PDF(Pubmed)
Abstract：
Aciclovir is considered the first-line treatment against Herpes simplex virus (HSV) infections in new-borns and infants. As renal excretion is the major route of elimination, in renally-impaired patients, aciclovir doses are adjusted according to the degree of impairment. However, limited attention has been given to the implications of immature renal function or dysfunction due to the viral disease itself. The aim of this investigation was to characterize the pharmacokinetics of aciclovir taking into account maturation and disease processes in the neonatal population. Pharmacokinetic data obtained from 2 previously published clinical trials (n = 28) were analyzed using a nonlinear mixed effects modeling approach. Post-menstrual age (PMA) and creatinine clearance (CLCR) were assessed as descriptors of maturation and renal function. Simulation scenarios were also implemented to illustrate the use of pharmacokinetic data to extrapolate efficacy from adults. Aciclovir pharmacokinetics was described by a one-compartment model with first-order elimination. Body weight and diagnosis (systemic infection) were statistically significant covariates on the volume of distribution, whereas body weight, CLCR and PMA had a significant effect on clearance. Median clearance varied from 0.2 to 1.0 L/h in subjects with PMA <34 or ≥34 weeks, respectively. Population estimate for volume of distribution was 1.93 L with systemic infection increasing this value by almost 3-fold (2.67 times higher). A suitable model parameterization was identified, which discriminates the effects of developmental growth, maturation, and organ function. Exposure to aciclovir was found to increase with decreasing PMA and renal function (CLCR), suggesting different dosing requirement for pre-term neonates.
摘要：
阿昔洛韦被认为是针对新生儿和婴儿单纯疱疹病毒（HSV）感染的一线治疗方法。由于肾脏排泄是主要的消除途径，在肾功能受损的患者中，阿昔洛韦剂量根据损伤程度进行调整。然而,对病毒性疾病本身引起的不成熟肾功能或功能障碍的影响给予了有限的关注。这项研究的目的是表征阿昔洛韦的药代动力学，同时考虑到新生儿人群的成熟和疾病过程。使用非线性混合效应建模方法分析了从2个先前发表的临床试验（n=28）获得的药代动力学数据。月经后年龄（PMA）和肌酐清除率（CLCR）被评估为成熟度和肾功能的描述指标。还实施了模拟方案以说明使用药代动力学数据来推断成人的功效。阿昔洛韦的药代动力学通过一阶消除的一室模型描述。体重和诊断（全身感染）是分布体积的统计学显著协变量，而体重，CLCR和PMA对清除率有显著影响。PMA<34周或≥34周的受试者中值清除率从0.2到1.0L/h不等。分别。分布体积的人口估计值为1.93L，全身感染使该值增加了近3倍（高2.67倍）。确定了合适的模型参数化，区分发育增长的影响，成熟,和器官功能。发现阿昔洛韦的暴露随着PMA和肾功能（CLCR）的降低而增加，提示早产儿需要不同的剂量。
