帕利哌酮棕榈酸盐的临床研究进展

帕利哌酮棕榈酸盐是一种非典型抗精神病药物的长效针剂,活性成分为帕利哌酮,也称9-羟利培酮,主要通过阻断5-羟色胺2A受体和多巴胺D2受体发挥抗精神病药作用。该药在制备过程中采用了特殊的纳米晶体技术,有效提高药物溶解度,使得药物在使用过程中更加安全有效。经试验证实,帕利哌酮棕榈酸盐对精神分裂症急性期治疗和维持治疗效果较好,与现有长效针剂相比具有一定优势,为精神分裂症患者的治疗提供了一种新的选择。     

帕利哌酮棕榈酸盐多次给药的稳态血药浓度与临床安全性的研究

目的研究帕利哌酮棕榈酸盐在精神分裂症患者中多次给药的血浆药物浓度水平及其与治疗安全性的关系。方法 18名符合DSM-IV精神分裂症诊断患者经过第1,8,38 d的固定剂量注射后,每30 d进行一次剂量可变的药物注射,按照最后3针实际给予的药物剂量分组。于试验第8,11,14,17,21,28,38,68,98,128,158,188 d采血,高效液相色谱法测定血浆中帕利哌酮浓度,临床症状在试验第1 d和188 d用PANSS评分,安全性则通过不良事件监测、生命体征监测、实验室检查以及锥体外系反应量表评估,用SPSS软件分析数据。结果17名最终完成试验的患者分为75 mg eq.(n=5)、100 mg eq.(n=9)、150 mgeq.(n=3)3组,各组的稳态血药浓度为(23.42±11.95),(24.52±12.44),(16.92±6.53)ng.mL-1,注射后的峰浓度出现在第11～18 d,平均为17 d。11例患者共出现17例次不良事件,程度均为轻中度。结论给药后,帕利哌酮棕榈酸盐各剂量组间稳态浓度无差异,但个体差异明显。药物剂量与不良反应间未见关联。     

棕榈酸帕利哌酮缓释注射液的体外表征及其药动学研究

目的:以Invega Sustenna?为参考进行制剂的仿制研究,并进行Invega Sustenna?和自研棕榈酸帕利哌酮缓释注射液的体外表征研究和体内药动学研究。方法:采用激光粒度分析法确定了Invega Sustenna?粒径分布范围,采用湿磨法制备了棕榈酸帕利哌酮缓释注射液;通过体外溶出实验、扫描电镜(SEM)、差示扫描量热(DSC)、粉末X射线衍射(XRPD)和红外光谱(IR)对Invega Sustenna?和自研棕榈酸帕利哌酮缓释注射液进行了体外表征,并进行了大鼠体内的药动学研究。结果:确定了Invega Sustenna?的粒径分布范围为d(0.1)=0.13~0.30 μm;d(0.5)=0.60~1.00 μm;d(0.9)=2.00~3.00 μm;Span=2.0~3.0;自研棕榈酸帕利哌酮缓释注射液与不同批次Invega Sustenna?间溶出曲线的相似因子均大于50;研磨前后棕榈酸帕利哌酮的晶型及结构无显著变化,且自研棕榈酸帕利哌酮缓释注射液和Invega Sustenna?的外部形貌、晶型及结构均保持一致。药动学研究中,自研棕榈酸帕利哌酮缓释注射液在大鼠体内的C_max值和AUC_0-t值分别是Invega Sustenna?的0.99倍和0.93倍,且自研棕榈酸帕利哌酮缓释注射液和Invega Sustenna? C_max与AUC比值的90%置信区间均在80%~125%。结论:该研究的自研棕榈酸帕利哌酮缓释注射液与Invega Sustenna?的体外溶出和体内药动学一致,获取的实验数据将为后期的制剂研究提供指导。     

Transitioning from oral risperidone or paliperidone to once-monthly paliperidone palmitate: a real-world analysis among Veterans Health Administration patients with schizophrenia who have had at least one prior hospitalization

Abstract

Objective: To address gaps in the literature on healthcare resource utilization (HRU) and costs among patients with schizophrenia and prior hospitalization who transition from oral risperidone or paliperidone (oral ris/pali) to once-monthly paliperidone palmitate (PP1M) in a real-world setting by comparing treatment patterns, HRU, and costs 12-months pre- and post-transition to PP1M among Veterans Health Administration (VHA) patients affected by schizophrenia who have had ≥1 hospitalization.

