Cai Lianjin, Zhai Jingchen, Ji Beihong, Han Fengyang, Niu Taoyu, Wang Luxuan, Wang Junmei
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
CPT Pharmacometrics Syst Pharmacol. 2025 Mar;14(3):435-447. doi: 10.1002/psp4.13186. Epub 2025 Feb 13.
Intranasal diamorphine (IND), approved for managing breakthrough pain in the UK, has been identified as an acceptable alternative offering effective, expedient, and less traumatic analgesia for children. However, the current dose regimen in pediatric populations relies on clinical expertise while the pharmacokinetics properties are poorly understood. This study aimed to develop diamorphine population pharmacokinetics (pop-PK) models and simulate the IND dosing in virtual pediatric subjects. An integrated four-compartment pop-PK model with first-order absorption and elimination provided an appropriate fit and characterized publicly available 385 concentration measurements of diamorphine, 6-monoacetylmorphine, and morphine collected from adults. Body weight allometry and renal function maturation (age) were incorporated into the final model, serving as two covariates. The estimated IND relative bioavailability was around 52% compared with intramuscularly injected diamorphine. Using this final model, the morphine plasma concentrations, as the active metabolite for pain relief, were simulated in virtual subjects. The utility of model extrapolation was supported by external verification with acceptable average fold errors of 1.06 ± 0.30 and 0.83 ± 0.07 for morphine maximum concentration and exposures. Meanwhile, the simulated morphine concentration-time profiles could recover the PK profiles observed in children after a single dose of IND. The model-based dosing simulations were therefore assessed in four children age groups to match the therapeutic window of morphine concentrations in steady state (10-20 μg/L). Our study demonstrates that the dose regimen of 0.3 mg/kg loading dose plus 0.1 mg/kg hourly maintenance dose is generally appropriate for multiple pediatric populations with breakthrough pain, in the view of PK.
鼻内注射二醋吗啡（IND）在英国已被批准用于治疗爆发性疼痛，它被认为是一种可接受的替代药物，能为儿童提供有效、快速且创伤较小的镇痛效果。然而，目前儿科人群的剂量方案依赖临床专业知识，其药代动力学特性却鲜为人知。本研究旨在建立二醋吗啡群体药代动力学（pop-PK）模型，并模拟虚拟儿科受试者的IND给药情况。一个具有一级吸收和消除的综合四室pop-PK模型提供了合适的拟合，并对从成人收集的385份二醋吗啡、6-单乙酰吗啡和吗啡的浓度测量数据进行了特征描述。体重异速生长和肾功能成熟（年龄）被纳入最终模型，作为两个协变量。与肌肉注射二醋吗啡相比，估计的IND相对生物利用度约为52%。使用这个最终模型，在虚拟受试者中模拟了作为缓解疼痛的活性代谢物的吗啡血浆浓度。通过外部验证支持了模型外推的效用，吗啡最大浓度和暴露量的平均倍数误差分别为1.06±0.30和0.83±0.07，均在可接受范围内。同时，模拟的吗啡浓度-时间曲线可以重现单次给予IND后儿童中观察到的药代动力学曲线。因此，基于模型的给药模拟在四个儿童年龄组中进行评估，以匹配稳态下吗啡浓度的治疗窗口（10 - 20μg/L）。我们的研究表明，从药代动力学角度来看，0.3mg/kg负荷剂量加0.1mg/kg每小时维持剂量的给药方案通常适用于多个患有爆发性疼痛的儿科人群。
