DataSheet1_Development of a pediatric physiologically-based pharmacokinetic model to support recommended dosing of atezolizumab in children with solid tumors.PDF

Background: Atezolizumab has been studied in multiple indications for both pediatric and adult patient populations. Generally, clinical studies enrolling pediatric patients may not collect sufficient pharmacokinetic data to characterize the drug exposure and disposition because of operational, ethical, and logistical challenges including burden to children and blood sample volume limitations. Therefore, mechanistic modeling and simulation may serve as a tool to predict and understand the drug exposure in pediatric patients.
Objective: To use mechanistic physiologically-based pharmacokinetic (PBPK) modeling to predict atezolizumab exposure at a dose of 15 mg/kg (max 1,200 mg) in pediatric patients to support dose rationalization and label recommendations.
Methods: A minimal mechanistic PBPK model was used which incorporated age-dependent changes in physiology and biochemistry that are related to atezolizumab disposition such as endogenous IgG concentration and lymph flow. The PBPK model was developed using both in vitro data and clinically observed data in adults and was verified across dose levels obtained from a phase I and multiple phase III studies in both pediatric patients and adults. The verified model was then used to generate PK predictions for pediatric and adult subjects ranging from 2- to 29-year-old.
Results: Individualized verification in children and in adults showed that the simulated concentrations of atezolizumab were comparable (76% within two-fold and 90% within three-fold, respectively) to the observed data with no bias for either over- or under-prediction. Applying the verified model, the predicted exposure metrics including Cmin, Cmax, and AUCtau were consistent between pediatric and adult patients with a geometric mean of pediatric exposure metrics between 0.8- to 1.25-fold of the values in adults.
Conclusion: The results show that a 15 mg/kg (max 1,200 mg) atezolizumab dose administered intravenously in pediatric patients provides comparable atezolizumab exposure to a dose of 1,200 mg in adults. This suggests that a dose of 15 mg/kg will provide adequate and effective atezolizumab exposure in pediatric patients from 2- to 18-year-old.

背景：阿替利珠单抗（atezolizumab）已在多个适应症中针对儿童及成人患者人群开展研究。通常，受操作、伦理及后勤层面的多重挑战制约——包括对儿童造成的负担与血液样本体积限制，纳入儿童患者的临床研究往往难以收集足够的药代动力学数据，以表征该药物的暴露特征与体内处置过程。因此，机制建模与模拟可作为工具，用于预测并解析儿童患者体内的药物暴露情况。
目的：采用基于生理学的药代动力学（physiologically-based pharmacokinetic, PBPK）机制建模方法，预测儿童患者接受15 mg/kg（最大剂量1200 mg）给药方案时的阿替利珠单抗暴露量，以支撑剂量合理化及药品说明书推荐内容的制定。
方法：本研究采用极简版机制PBPK模型，该模型纳入了与阿替利珠单抗体内处置相关的生理学与生物化学年龄依赖性变化，如内源性免疫球蛋白G（IgG）浓度及淋巴流量。本PBPK模型基于成人的体外数据与临床观测数据构建，并通过I期及多项III期临床研究中儿童与成人患者的不同剂量水平数据完成验证。随后，利用验证后的模型对2岁至29岁的儿童及成人受试者开展药代动力学预测。
结果：针对儿童与成人的个体化验证结果显示，模拟得到的阿替利珠单抗浓度与观测数据具有良好一致性：分别有76%的模拟值处于观测值2倍范围内、90%处于3倍范围内，且不存在高估或低估的偏倚。应用验证后的模型，预测得到的包括谷浓度（Cmin）、峰浓度（Cmax）及时间τ下的药时曲线下面积（AUCτ）在内的暴露指标在儿童与成人患者中表现一致，儿童暴露指标的几何均值为成人的0.8~1.25倍。
结论：研究结果表明，儿童患者静脉输注15 mg/kg（最大剂量1200 mg）的阿替利珠单抗，其药物暴露水平与成人患者1200 mg剂量的暴露水平相当。这提示，15 mg/kg的给药剂量可为2岁至18岁的儿童患者提供充足且有效的阿替利珠单抗暴露。