Methods: VHA patients with schizophrenia (aged ≥18?years) who initiated oral ris/pali, had ≥1 all-cause inpatient stay, and transitioned to PP1M from January 2015–March 2017 were included from the VHA database. The first transition date to PP1M was identified as the index date. Patients were required to have continuous health plan eligibility for 12?months pre- and post-PP1M. Outcomes were compared using the Wilcoxon signed-rank and McNemar’s test, as appropriate.

Results: The study included 319 patients (mean [SD] age?=?51.6 [4.2] years) during 12 months of baseline and follow-up. During pre-PP1M transition, 7.2% of the patients were adherent (proportion of days covered [PDC]?≥?80%) to oral ris/pali. Post-PP1M transition, 27.6% of the patients were adherent to PP1M. Comparison of HRU outcomes from the pre- to post-PP1M transition revealed significantly lower all-cause inpatient stays (3.5 vs 1.4, p?<?.0001) and shorter inpatient length of stay (43.4 vs 18.3?days, p?<?.0001). Similar trends were seen for mental health and schizophrenia-related HRU. Cost outcome comparison indicated significantly lower all-cause inpatient costs ($64,702 vs $24,147, p?<?.0001), total medical costs ($87,917 vs $56,947, p?<?.0001), and total costs ($91,181 vs $69,106, p?<?.0001). A similar trend was observed for mental health and schizophrenia-related costs.

Conclusions: Transitioning from oral ris/pali to PP1M may significantly improve HRU and provide potential cost savings in VHA patients with schizophrenia and ≥1 prior hospitalization.     

Once-monthly injection of paliperidone palmitate in patients with recently diagnosed and chronic schizophrenia: a post-hoc comparison of efficacy and safety

Background: The use of long-acting injectable antipsychotics in recently diagnosed schizophrenia remains less explored. We evaluated the efficacy and safety of paliperidone palmitate once-monthly (PP1M) treatment in adult patients with recently diagnosed vs. chronic schizophrenia.

Research design and methods: These post-hoc analyses included two multicenter studies. Study 1 (NCT01527305) enrolled recently diagnosed (≤5 years) and chronic (>5 years) patients; Study 2 (NCT01051531) enrolled recently diagnosed patients only. Recently diagnosed patients were further sub-grouped into ≤2 years or 2–5 years. The primary efficacy endpoint was the change from baseline in Positive and Negative Syndrome Scale (PANSS) total score.

Results: In Study 1, 41.5% patients had recent diagnosis (≤2 years: 56.8%; 2–5 years: 43.2%); 58.5% had chronic schizophrenia. In Study 2, 52.8% and 47.2% patients were grouped into ≤2 years and 2–5 years, respectively. PANSS total score showed significantly greater improvement in patients with recently diagnosed vs. chronic schizophrenia. Similar results were obtained for PANSS responder rate, improvements in PANSS, and CGI-S scores.

Conclusion: PP1M was efficacious in both recently diagnosed and chronic schizophrenia, with the benefits being more pronounced in patients with recently diagnosed schizophrenia. This adds to growing evidence recommending long-acting antipsychotic interventions at early stages of schizophrenia.     

Changes in schizophrenia-related hospitalization and ER use among patients receiving paliperidone palmitate: results from a clinical trial with a 52-week open-label extension (OLE)

Abstract

Background:

Schizophrenia affects ～1.1% of the United States population, resulting in substantial direct, indirect and societal costs.     

A systematic review and combined analysis of therapeutic drug monitoring studies for oral paliperidone

Introduction: This article includes a combined analysis of therapeutic drug monitoring (TDM) studies and a review of the marketer’s data on pharmacological mechanisms.

Areas covered: An article search led to the inclusion of 21 paliperidone studies in the systematic review plus 2 case reports. Paliperidone clearance was calculated from: 1) steady-state studies using concentration/dose (C/D) ratios, and 2) single-dose studies describing 24-h area under the curve calculations. The marketed extended-release formulation has 28% bioavailability. Calculated mean C/D ratios (ng/ml/mg/d) were: 1) 4.09 in 6 studies of 221 non-Korean and non-geriatric adult patients, 2) 2.59 in 2 studies of 100 Korean adult patients, and 3) 6.89 in 1 study with 15 elderly Japanese patients. The limited drug–drug interaction studies indicated that carbamazepine is a clinically relevant inducer requiring three times the dosage, and that valproate, probably an inhibitor, requires half the dosage. Renal impairment markedly decreased paliperidone elimination, and other antipsychotics should be considered.

Expert Commentary: We recommend more use of: 1) paliperidone TDM in clinical practice, 2) TDM when moving from oral to long-acting paliperidone, 3) better designs for paliperidone TDM studies, 4) laboratory studies on paliperidone pharmacokinetic mechanisms, and 5) TDM studies comparing paliperidone and risperidone dosing.     

