Abstract：
In order to accelerate drug development and avoid unnecessary drug trials in vulnerable pediatric populations, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents. Extrapolation is based on the evidence-based assumptions that (1) disease characteristics and (2) response to therapy, are similar in adults and adolescents. Whereas the FDA validated the extrapolation approach using data from multiple drug development programs, aripiprazole data are the most relevant to confirm the validity of the extrapolation approach for brexpiprazole, since aripiprazole and brexpiprazole both modulate dopaminergic and serotonergic signaling in the brain. The aims of this analysis were (1) to quantitatively assess the aripiprazole exposure (average steady-state concentration)-response (Positive and Negative Syndrome Scale total score change from baseline) similarity between adults and adolescents with schizophrenia, (2) to extend the aripiprazole exposure-response modeling to brexpiprazole using adult data, and (3) to use the brexpiprazole model to predict schizophrenia symptom response in adolescents. Disease-drug-dropout models were developed using patient-level data from clinical studies of aripiprazole (1007 adults, 294 adolescents) and brexpiprazole (1235 adults) in schizophrenia. The aripiprazole model demonstrated similar exposure-response between adults and adolescents with schizophrenia, validating the extrapolation approach. Extrapolation of the brexpiprazole adult exposure-response model to adolescents predicted the efficacy of brexpiprazole in adolescents aged 13-17 years with schizophrenia.
摘要：
为了加快药物开发，避免在弱势儿科人群中进行不必要的药物试验，美国食品和药物管理局(FDA)发布了一封致赞助商的一般性建议信,允许将非典型抗精神病药物治疗成人精神分裂症的有效性外推到青少年.外推是基于基于证据的假设，即(1)疾病特征和(2)对治疗的反应，在成人和青少年中相似。尽管FDA使用来自多个药物开发计划的数据验证了外推方法，阿立哌唑的数据是最相关的，以证实外推方法的有效性，因为阿立哌唑和巴立哌唑都能调节大脑中的多巴胺能和5-羟色胺能信号。该分析的目的是（1）定量评估成人和青少年精神分裂症患者之间的阿立哌唑暴露（平均稳态浓度）-反应（阳性和阴性综合征量表总分相对于基线的变化）相似性，(2)使用成人数据将阿立哌唑暴露-反应模型扩展到布立哌唑，和（3）使用brexpiprazole模型预测青少年精神分裂症症状反应。使用来自阿立哌唑临床研究的患者水平数据开发了疾病-药物-脱失模型（1007名成人，294名青少年）和布立哌唑（1235名成人）在精神分裂症中。阿立哌唑模型在患有精神分裂症的成年人和青少年之间显示出相似的暴露反应，验证外推方法。对青少年的brexiprazole成人暴露-反应模型的外推可预测13-17岁精神分裂症青少年中brexiprazole的疗效。
