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O-33 Feasibility of a paediatric micro-dose study of [14c]midazolam to study the ontogeny of cyp3a-mediated drug metabolism
  1. Van Groen1,
  2. Mooij2,
  3. Van Duijn4,
  4. Knibbe4,
  5. Allegaert1,
  6. Windhorst5,
  7. Van Rosmalen1,
  8. Hendrikse5,
  9. Tibboel1,
  10. Vaes3,
  11. De Wildt6
  1. 1Erasmus MC, ROTTERDAM, Nederland
  2. 2Leiden University Medical Centre – Willem-Alexander Children’s Hospital, LEIDEN, Netherlands
  3. 3TNO, ZEIST, Netherlands
  4. 4St. Antonius Hospital, NIEUWEGEIN, Netherlands
  5. 5VUmc, AMSTERDAM, Netherlands
  6. 6Radboudumc, NIJMEGEN, Netherlands

Abstract

Background Microdose studies present an interesting innovation to study age-related changes in drug metab-olism in young children. To further delineate maturation of intestinal and hepatic CYP3A activity, in this pilot study we aimed to study the feasibility of an oral [14C]midazol-am (MDZ) microdosing study in children.

Methods Children admitted to the paediatric intensive care unit were eligible to receive a single oral [14C]MDZ microdose when they received IV midazolam for thera-peutic reasons and had an arterial line in place enabling blood sampling. Blood samples were taken up to 24 hours after dose administration. Plasma concentrations of [14C] MDZ and the metabolite [14C]OH-MDZ were determined by accelator mass spectrometry (AMS). Pharmacokinetic (PK) parameters were estimated using non-compartmen-tal PK models with PKSolver software (Microsoft Excel).

Results Of 139 eligible patients, 125 were excluded and informed consent was obtained from parents of nine chil-dren [median age 3.3 months (range 12 days – 4.2 years)] who received a midazolam microdose (19.3 [18.7–21.3] ng/kg; 58 [56-64] Bq/kg). [14C]MDZ and [14C]1-OH-MDZ were detectable at expected concentrations: plasma [14C]MDZ AUC0-∞ was 49.9 (4.0–107.7) ng/L*h, Cmax was 7.5 (1.5–22.2) ng/L, Tmax was 0.5 (0.3–3.1) hour, T0.5 was 4.6 (1.1–14.0) hour, CL/F was 0.4 (0.2–5.3) L/h/kg and Vss/F was 3.1 (1.7–10.7) L/kg. Plasma [14C]1-OH-MDZ AUC0-∞ was 7.8 (1.3–28.3) ng/L*h and CL/F was 2.4 (0.7–14.6) L/h/kg. Plasma Cmax of [14C]MDZ normalised to a dose of 0.1 mg/kg was 39.9 (7.0–114.9) ng/ml.

Conclusion We demonstrate the feasibility of an oral [14C]MDZ microdose to study MDZ and 1-OHMDZ dis-position in young infants and children with AMS. This method can be used to study developmental changes in intestinal and hepatic CYP3A activity.

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