Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Centre de Pharmacocinétique et Métabolisme, Technologie Servier, Orléans, France.
Clin Pharmacol Ther. 2021 Jun;109(6):1618-1630. doi: 10.1002/cpt.2134. Epub 2020 Dec 31.
Clinical assessment of drug-drug interactions (DDIs) in children is not a common practice in drug development. Therefore, physiologically-based pharmacokinetic (PBPK) modeling can be beneficial for informing drug labeling. Using ivabradine and its metabolite (both cytochrome P450 3A4 enzyme (CYP3A4) substrates), the objectives were (i) to scale ivabradine-metabolite adult PBPK/PD to pediatrics, (ii) to predict the DDIs with a strong CYP3A4 inhibitor, and (iii) to compare the sensitivity of children to DDIs using two CYP3A4 hepatic ontogeny functions: Salem and Upreti. A scaled parent-metabolite PBPK/PD model from adults to children satisfactorily predicted pharmacokinetics (PK) and pharmacodynamics (PD) in 74 children (0.5-18 years) regardless of CYP3A4 hepatic ontogeny function applied. However, using the Salem ontogeny, mean predicted parent and metabolite area under the concentration-time curve over 12 hours (AUC ) and heart rate change from baseline were 2-fold, 1.5-fold, and 1.4-fold higher in young children (0.5-3 years old) compared with Upreti ontogeny, respectively. Despite these differences, choice of appropriate hepatic CYP3A4 ontogeny was challenging due to sparse PK and PD data. Different sensitivity to ivabradine-ketoconazole DDIs was simulated in young children relative to adults depending on the choice of hepatic CYP3A4 ontogeny. Predicted ivabradine and metabolite AUC /AUC were 2-fold lower in the youngest children (0.5-1 year old) compared with adults (Salem function). In contrast, the Upreti function predicted comparable ivabradine DDIs across all age groups, although predicted metabolite AUC AUC was 1.3-fold higher between the youngest children and adults. In the case of PD, differences in predicted DDIs were minor across age groups and between both functions. Current work highlights the importance of careful consideration of hepatic CYP3A4 ontogeny function and implications on labeling recommendations in the pediatric population.
在药物开发中，临床评估药物-药物相互作用（DDI）在儿童中并不常见。因此，基于生理学的药代动力学（PBPK）模型对于提供药物标签信息可能是有益的。本研究使用伊伐布雷定及其代谢物（均为细胞色素 P450 3A4 酶（CYP3A4）底物），目的是（i）将成人伊伐布雷定-代谢物 PBPK/PD 模型扩展至儿科，（ii）预测与强 CYP3A4 抑制剂的 DDI，（iii）使用两种 CYP3A4 肝发生功能（Salem 和 Upreti）比较儿童对 DDI 的敏感性。应用两种 CYP3A4 肝发生功能（Salem 和 Upreti），无论采用哪种功能，从成人扩展至儿童的 PBPK/PD 模型都能很好地预测 74 名儿童（0.5-18 岁）的药代动力学（PK）和药效动力学（PD）。然而，使用 Salem 发生功能，与 Upreti 发生功能相比，幼儿（0.5-3 岁）的预测母药和代谢物 AUC 0-12 小时和心率基线变化的平均值分别高出 2 倍、1.5 倍和 1.4 倍。尽管存在这些差异，但由于 PK 和 PD 数据稀疏，选择合适的 CYP3A4 肝发生功能仍然具有挑战性。根据 CYP3A4 肝发生功能的选择，模拟了伊伐布雷定-酮康唑 DDI 在儿童中相对于成人的不同敏感性。与成人（Salem 函数）相比，年幼儿童（0.5-1 岁）的预测伊伐布雷定和代谢物 AUC /AUC 低 2 倍。相比之下，Upreti 函数在所有年龄组中预测伊伐布雷定相似，但在最年幼儿童和成人之间预测代谢物 AUC AUC 高 1.3 倍。在 PD 方面，两种函数之间的预测 DDI 在不同年龄组之间差异较小。目前的工作强调了在儿科人群中仔细考虑 CYP3A4 肝发生功能及其对标签建议的影响的重要性。
