壓或腎功能異常者。 納入之受試者隨機分派到樂伯克速效劑型(IR)一天三次或長效劑型(ER)一天一次兩組，使達到穩定劑量四週後，再以相同日劑量做劑型轉換並維持四週。主要評估轉換前後長、速效劑型間之劑型成功轉換比率及用藥順服性。次要評估兩劑型對帕金森病人之動作功能(UPDRS)、臨床整體印象(CGI-I, PGI-C)、用藥滿意度(TSQM)與安全性上之影響。 研究結果 本研究共有27位帕金森病人納入此試驗，其中有15位病人完成試驗。由速效劑型轉移至長效劑型，及由長效劑型轉移至速效劑型的成功轉移率各為87.5%與85.7%。用藥順服性方面在速效及長效劑型間並無顯著差異(速效: 97.3%; 長效: 100%)。儘管在UPDRS, CGI-I, PGI-C等次要評估項目的結果在兩劑型間顯示都無顯著差異，但在兩劑型的TSQM之方便性評估上以長效劑型較佳(p < 0.05)；而在劑型的偏好程度上，病人對長效劑型之偏好(67%)也比速效劑型(33%)高，主因為長效劑型有較佳的方便性。 副作用產生的比例在兩劑型也無顯著差異；頭暈、噁心、嘔吐、腹部不適為其最常見之副作用，然而這些副作用通常出現在劑量提升期，而在維持期或降低劑量後可得到緩解。 結論 本研究結果確認樂伯克 (MirapexR) 長效與速效劑型間具有相似的藥效及安全性。而基於長效劑型每日一次給藥頻次的方便性，而有較佳的用藥順服性傾向及較高的偏好程度。由於兩劑型間成功轉移率皆大於80%，故推估對於台灣的早期巴金森病人，以相同日劑量來做隔夜迅速劑型轉換是可行的。
並列摘要
OBJECTIVES Parkinson’s disease (PD) is one of the degenerative brain disorders in elderly population. It is a progressive neurodegeneration of the extrapyramidal dopaminergic system. Pramipexole (MirapexR) is a non-ergot dopamine agonist (DA). It is well-tolerated and can serve as a monotherapy in early PD patients or an add-on therapy to L-DOPA in advanced PD patients, thus the dose of L-DOPA can be reduced and hence decrease its motor complications. Recent studies indicate that pramipexole also possesses neuroprotective and anti-depressive effect. The extended-release form (ER) of pramipexole was approved for the treatment of PD in February 2010 by FDA and August 2010 by DOH in Taiwan; Pramipexole ER is expected to provide more stable serum concentration, less adverse effects, and better compliance due to once-daily dose. In this open-labeled, crossover study design, we evaluated the feasibility of overnight switching of pramipexole IR and ER formulations at the same daily dose, and also compared the safety and efficacy of pramipexole ER with immediate-release (IR) formulation in patients with early PD. METHODS This was an open-labeled, crossover, post-marketing study. During initial clinical evaluation, patients with early PD (Hoehn and Yahr stage 1-3) were included in this study. Patients with dementia (Mini-mental State Examination < 25 and Clinical Dementia Rating scale > 0.5), secondary or atypical parkinsonism, psychosis symptoms or substance abuse were excluded. Neuroleptics, rescue antiemetics, other DA, kava were not allowed before and during the study. Additional exclusion criteria included patients who have hypotension or renal function abnormality at screening for safety concern. The primary endpoints were the proportion of successfully switched patients and the difference of compliance between the two formulations. Secondary endpoints were UPDRS part II and III, Clinical Global Impression of Improvement (CGI-I), Patient Global Impression of Change (PGI-C), Treatment Satisfaction Questionnaire for Medication (TSQM) and medication preference for efficacy evaluation. Adverse events were reported by patients during the study. The study was performed at the Taipei Medical University Hospital immediately after receiving the approval of JIRB in November 2011. Each PD participants agreed and signed the informed consent. RESULTS Twenty-seven patients were enrolled in this study, and fifteen patients completed the study. The proportions of successful switch from IR to ER and from ER to IR were 87.5% and 83.3%, respectively. There was no significant difference of the compliance between pramipexole IR and ER users (IR: 97.1%; ER: 100%). Although most of the secondary endpoints (i.e., UPDRS, CGI-I, PGI-C) showed no significant differences between the formulations, pramipexole ER showed significantly higher score in the convenience section of TSQM scale (p < 0.05). In addition, the preference rate of pramipexole ER was 71% which was much higher than that of IR (29%) due mainly to its convenience. Adverse effects were comparable between ER and IR; dizziness, nausea and vomiting were the most common adverse events and usually could be relieved during maintenance phase or by decreasing the dose. CONCLUSION The present study results confirm that pramipexole IR and ER had comparable safety and efficacy profiles. ER users had the tendency of better compliance and significantly higher preference rate due to once daily dosing. Since the rate of successful switch from the two formulations at the same daily dose was above 80%, the practice of overnight switch was applicable to PD patients in Taiwan.