Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.
TNO, Zeist, The Netherlands.
Br J Clin Pharmacol. 2019 Oct;85(10):2332-2340. doi: 10.1111/bcp.14047. Epub 2019 Jul 30.
Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [ C]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose.
Preterm to 2-year-old infants admitted to the intensive care unit received [ C]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [ C]midazolam and [ C]1-hydroxy-midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed.
Of 15 infants (median gestational age 39.4 [range 23.9-41.4] weeks, postnatal age 11.4 [0.6-49.1] weeks), 6 received a microtracer and 9 a microdose of [ C]midazolam (111 Bq kg ; 37.6 ng kg ). In a 2-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [ C]1-OH-midazolam/[ C]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses.
Our data support the dose linearity of the PK of an IV [ C]midazolam microdose in children. Hence, a [ C]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children.
由于儿童的药物代谢随年龄变化而变化，因此药物在儿童体内的处置可能与成人不同。微剂量研究为儿科研究药代动力学（PK）提供了一种创新方法；然而，只有当 PK 呈剂量线性时，才应使用微剂量研究。我们旨在通过比较静脉（IV）微示踪剂（与治疗性咪达唑仑剂量同时给予的微剂量）与单次单独微剂量的 PK，评估[ C]咪达唑仑微剂量的剂量线性。
入住重症监护病房的早产儿至 2 岁婴儿接受 IV [ C]咪达唑仑作为微示踪剂或微剂量，随后在 36 小时内密集采血。通过加速质谱法测定[ C]咪达唑仑和[ C]1-羟基-咪达唑仑的血浆浓度。进行非房室 PK 分析并建立群体 PK 模型。
15 名婴儿（中位胎龄 39.4 [23.9-41.4] 周，生后年龄 11.4 [0.6-49.1] 周）中，6 名婴儿接受微示踪剂，9 名婴儿接受[ C]咪达唑仑微剂量（111 Bq kg；37.6 ng kg）。在 2 室 PK 模型中，体重是分布容积的最重要协变量。微剂量和微示踪剂之间的任何 PK 参数均无统计学差异，[ C]1-OH-咪达唑仑/[ C]咪达唑仑 AUC 比值也无差异，表明咪达唑仑的 PK 在治疗剂量和微剂量范围内呈线性。
我们的数据支持 IV [ C]咪达唑仑微剂量 PK 的剂量线性。因此，咪达唑仑微剂量法可作为治疗剂量咪达唑仑的替代方法，用于研究婴幼儿肝 CYP3A 活性的发育变化。
