Department of Pharmacology & Clinical Pharmacology, Auckland University, Auckland, New Zealand.
Department of Anaesthesiology, University of Auckland, Auckland, New Zealand.
Paediatr Anaesth. 2022 Jun;32(6):716-726. doi: 10.1111/pan.14425. Epub 2022 Mar 1.
Pharmacokinetic-pharmacodynamic modeling and simulation can facilitate understanding and prediction of exposure-response relationships in children with acute or chronic pain. The pharmacokinetics of diamorphine (diacetylmorphine, heroin), a strong opioid, remain poorly quantified in children and dose is often guided by clinical acumen. This tutorial demonstrates how a model to describe intranasal and intravenous diamorphine pharmacokinetics can be fashioned from a model for diamorphine disposition in adults and a model describing morphine disposition in children. Allometric scaling and maturation models were applied to clearances and volumes to account for differences in size and age between children and adults. The utility of modeling and simulation to gain insight into the analgesic exposure-response relationship is demonstrated. The model explains reported observations, can be used for interrogation, interpolated to determine equianalgesia and inform future clinical studies. Simulation was used to illustrate how diamorphine is rapidly metabolized to morphine via its active metabolite 6-monoacetylmorphine, which mediates an early dopaminergic response accountable for early euphoria. Morphine formation is then responsible for the slower, prolonged analgesic response. Time-concentration profiles of diamorphine and its metabolites reflected disposition changes with age and were used to describe intravenous and intranasal dosing regimens. These indicated that morphine exposure in children after intranasal diamorphine 0.1 mg.kg was similar to that after intranasal diamorphine 5 mg in adults. A target concentration of morphine 30 μg.L can be achieved by a diamorphine intravenous infusion in neonates 14 μg.kg .h , in a 5-year-old child 42 μg.kg .h and in an 15 year-old-adolescent 33 μg.kg .h .
药代动力学-药效学建模和模拟有助于理解和预测急性或慢性疼痛儿童的暴露-反应关系。阿片类药物（二乙酰吗啡，海洛因）的药代动力学在儿童中仍未得到充分量化，剂量通常取决于临床经验。本教程演示了如何从成人阿片类药物处置模型和描述儿童吗啡处置的模型中构建用于描述鼻内和静脉内阿片类药物药代动力学的模型。应用比例缩放和成熟模型来解释清除率和体积的差异，以说明儿童和成人之间的大小和年龄差异。建模和模拟用于深入了解镇痛作用的暴露-反应关系的实用性。该模型解释了报告的观察结果，可以进行询问、插值以确定等效镇痛作用，并为未来的临床研究提供信息。模拟用于说明阿片类药物如何通过其活性代谢物 6-单乙酰吗啡迅速代谢为吗啡，这介导了早期多巴胺反应，负责早期欣快。然后，吗啡的形成负责较慢、延长的镇痛反应。阿片类药物及其代谢物的时间浓度曲线反映了随年龄变化的处置变化，并用于描述静脉内和鼻内给药方案。这表明，儿童鼻内给予 0.1 mg.kg 阿片类药物后，其吗啡暴露量与成人鼻内给予 5 mg 阿片类药物相似。通过新生儿 14 μg.kg.h 、5 岁儿童 42 μg.kg.h 和 15 岁青少年 33 μg.kg.h 的静脉内阿片类药物输注，可达到 30 μg.L 的吗啡目标浓度。
