Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Br J Clin Pharmacol. 2022 Jun;88(6):2885-2898. doi: 10.1111/bcp.15194. Epub 2022 Jan 28.
Our objectives were to perform a population pharmacokinetic analysis of dexmedetomidine in children using remnant specimens and electronic health records (EHRs) and explore the impact of patient's characteristics and pharmacogenetics on dexmedetomidine clearance.
Dexmedetomidine dosing and patient data were gathered from EHRs and combined with opportunistically sampled remnant specimens. Population pharmacokinetic models were developed using nonlinear mixed-effects modelling. Stage 1 developed a model without genotype variables; Stage 2 added pharmacogenetic effects.
Our final study population included 354 post-cardiac surgery patients aged 0-22 years (median 16 mo). The data were best described with a 2-compartment model with allometric scaling for weight and Hill maturation function for age. Population parameter estimates and 95% confidence intervals were 27.3 L/h (24.0-31.1 L/h) for total clearance, 161 L (139-187 L) for central compartment volume of distribution, 26.0 L/h (22.5-30.0 L/h) for intercompartmental clearance and 7903 L (5617-11 119 L) for peripheral compartment volume of distribution. The estimate for postmenstrual age when 50% of adult clearance is achieved was 42.0 weeks (41.5-42.5 weeks) and the Hill coefficient estimate was 7.04 (6.99-7.08). Genotype was not statistically or clinically significant.
Our study demonstrates the use of real-world EHR data and remnant specimens to perform a population pharmacokinetic analysis and investigate covariate effects in a large paediatric population. Weight and age were important predictors of clearance. We did not find evidence for pharmacogenetic effects of UGT1A4 or UGT2B10 genotype or CYP2A6 risk score.
本研究旨在使用残留标本和电子健康记录（EHR）对儿童右美托咪定进行群体药代动力学分析，并探讨患者特征和药物遗传学对右美托咪定清除率的影响。
从 EHR 中收集右美托咪定给药和患者数据，并与机会性采集的残留标本相结合。使用非线性混合效应模型建立群体药代动力学模型。第 1 阶段建立不包含基因型变量的模型；第 2 阶段加入药物遗传学效应。
最终研究人群包括 354 例心脏手术后 0-22 岁（中位数 16 个月）患儿。数据最好用 2 隔室模型描述，模型包含体重比例缩放和年龄 Hill 成熟函数。群体参数估计和 95%置信区间为总清除率 27.3 L/h（24.0-31.1 L/h），中央隔室分布容积 161 L（139-187 L），隔室间清除率 26.0 L/h（22.5-30.0 L/h），外周隔室分布容积 7903 L（5617-11 119 L）。达到成人清除率 50%时的估计胎龄为 42.0 周（41.5-42.5 周），Hill 系数估计值为 7.04（6.99-7.08）。基因型无统计学或临床意义。
本研究证明了使用真实世界的 EHR 数据和残留标本进行群体药代动力学分析，并在大型儿科人群中研究了协变量的影响。体重和年龄是清除率的重要预测因素。我们没有发现 UGT1A4 或 UGT2B10 基因型或 CYP2A6 风险评分的药物遗传学效应的证据。
