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, 85 (10), 2332-2340

Dose-linearity of the Pharmacokinetics of an Intravenous [ 14 C]midazolam Microdose in Children


Dose-linearity of the Pharmacokinetics of an Intravenous [ 14 C]midazolam Microdose in Children

Bianca D van Groen et al. Br J Clin Pharmacol.


Aims: 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 [14 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.

Methods: Preterm to 2-year-old infants admitted to the intensive care unit received [14 C]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [14 C]midazolam and [14 C]1-hydroxy-midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed.

Results: 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 [14 C]midazolam (111 Bq kg-1 ; 37.6 ng kg-1 ). 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 [14 C]1-OH-midazolam/[14 C]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses.

Conclusion: Our data support the dose linearity of the PK of an IV [14 C]midazolam microdose in children. Hence, a [14 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.

Keywords: cytochrome P450; drug metabolism; paediatrics.


Figure 1
Figure 1
Explanation of the terms intravenous microdose and microtracer midazolam
Figure 2
Figure 2
Individual (n = 9) semilog plasma concentration–time profiles of [14C]midazolam and [14C]1‐hydroxy‐midazolam after administration of a [14C]midazolam microdose
Figure 3
Figure 3
Individual (n = 6) semilog plasma concentration–time profiles of [14C]midazolam and [14C]1‐hydroxy‐midazolam after administration of a [14C]midazolam microtracer
Figure 4
Figure 4
Diagnostic plots for [14C]midazolam pharmacokinetic model, using different symbols for the different treatments. (A) Observed vs population predicted [14C]midazolam concentrations. (B) Observed vs individually predicted [14C]midazolam concentrations. (C) Weighted residuals vs population predicted [14C]midazolam concentration. (D) Weighted residuals vs time. Solid lines represent the line of unity in A and B, and a value of 0 in C and D. dotted line represent ±1.96 standard deviation, representing the interval in which 95% of the conditional weighted residual (CWRES) values are expected

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