Wang Xiaofeng, Gopalakrishnan Mathangi, Rich Benjamin, Gobburu Jogarao V, Larsen Frank, Raoufinia Arash
Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA.
Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, MD, USA.
J Clin Pharmacol. 2024 Oct;64(10):1236-1245. doi: 10.1002/jcph.2464. Epub 2024 Jul 8.
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.
为了加速药物研发并避免在脆弱的儿科人群中进行不必要的药物试验，美国食品药品监督管理局（FDA）向申办方发布了一封通用建议函，允许将成人非典型抗精神病药物治疗精神分裂症的有效性外推至青少年。外推基于以下循证假设：（1）疾病特征和（2）对治疗的反应，在成人和青少年中相似。虽然FDA使用来自多个药物研发项目的数据验证了外推方法，但阿立哌唑的数据对于确认布瑞哌唑外推方法的有效性最为相关，因为阿立哌唑和布瑞哌唑都调节大脑中的多巴胺能和5-羟色胺能信号传导。本分析的目的是：（1）定量评估精神分裂症成人和青少年之间阿立哌唑暴露（平均稳态浓度）-反应（阳性和阴性症状量表总分相对于基线的变化）的相似性；（2）使用成人数据将阿立哌唑暴露-反应模型扩展至布瑞哌唑；（3）使用布瑞哌唑模型预测青少年精神分裂症症状反应。使用来自阿立哌唑（1007名成人，294名青少年）和布瑞哌唑（1235名成人）治疗精神分裂症的临床研究的患者水平数据建立疾病-药物-脱落模型。阿立哌唑模型显示精神分裂症成人和青少年之间具有相似的暴露-反应，验证了外推方法。将布瑞哌唑成人暴露-反应模型外推至青少年预测了布瑞哌唑对13-17岁精神分裂症青少年的疗效。