A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting paliperidone

ABSTRACT

Introduction: This is a combined analysis of therapeutic drug monitoring (TDM) studies of long-acting injectable paliperidone formulations: monthly (PP1M) and three-month (PP3M) injections.

Areas covered: Fourteen PP1M articles and one PP3M article were identified. Using the paliperidone concentration/dose (C/D) ratio as a measure of clearance provided a weighted mean of 7.7 ng/ml per mg/day among 69 patients from three steady-state PP1M studies (twice as high as oral paliperidone). C/D ratios were: 1) higher by a factor of 1.26 in 12 geriatric patients, 2) lower in obese patients, and 3) 50% lower in three patients taking carbamazepine. No clinically meaningful PP3M pharmacokinetic data have been published.

Expert commentary: Half-life studies and more TDM PP1M studies using steady state are urgently needed. Early TDM studies may help orient PP1M dosing but steady state may not be reached until after the ninth injection (8 months). PP3M may take > 1 year to reach steady state. Any clinician considering switching patients to PP1M: 1) should switch from oral risperidone to PP1M rather than from oral paliperidone to PP1M, and 2) become proficient in paliperidone TDM to use during switches. TDM is highly recommended for patients with abnormal clearance (from obesity, geriatric age, or potent inducers).     

Perceptions of behavioral health care among veterans with substance use disorders: Results from a national evaluation of mental health services in the Veterans Health Administration

Understanding patients' perceptions of care is essential for health care systems. We examined predictors of perceptions of behavioral health care (satisfaction with care, helpfulness of care, and perceived improvement) among veterans with substance use disorders (SUD; n = 1,581) who participated in a phone survey as part of a national evaluation of mental health services in the U.S. Veterans Health Administration. In multivariate analyses, SUD specialty care utilization and higher mental health functioning were associated positively with all perceptions of care, and comorbid schizophrenia, bipolar, and PTSD were associated positively with multiple perceptions of care. Perceived helpfulness of care was associated with receipt of SUD specialty care in the prior 12 months (adjusted OR = 1.77, p < .001). Controlling for patient characteristics, satisfaction with care exhibited strong associations with perceptions of staff as supportive and empathic, whereas perceived improvement was strongly linked to the perception that staff helped patients develop goals beyond symptom management. Survey responses that account for variation in SUD patients' perceptions of care could inform and guide quality improvement efforts with this population.     

Budgetary impact of treating acute bipolar mania in hospitalized patients with quetiapine: an economic analysis of clinical trials

ABSTRACT

Objective: To present a tool that allows estimation of the budget impact of treatments for acute mania in bipolar I disorder from a US healthcare payer perspective.

Methods: Using discrete event simulation, the course of individuals is simulated beginning with hospitalization. Discharge depends on symptom level measured by the Young Mania Rating Scale (YMRS). The treatment effect is determined using time-dependent regression equations derived from trial data, and decision rules obtained from clinical experts. Outcomes include: time to response and symptom resolution; proportion of subjects reaching each outcome; number of adverse events. Costs were obtained from hospital discharge databases, the National Medicare Physician Fee Schedule and RedBook. Different scenarios are examined, each describing the proportion of subjects on the various treatments (lithium, divalproex sodium, olanzapine, risperidone, and quetiapine – monotherapy and in combination with lithium). Analyses are intention-to-treat over 100 days, corresponding to follow-up in mania trials. Despite its flexibility and structural adaptability, the model has some important limitations related to the characteristics of the clinical trials. These include focus on inpatient management of acute mania, use of the YMRS as the model driver, polypharmacy restricted to two-drug regimens, no explicit consideration of titration and dose changes, and relatively short time horizon.

Results: Scenarios with a greater proportion of quetiapine users (5% vs. 40% and 100%) result in a smaller impact on the healthcare budget ($6912, $6277, and $5525 per patient, respectively) and improvements in patient outcomes (e.g., 43%, 47%, and 54% responding at day 21; 74%, 77%, and 80% remitting by day 84). Sensitivity analyses showed that the budget impact is influenced by drug prices, discharge criteria and side-effect management.

Conclusion: Results suggest that increased use of quetiapine for bipolar mania in the US is economically justified and improves health outcomes. In addition, this model illustrates that discrete event simulation is a useful and versatile tool for budget impact analyses.     

Impact of source data verification on data quality in clinical trials: an empirical post hoc analysis of three phase 3 randomized clinical trials

AIM

The aim of this project was to perform an empirical evaluation of the impact of on site source data verification (SDV) on the data quality in a clinical trial database to guide an informed decision on selection of the monitoring approach.

