当前位置:
X-MOL 学术
›
Clin. Pharmacol. Ther.
›
论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Population PK and PD Analysis of Domagrozumab in Pediatric Patients with Duchenne Muscular Dystrophy
Clinical Pharmacology & Therapeutics ( IF 6.7 ) Pub Date : 2022-09-14 , DOI: 10.1002/cpt.2747 Jessica Wojciechowski 1 , Vivek S Purohit 1 , Lutz O Harnisch 2 , Pinky Dua 2 , Beesan Tan 3 , Timothy Nicholas 1
Clinical Pharmacology & Therapeutics ( IF 6.7 ) Pub Date : 2022-09-14 , DOI: 10.1002/cpt.2747 Jessica Wojciechowski 1 , Vivek S Purohit 1 , Lutz O Harnisch 2 , Pinky Dua 2 , Beesan Tan 3 , Timothy Nicholas 1
Affiliation
Myostatin, a negative regulator of skeletal muscle growth, is a therapeutic target in muscle-wasting diseases. Domagrozumab, a humanized recombinant monoclonal antibody, binds myostatin and inhibits activity. Domagrozumab was investigated in a phase II trial (NCT02310763) as a potential treatment for boys with Duchenne muscular dystrophy (DMD). Pharmacokinetic/pharmacodynamic (PK/PD) modeling is vital in clinical trial design, particularly for determining dosing regimens in pediatric populations. This analysis sought to establish the PK/PD relationship between free domagrozumab and total myostatin concentrations in pediatric patients with DMD using a prior semimechanistic model developed from a phase I study in healthy adult volunteers (NCT01616277) and following inclusion of phase II data. The refined model was developed using a multiple-step approach comprising structural, random effects, and covariate model development; assessment of model adequacy (goodness-of-fit); and predictive performance. Differences in PKs/PDs between healthy adult volunteers and pediatric patients with DMD were quantitatively accounted for and evaluated by predicting myostatin coverage (the percentage of myostatin bound by domagrozumab). The final model parameter estimates and semimechanistic target-mediated drug disposition structure sufficiently described both domagrozumab and myostatin concentrations in pediatric patients with DMD, and most population parameters were comparable with the prior model (in healthy adult volunteers). Predicted myostatin coverage for phase II patients with DMD was consistently > 90%. Baseline serum myostatin was ~ 65% lower than in healthy adult volunteers. This study provides insights into the regulation of myostatin in healthy adults and pediatric patients with DMD. Clinicaltrials.gov identifiers: NCT01616277 and NCT02310763.
中文翻译:
Domagrozumab 在杜氏肌营养不良症儿童患者中的群体 PK 和 PD 分析
肌肉生长抑制素是骨骼肌生长的负调节剂,是肌肉萎缩疾病的治疗靶点。Domagrozumab 是一种人源化重组单克隆抗体,可结合肌肉生长抑制素并抑制活性。Domagrozumab 在一项 II 期试验 (NCT02310763) 中被研究作为一种潜在的治疗男孩杜氏肌营养不良症 (DMD) 的方法。药代动力学/药效学 (PK/PD) 建模在临床试验设计中至关重要,特别是对于确定儿科人群的给药方案。该分析试图使用先前的半机械模型建立 DMD 儿科患者的游离 domagrozumab 和总肌肉生长抑制素浓度之间的 PK/PD 关系,该模型是从健康成人志愿者的 I 期研究 (NCT01616277) 和纳入 II 期数据后开发的。使用包括结构、随机效应和协变量模型开发的多步方法开发改进模型;评估模型的充分性(拟合优度);和预测性能。通过预测肌肉生长抑制素覆盖率(domagrozumab 结合的肌肉生长抑制素的百分比),定量说明和评估健康成年志愿者和 DMD 儿科患者之间 PK/PD 的差异。最终模型参数估计和半机械靶介导的药物配置结构充分描述了 DMD 儿科患者的 domagrozumab 和肌肉生长抑制素浓度,并且大多数人群参数与之前的模型(在健康成年志愿者中)相当。II 期 DMD 患者的预测肌肉生长抑制素覆盖率始终 > 90%。基线血清肌肉生长抑制素比健康成年志愿者低约 65%。这项研究提供了对健康成人和儿童 DMD 患者肌肉生长抑制素调节的见解。Clinicaltrials.gov 标识符:NCT01616277 和 NCT02310763。
更新日期:2022-09-14
中文翻译:
Domagrozumab 在杜氏肌营养不良症儿童患者中的群体 PK 和 PD 分析
肌肉生长抑制素是骨骼肌生长的负调节剂,是肌肉萎缩疾病的治疗靶点。Domagrozumab 是一种人源化重组单克隆抗体,可结合肌肉生长抑制素并抑制活性。Domagrozumab 在一项 II 期试验 (NCT02310763) 中被研究作为一种潜在的治疗男孩杜氏肌营养不良症 (DMD) 的方法。药代动力学/药效学 (PK/PD) 建模在临床试验设计中至关重要,特别是对于确定儿科人群的给药方案。该分析试图使用先前的半机械模型建立 DMD 儿科患者的游离 domagrozumab 和总肌肉生长抑制素浓度之间的 PK/PD 关系,该模型是从健康成人志愿者的 I 期研究 (NCT01616277) 和纳入 II 期数据后开发的。使用包括结构、随机效应和协变量模型开发的多步方法开发改进模型;评估模型的充分性(拟合优度);和预测性能。通过预测肌肉生长抑制素覆盖率(domagrozumab 结合的肌肉生长抑制素的百分比),定量说明和评估健康成年志愿者和 DMD 儿科患者之间 PK/PD 的差异。最终模型参数估计和半机械靶介导的药物配置结构充分描述了 DMD 儿科患者的 domagrozumab 和肌肉生长抑制素浓度,并且大多数人群参数与之前的模型(在健康成年志愿者中)相当。II 期 DMD 患者的预测肌肉生长抑制素覆盖率始终 > 90%。基线血清肌肉生长抑制素比健康成年志愿者低约 65%。这项研究提供了对健康成人和儿童 DMD 患者肌肉生长抑制素调节的见解。Clinicaltrials.gov 标识符:NCT01616277 和 NCT02310763。