Certara UK Limited, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK.
AAPS J. 2022 Jun 1;24(4):72. doi: 10.1208/s12248-022-00722-0.
New drugs may in some cases need to be tested in paediatric and pregnant patients. However, it is difficult to recruit such patients and there are many ethical issues around their inclusion in clinical trials. Modelling and simulation can help to plan well-designed clinical trials with a reduced number of participants and to bridge gaps where recruitment is difficult. Physiologically based pharmacokinetic (PBPK) models for small molecule drugs have been used to aid study design and dose adjustments in paediatrics and pregnancy, with several publications in the literature. However, published PBPK models for monoclonal antibodies (mAb) in these populations are scarce. Here, the current status of mAb PBPK models in paediatrics and pregnancy is discussed. Seven mAb PBPK models published for paediatrics were found, which report good prediction accuracy across a wide age range. No mAb PBPK models for pregnant women have been published to date. Current challenges to the development of such PBPK models are discussed, including gaps in our knowledge of relevant physiological processes and availability of clinical data to verify models. As the availability of such data increases, it will help to improve our confidence in the PBPK model predictive ability. Advantages for using PBPK models to predict mAb PK in paediatrics and pregnancy are discussed. For example, the ability to incorporate ontogeny and gestational changes in physiology, prediction of maternal, placental and foetal exposure and the ability to make predictions from in vitro and preclinical data prior to clinical data being available.
新药物在某些情况下可能需要在儿科和孕妇患者中进行测试。然而，招募此类患者非常困难，并且在将其纳入临床试验方面存在许多伦理问题。建模和模拟有助于规划设计良好的临床试验，减少参与者的数量，并在招募困难的情况下弥合差距。小分子药物的基于生理学的药代动力学（PBPK）模型已用于辅助儿科和妊娠的研究设计和剂量调整，并在文献中有多项出版物。然而，在这些人群中，用于单克隆抗体（mAb）的已发表 PBPK 模型却很少。本文讨论了 PBPK 模型在儿科和妊娠中的当前状态。发现了 7 种已发表用于儿科的 mAb PBPK 模型，这些模型在广泛的年龄范围内均具有良好的预测准确性。迄今为止，尚无针对孕妇的 mAb PBPK 模型发表。目前正在讨论开发此类 PBPK 模型所面临的挑战，包括我们对相关生理过程的知识差距以及用于验证模型的临床数据的可用性。随着此类数据的可用性增加，将有助于提高我们对 PBPK 模型预测能力的信心。讨论了在儿科和妊娠中使用 PBPK 模型预测 mAb PK 的优势。例如，能够纳入生理学中的个体发生和妊娠变化，预测母体、胎盘和胎儿的暴露情况，以及能够在临床数据可用之前从体外和临床前数据进行预测的能力。
