Huang Weize, Stader Felix, Chan Phyllis, Shemesh Colby S, Chen Yuan, Gill Katherine L, Jones Hannah M, Li Linzhong, Rossato Gianluca, Wu Benjamin, Jin Jin Y, Chanu Pascal
Genentech Inc, South San Francisco, CA, United States.
Certara UK Limited, Sheffield, United Kingdom.
Front Pharmacol. 2022 Sep 26;13:974423. doi: 10.3389/fphar.2022.974423. eCollection 2022.
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. 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. 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 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. 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 C, C, and AUC 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. 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.
阿替利珠单抗已在儿科和成人患者群体的多种适应症中进行了研究。一般来说，纳入儿科患者的临床研究可能无法收集到足够的药代动力学数据来表征药物暴露和处置情况，因为存在操作、伦理和后勤方面的挑战，包括对儿童的负担和血样体积限制。因此，机制建模和模拟可作为预测和理解儿科患者药物暴露的工具。使用基于生理的药代动力学（PBPK）机制模型来预测儿科患者接受15mg/kg（最大1200mg）剂量阿替利珠单抗时的暴露情况，以支持剂量合理化和标签建议。使用了一个最小的机制PBPK模型，该模型纳入了与阿替利珠单抗处置相关的生理学和生物化学的年龄依赖性变化，如内源性IgG浓度和淋巴流量。PBPK模型是使用成人的临床前数据和临床观察数据开发的，并在儿科患者和成人的I期和多项III期研究获得的剂量水平上进行了验证。然后，使用经过验证的模型为2至29岁的儿科和成人受试者生成PK预测。儿童和成人的个体化验证表明，阿替利珠单抗的模拟浓度与观察数据具有可比性（分别有76%在两倍以内和90%在三倍以内），且不存在预测过高或过低的偏差。应用经过验证的模型，预测的暴露指标包括Cmax、Cmin和AUC在儿科和成人患者之间是一致的，儿科暴露指标的几何平均值是成人值的0.8至1.25倍。结果表明，儿科患者静脉注射15mg/kg（最大1200mg）剂量的阿替利珠单抗与成人1200mg剂量的阿替利珠单抗暴露相当。这表明15mg/kg的剂量将为2至18岁的儿科患者提供足够且有效的阿替利珠单抗暴露。
