Medical School, University of Western Australia, Crawley, WA, Australia.
Centre for Neonatal Research and Education, School of Medicine, University of Western Australia, Crawley, WA, Australia.
Br J Clin Pharmacol. 2019 Jan;85(1):147-159. doi: 10.1111/bcp.13775. Epub 2018 Nov 16.
Infection-induced inflammation is associated with adverse long-term outcomes in preterm infants. Pentoxifylline (PTX) is a candidate for adjunct immunomodulatory therapy in preterm infants with late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but pharmacokinetic data in this population are extremely limited. This study aims to characterize the pharmacokinetic properties of intravenous PTX and its metabolites in preterm infants.
An open label pilot clinical study of intravenous PTX as an adjunct therapy in preterm infants (gestation <32 weeks) with suspected LOS or NEC was undertaken. PTX was infused for 12 h for two days (60 mg kg per 12 h), and in infants with confirmed diagnosis of LOS or NEC, for 6 h for another 4 days (30 mg kg per 6 h). Plasma concentrations of PTX and its principal metabolites from collected blood samples were measured using a validated LCMS assay. NONMEM was used to analyse the data using population pharmacokinetic modelling.
The preterm infants (n = 26) had a median (range) gestation of 24.8 weeks (23.3-30.4) and birthweight of 689 g (370-1285). PTX was well tolerated and without treatment-limiting adverse effects. Changes in size (weight) and maturation were successfully modelled for PTX and metabolites. After allometric scaling, clearance increased with postmenstrual age, increasing by approximately 30% per week for PTX and M1 (lisofylline) and simulations of current dosing demonstrated a six-fold difference in exposure between 24 and 35 weeks postmenstrual age.
The developed model can be used to explore dosing strategies based on size and maturation for preterm infants.
感染引起的炎症与早产儿的不良长期预后有关。己酮可可碱（PTX）是早产儿晚发性败血症（LOS）和坏死性小肠结肠炎（NEC）辅助免疫调节治疗的候选药物，但该人群的药代动力学数据极为有限。本研究旨在描述早产儿静脉注射 PTX 及其代谢物的药代动力学特征。
进行了一项开放性标签的试点临床研究，研究对象为疑似 LOS 或 NEC 的早产儿（胎龄 <32 周），采用静脉注射 PTX 作为辅助治疗。PTX 连续两天每 12 小时输注 12 小时（60mg/kg/12 小时），对于确诊 LOS 或 NEC 的婴儿，另外再连续 4 天每 6 小时输注 6 小时（30mg/kg/6 小时）。使用经过验证的 LCMS 测定法测量从采集的血样中 PTX 及其主要代谢物的血浆浓度。使用群体药代动力学模型对 NONMEM 进行数据分析。
早产儿（n=26）的中位（范围）胎龄为 24.8 周（23.3-30.4），出生体重为 689g（370-1285）。PTX 耐受性良好，无治疗相关的不良事件。成功地对 PTX 和代谢物的大小（体重）和成熟度变化进行了建模。经过比例缩放后，清除率随胎龄后(postmenstrual age)增加，PTX 和 M1（茶碱）每周增加约 30%，模拟当前给药方案表明，胎龄后 24 至 35 周之间的暴露量差异高达六倍。
所开发的模型可用于基于大小和成熟度探索早产儿的给药策略。
