Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson's disease psychosis

IntroductionPimavanserin is a selective 5-HT_2A inverse agonist/antagonist approved for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Results from short-term, placebo-controlled studies demonstrated a positive benefit/risk profile. This multi-year, open-label study assessed long-term safety and tolerability of pimavanserin.MethodsThis was an open-label extension (OLE) study in patients previously completing a double-blind, placebo-controlled study or a previous OLE study. Safety was evaluated from adverse events (AEs), clinical laboratory results, motor symptoms, electrocardiograms (ECG), and mortality. Durability of response was assessed from the Clinical Global Impression-Severity (CGI-S) scale and Caregiver Burden Scale (CBS).ResultsOf 459 participants treated in this OLE study (average age 71.2 years), the median duration of treatment was 454 days. Over the entire study period (approximately 11 years), ≥1 AE occurred in 392 (85.4%) patients; the majority were of mild to moderate intensity, with fall (32.0%), urinary tract infection (19.0%), and hallucination (13.7%) most common. Serious AEs occurred in 188 (41.0%) patients, and an AE leading to study termination or dose discontinuation occurred in 133 (29.0%) patients. Sixty-one patients died, 59 (12.9%) during treatment or within 30 days after the last dose of study drug; the observed mortality rate was 6.45 per 100 patient-years of exposure. Mean scores for the CGI-S scale and CBS generally remained stable for up to 192 weeks (>3.5 years).ConclusionsLong-term treatment with pimavanserin 34 mg once daily demonstrated a favorable benefit/risk profile with no unexpected safety concerns. Mortality rates suggested no increased risk following long-term treatment.     

LC-MS/MS法测定比格犬血浆中匹莫范色林浓度及药代动力学研究

目的建立一种高效、灵敏的液相色谱-串联质谱(LC-MS/MS)法测定匹莫范色林在比格犬血浆中的浓度并应用于药代动力学研究。方法血浆样品用甲基叔丁基醚(MTBE)液液萃取预处理,使用Agilent Eclipse XDB-C 18(4.6 mm×150 mm,3.5μm)色谱柱进行分离,流动相为乙腈(含0.1%甲酸)-水(含5%乙腈,0.1%甲酸)梯度洗脱,流速为1.2 mL·min-1,分流比为1∶1,质谱检测用电喷雾离子(ESI)源,正离子模式下采用多反应监测(MRM)模式,分析时间为4.5 min。使用WinNonlin 6.1软件的NCA模块计算药动学参数。结果匹莫范色林在0.05~20 ng·mL-1浓度范围内线性关系良好,定量下限为0.05 ng·mL-1,批内和批间精密度良好CV均小于7.1%(LLOQ均小于18.4%),准确度RE均在-6.6%~12.7%之内(LLOQ均在3.8%~19.9%)。结论本方法高效、灵敏、准确,成功用于比格犬血浆中匹莫范色林浓度的测定及其药代动力学研究。     

Treatment of psychosis in Parkinson's disease and dementia with Lewy Bodies: A review

There is a considerable overlap between Parkinson's Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). They present a challenge therapeutically, with regard to morbidity and mortality risk. In particular, symptoms of psychosis in these conditions augur a considerably increased burden.To date, there has been a myriad of prospective, retrospective and case studies examining the use of neuroleptics in the treatment of psychotic symptoms in PDD/DLB. Clozapine has the most robust evidence base however its use is limited by agranulocytosis risk and the associated need for frequent blood count monitoring. Quetiapine is more readily used, however, it has a more equivocal evidence base, in terms of efficacy. Other neuroleptics have thus far demonstrated mixed results with increased risk of extrapyramidal worsening. In addition to the atypical agents, the introduction of pimavanserin has provided another treatment option for Parkinson's Disease Psychosis (PDP), decreasing concern for deterioration in motor function. We await further research to confidently demonstrate its efficacy and safety in DLB psychosis. Cholinesterase inhibitors likely have a limited role in treating milder psychosis symptomatology in DLB and perhaps PDD.After review of the current literature for antipsychotic therapy in both PDD and DLB, we provide a logical framework for addressing psychotic symptoms in each condition.