一项1期C研究，评估BI 409306在轻至中度精神分裂症患者中的安全性、耐受性、药代动力学和认知结果。
A Phase IC Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Cognitive Outcomes of BI 409306 in Patients with Mild-to-Moderate Schizophrenia.
作者信息
Brown David, Daniels Kristen, Pichereau Solen, Sand Michael
机构信息
Community Clinical Research, Inc., Austin, TX, USA.
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
出版信息
Neurol Ther. 2018 Jun;7(1):129-139. doi: 10.1007/s40120-017-0085-5. Epub 2017 Nov 24.
INTRODUCTION
This randomized, double-blind, parallel-group study investigated the safety, tolerability, pharmacokinetics (PK), and cognitive outcomes of BI 409306-a selective phosphodiesterase 9A (PDE9A) inhibitor-in patients with schizophrenia.
METHODS
Patients with mild-to-moderate schizophrenia were randomized (1:1:1:1) to receive BI 409306 at 25, 50, or 100 mg or placebo once daily over 14 days. The primary endpoints were safety and tolerability; the secondary endpoints were PK and cognitive outcomes.
RESULTS
Of the 40 randomized patients, 38 (95%) completed the study. Patients were predominantly male (87.5%; mean age, 40.2 years). After a single dose, C was reached within 30-45 min. The geometric mean (gMean) C and AUC ranged from 138 to 998 nmol/L and 217 to 2020 nmol∙h/L, respectively. Elimination was rapid (gMean t range 1.10-1.85 h). After multiple doses, C was reached within 1 h; elimination was similar to that observed after a single dose. Total exposure at steady state and after a single dose were similar (accumulation ratio range: AUC, 0.758-1.13 and C, 0.768-1.40). No deaths, adverse events (AEs) leading to discontinuation, or serious AEs were observed. Treatment-emergent AEs were mild, with no apparent dose-related trends. There was no worsening of schizophrenia symptoms (Positive and Negative Syndrome Scale) and no trends in suicidality (Columbia Suicide Severity Rating Scale). The Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R) showed no effect on cognitive function.
CONCLUSION
Administration of BI 409306 in patients with mild-to-moderate schizophrenia resulted in satisfactory safety and tolerability. BI 409306, PK was characterized by rapid absorption, monophasic to biphasic elimination, and minor accumulation with multiple dosing.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT01892384.
FUNDING
Boehringer Ingelheim Pharma GmbH & Co. KG.
引言
本随机、双盲、平行组研究调查了选择性磷酸二酯酶9A（PDE9A）抑制剂BI 409306在精神分裂症患者中的安全性、耐受性、药代动力学（PK）及认知结果。
方法
将轻度至中度精神分裂症患者按1:1:1:1随机分组，接受25、50或100mg的BI 409306或安慰剂，每日一次，共14天。主要终点为安全性和耐受性；次要终点为PK和认知结果。
结果
40例随机分组患者中，38例（95%）完成研究。患者以男性为主（87.5%；平均年龄40.2岁）。单次给药后，30 - 45分钟内达到C 。几何平均（gMean）C 和AUC分别为138至998nmol/L和217至2020nmol∙h/L。消除迅速（gMean t 范围1.10 - 1.85小时）。多次给药后，1小时内达到C ；消除情况与单次给药后相似。稳态时和单次给药后的总暴露量相似（累积比范围：AUC为0.758 - 1.13，C为0.768 - 1.40）。未观察到死亡、导致停药的不良事件（AE）或严重AE。治疗中出现的AE为轻度，无明显剂量相关趋势。精神分裂症症状（阳性和阴性症状量表）无恶化，自杀倾向（哥伦比亚自杀严重程度评定量表）无趋势变化。修订的霍普金斯言语学习测验（HVLT - R）和修订的简短视觉空间记忆测验（BVMT - R）显示对认知功能无影响。
结论
在轻度至中度精神分裂症患者中给予BI 409306可获得满意的安全性和耐受性。BI 409306的PK特征为吸收迅速、单相至双相消除以及多次给药后少量蓄积。
试验注册
ClinicalTrials.gov标识符NCT01892384。
资助
勃林格殷格翰制药有限公司。
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