TY - JOUR T1 - O-33 Feasibility of a paediatric micro-dose study of [14c]midazolam to study the ontogeny of cyp3a-mediated drug metabolism JF - Archives of Disease in Childhood JO - Arch Dis Child SP - A15 LP - A15 DO - 10.1136/archdischild-2017-esdppp.33 VL - 102 IS - 10 AU - Van Groen AU - Mooij AU - Van Duijn AU - Knibbe AU - Allegaert AU - Windhorst AU - Van Rosmalen AU - Hendrikse AU - Tibboel AU - Vaes AU - De Wildt Y1 - 2017/10/01 UR - http://adc.bmj.com/content/102/10/A15.2.abstract N2 - 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. ER -