METHODS

We used data from three randomized phase III trials monitored with a combination of complete SDV or partial SDV. After database lock, individual subject data were extracted from the clinical database and subjected to post hoc complete SDV. Error rates were calculated with focus on the degree of on study monitoring and relevance and analyzed for potential impact on end points.

RESULTS

Data from a total of 2566 subjects including more than 3 million data fields were 100% source data verified post hoc. An overall error rate of 0.45% was found. No sites had 0% errors. 100% SDV yielded an error rate of 0.27% as compared with partial SDV having an error rate of 0.53% (P < 0.0001). Comparing partly and fully monitored subjects, minor differences were identified between variables of major importance to efficacy or safety.

CONCLUSIONS

The findings challenge the notion that a 0% error rate is obtainable with on site monitoring. Data indicate consistently low error rates across the three trials analyzed. The use of complete vs. partial SDV offers a marginal absolute error rate reduction of 0.26%, i.e. a need to perform complete SDV of about 370 data points to avoid one unspecified error and does not support complete SDV as a means of providing meaningful improvements in data accuracy.     

Encouraging practitioners to use resources: evaluation of the national implementation of a resource to improve the clinical management of alcohol-related problems in Indigenous primary care settings

This paper reports on the evaluation of the implementation of the National Recommendations for the Clinical Management of Alcohol-Related Problems in Indigenous Primary Care Settings undertaken in 2001 through 74 standardized workshops, which sought to determine: (1) whether this approach to implementation influenced the likelihood that the National Recommendations would be used; (2) whether it influenced participants' willingness to engage with Indigenous patients regarding alcohol-related issues; and (3) whether the implementation as a whole influenced both practice and clinicians' willingness to engage. Evaluation included pre-/post-workshop and follow-up questionnaires and a focus group. The findings presented indicate that distribution of clinical resources alone is not sufficient to ensure use and that, particularly for medical practitioners, appropriate introduction not only increases use but also positively influences willingness to engage with alcohol-related problems as part of primary clinical care. Further, the enthusiasm for guideline production should be tempered by the need to develop effective implementation strategies. [Hunter E, Brown J, McCullogh B. Encouraging practitioners to use resources: evaluation of the national implementation of a resource to improve the clinical management of alcohol-related problems in Indigenous primary care settings. Drug Alcohol Rev 2004;23:89-100]     

2018年10月美国、欧盟和日本新批准药物概述

2018年10月,美国、欧盟和日本共批准16个新药,包括新分子实体、新有效成分、新生物制品、新增适应证及新剂型药物。对全球首次获得批准的新分子实体、新有效成分、新生物制品进行分析,重点介绍这些药物的临床研究结果和研发历史进程。

     

Combined effects of alcohol and hepatitis C: A secondary analysis of alcohol use biomarkers and high-risk behaviors from two medication trials for alcohol dependence

Objectives

The goal of this secondary analysis was to examine the combined effects of HCV infection and recent alcohol use on baseline biologic markers of alcohol consumption in two outpatient medication trials for alcohol dependence. In addition, the relationship between Hepatitis C virus (HCV) infection and behavioral risk factors for HCV infection in these clinical populations were examined.

Methods

Data (n = 345) from two randomized, placebo-controlled trials of naltrexone and psychosocial treatment for alcohol dependence (Study I, n = 212) and comorbid alcohol and cocaine dependence (Study II, n = 133) were used to examine baseline measures of HCV risk behaviors (injection drug use, needle sharing), and biomarkers of alcohol use (AST, ALT, GGT and CDT) were compared by HCV serostatus first within each study and then across studies.

Results

Although groups had differing sociodemographic profiles (as indicated by race, marital status, level of education) subjects in Study I exhibited no statistically significant differences from the Study II cohort in HCV prevalence (12.7 vs. 20.0%, p = 0.07), lifetime history of injection drug use (13.8 vs. 22.0%, p = 0.74), lifetime history of needle sharing (9.1 vs. 18.0%, p = 0.62). As such, the data from both studies were analyzed together. Regardless of drinking status, HCV infection was significantly associated with an upward shift in the baseline level of ALT, AST, and GGT (p < 0.006 for all measures) and a downward shift in baseline CDT (p = 0.002). When using standard laboratory cutoff values to determine clinically significant elevations, HCV seropositivity was significantly associated with elevations in ALT, AST, GGT (p < 0.001), and with decreases in CDT (p = .002).

Conclusions

These data emphasize the importance of evaluating HCV infection and HCV risk behaviors at intake in medication trials for alcohol dependence and also raise questions regarding the use of cutoff scores for ALT, AST, GGT and CDT levels as biologic markers of alcohol use in subjects when HCV status is unknown.