van Rongen Anne, Vaughns Janelle D, Moorthy Ganesh S, Barrett Jeffrey S, Knibbe Catherijne A J, van den Anker Johannes N
Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands.
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
Br J Clin Pharmacol. 2015 Nov;80(5):1185-96. doi: 10.1111/bcp.12693. Epub 2015 Sep 10.
In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and obese adolescents.
Overweight (BMI for age ≥ 85(th) percentile) and obese (BMI for age ≥ 95(th) percentile) adolescents undergoing surgery received 2 or 3 mg intravenous midazolam as a sedative drug pre-operatively. Blood samples were collected until 6 or 8 h post-dose. Population pharmacokinetic modelling and systematic covariate analysis were performed using nonmem 7.2.
Nineteen overweight and obese patients with a mean body weight of 102.7 kg (62-149.8 kg), a mean BMI of 36.1 kg m(-2) (24.8-55 kg m(-2)), and a mean age of 15.9 years (range 12.5-18.9 years) were included. In the model for midazolam and metabolites, total body weight was not of influence on clearance (0.66 l min(-1) (RSE 8.3%)), while peripheral volume of distribution of midazolam (154 l (11.2%)), increased substantially with total body weight (P < 0.001). The increase in peripheral volume could be explained by excess body weight (WTexcess ) instead of body weight related to growth (WTfor age and length ).
The pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents show a marked increase in peripheral volume of distribution and a lack of influence on clearance. The findings may imply a need for a higher initial infusion rate upon initiation of a continuous infusion in obese adolescents.
鉴于青少年肥胖患病率不断上升，本研究旨在确定CYP3A底物咪达唑仑及其代谢产物在超重和肥胖青少年中的药代动力学。
接受手术的超重（年龄别BMI≥第85百分位数）和肥胖（年龄别BMI≥第95百分位数）青少年术前静脉注射2或3毫克咪达唑仑作为镇静药物。给药后6或8小时内采集血样。使用非房室模型7.2进行群体药代动力学建模和系统协变量分析。
纳入了19名超重和肥胖患者，平均体重为102.7千克（62-149.8千克），平均BMI为36.1千克/米²（24.8-55千克/米²），平均年龄为15.9岁（范围12.5-18.9岁）。在咪达唑仑及其代谢产物模型中，总体重对清除率无影响（清除率为0.66升/分钟（相对标准误8.3%）），而咪达唑仑的外周分布容积（154升（11.2%））随总体重显著增加（P<0.001）。外周分布容积的增加可用超重体重（WTexcess）而非与生长相关的体重（WTfor age and length）来解释。
超重和肥胖青少年中咪达唑仑及其代谢产物的药代动力学显示外周分布容积显著增加，且对清除率无影响。这些发现可能意味着肥胖青少年开始持续输注时需要更高的初始输注速率。
