DMPK Consultants, Inc., USA.
Curr Drug Metab. 2012 Sep 1;13(7):882-900. doi: 10.2174/138920012802138624.
Human development of an individual from a fertilized ovum to maturity alters the body anatomy and physiology. Changes of size and function, from birth onwards, cause significant alterations in the pharmacokinetics (PK) of drugs and subsequently their response pharmacodynamics (PD) in infants and children from those in adults. During the last three decades, hundreds of mechanistic and clinical pharmacology studies have been conducted to investigate the age-mediated changes of absorption, distribution, metabolism and excretion processes of drugs, which subsequently affect the pharmacology response and the safety in pediatric patients compared to adults. The practice of determining pediatric dose based on simplistic scaling of an adult dose assuming linear relationship between postnatal age and body weight or surface area that may lead to under prediction of therapeutic dose or over prediction of the dose is now under scrutiny. By understanding the disposition mechanism of therapeutic agents thoroughly, their potential drug interactions and their PK/PD relationships can be better determined in pediatric populations. As such, dosing regimens can be estimated based on actual clearance and exposure and not just by simplistic scaling of an adult dose. Accurate prediction of clearance in pediatrics is so critical that extensive translational research is warranted to improve our ability to estimate safe and efficacious doses in different pediatric populations from retrospective clinical studies in adults. Biotherapeutics, proteins and peptides-based drugs, generally depend on absorption (A), distribution (D), metabolism (M), and excretion (E) in their disposition as small molecules, but the underlying mechanisms and potential drug interaction propensity can be very different. In this article, the factors that alter pediatric and adult PK parameters are compared, and pediatric and adult PK parameters and potential drug interactions for selected biotherapeutics are summarized. Moreover, challenges of studying therapeutic proteins and peptides in pediatrics are discussed.
从受精卵到成熟的个体发育会改变人体解剖结构和生理学。从出生起，大小和功能的变化会导致药物的药代动力学（PK）发生显著变化，从而影响婴儿和儿童与成人相比的药物反应药效动力学（PD）。在过去的三十年中，已经进行了数百项机制和临床药理学研究，以研究药物吸收、分布、代谢和排泄过程随年龄的变化，这些变化会影响儿科患者的药理学反应和安全性。根据简单的成人剂量比例来确定儿科剂量的做法，假设出生后年龄与体重或体表面积之间存在线性关系，可能会导致治疗剂量预测不足或剂量预测过高，目前正在受到审查。通过彻底了解治疗剂的处置机制，可以更好地确定儿科人群中的潜在药物相互作用及其 PK/PD 关系。因此，可以根据实际清除率和暴露率来估计剂量方案，而不仅仅是通过简单的成人剂量比例来估计。准确预测儿科清除率至关重要，需要进行广泛的转化研究，以提高我们从成人回顾性临床研究中估算不同儿科人群中安全有效剂量的能力。生物治疗药物、蛋白质和肽类药物通常依赖于小分子的吸收（A）、分布（D）、代谢（M）和排泄（E），但其潜在的机制和潜在的药物相互作用倾向可能非常不同。本文比较了改变儿科和成人 PK 参数的因素，并总结了选定生物治疗药物的儿科和成人 PK 参数和潜在药物相互作用。此外，还讨论了在儿科研究治疗性蛋白质和肽类的挑战。
