Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.
KU Leuven Department of Development and Regeneration, Leuven, Belgium.
Br J Clin Pharmacol. 2021 Apr;87(4):2089-2097. doi: 10.1111/bcp.14620. Epub 2020 Nov 20.
Develop a population pharmacokinetic model describing propofol pharmacokinetics in (pre)term neonates and infants, that can be used for precision dosing (e.g. during target-controlled infusion) of propofol in this population.
A nonlinear mixed effects pharmacokinetic analysis (Monolix 2018R2) was performed, based on a pooled study population in 107 (pre)term neonates and infants.
In total, 836 blood samples were collected from 66 (pre)term neonates and 41 infants originating from 3 studies. Body weight (BW) of the pooled study population was 3.050 (0.580-11.440) kg, postmenstrual age (PMA) was 36.56 (27.00-43.00) weeks and postnatal age (PNA) was 1.14 (0-104.00) weeks (median and min-max range). A 3-compartment structural model was identified and the effect of BW was modelled using fixed allometric exponents. Elimination clearance maturation was modelled accounting for the maturational effect on elimination clearance until birth (by gestational age [GA]) and postpartum (by PNA and GA). The extrapolated adult (70 kg) population propofol elimination clearance (1.64 L min , estimated relative standard error = 6.02%) is in line with estimates from previous population pharmacokinetic studies. Empirical scaling of BW on the central distribution volume in function of PNA improved the model fit.
It is recommended to describe elimination clearance maturation by GA and PNA instead of PMA on top of size effects when analyzing propofol pharmacokinetics in populations including preterm neonates. Changes in body composition in addition to weight changes or other physio-anatomical changes may explain the changes in central distribution volume. The developed model may serve as a prior for propofol dose finding and target-controlled infusion in (preterm) neonates.
开发一个描述早产儿和婴儿中丙泊酚药代动力学的群体药代动力学模型，该模型可用于该人群中丙泊酚的精准给药（例如，靶控输注）。
基于来自 3 项研究的 66 例早产儿和 41 例婴儿的汇总研究人群，进行了非线性混合效应药代动力学分析（Monolix 2018R2）。
汇总研究人群的体重（BW）为 3.050（0.580-11.440）kg，胎龄（GA）为 36.56（27.00-43.00）周，出生后年龄（PNA）为 1.14（0-104.00）周（中位数和最小-最大范围）。确定了一个 3 室结构模型，并使用固定的全部比例指数来模拟 BW 的影响。通过考虑到出生前（通过 GA）和出生后（通过 PNA 和 GA）对消除清除率的成熟作用，对消除清除率的成熟进行建模。从以前的群体药代动力学研究中得出的估计值，外推到成人（70kg）人群的丙泊酚消除清除率（1.64L min ，估计相对标准误差=6.02%）是合理的。根据 PNA 对中央分布容积的经验性 BW 缩放，改善了模型拟合。
在分析包括早产儿在内的人群中丙泊酚的药代动力学时，建议在考虑尺寸效应的基础上，用 GA 和 PNA 来描述消除清除率的成熟，而不是用 PMA。除体重变化外，身体成分的变化或其他生理-解剖变化可能解释中央分布容积的变化。开发的模型可作为早产儿丙泊酚剂量发现和靶控输注的先验模型。
