Critical illness is a major determinant for midazolam and metabolite clearance in children
I. Ince[1,2], S.N. de Wildt, M.Y.M. Peeters, D.J. Murry, D. Tibboel, M. Danhof, C.A. Knibbe[1,2,3]
ErasmusMC Sophia Children’s Hospital, Department of Paediatric Surgery and Intensive Care, Rotterdam, The Netherlands, Leiden/Amsterdam Center For Drug Research, Division of Pharmacology, Leiden, The Netherlands, St. Antonius Hospital, Department of Clinical Pharmacy, Nieuwegein, The Netherlands,University of Iowa College of Pharmacy, Iowa City, Iowa, USA
Objectives: The specific CYP3A4/5 substrate midazolam, is often used for sedation in pediatric intensive care units. However, the exact influence of severity of illness and developmental changes throughout childhood on the PK of CYP3A substrates has not been quantified. We aimed to estimate midazolam and metabolite disposition in relatively healthy and critically ill children from 1 month to 17 years of age and to study possible underlying mechanisms for variation.
Methods: Midazolam and metabolite data from three different studies were used; 24 previously healthy children receiving midazolam iv bolus and infusion postoperatively after elective craniofacial surgery , 18 pediatric oncology patients without hepatic or renal organ failure receiving midazolam iv infusion before undergoing an invasive procedure  and 13 critically ill patients receiving midazolam iv bolus and infusion for conscious sedation . The datasets were merged in R and population PK modeling was performed using NONMEM 6.2. The influence of age and body weight was investigated for the PK of midazolam, 1-OH-midazolam and 1-OH-midazolam-glucuronide. In addition, we used SimCYP® to study the possible effect of liver flow, CYP3A4/5 activity and protein binding on PK variability.
Results: Population PK analysis showed that critically ill patients have a 80% to 90% lower CYP3A (midazolam to 1-OH-midazolam) and UGT (1-OH-midazolam to 1-OH-midazolam glucuronide) mediated clearance. No influence of age or body weight on the CYP3A4 mediated clearance was found. Body weight as a covariate for the UGT mediated clearance, significantly improved the model. Different scenario simulations with SimCYP® showed major impact of liver bloodflow and a combination of CYP3A4 & CYP3A5 abundance on the total clearance of midazolam.
Conclusions: From infancy to adolescence, critical illness shows to be a major determinant of midazolam clearance. Most likely causes are decreased liver flow and/or combined CYP3A4 and CYP3A5 abundance. While no influence of developmental changes on CYP3A4 mediated clearance was found, we did find a bodyweight-related influence on the UGT mediated clearance. These findings suggest that severity of illness in stead of age or body weight should be considered for dosing of midazolam in children.
. Peeters MY, Prins SA, Knibbe CA, Dejongh J, Mathot RA, Warris C, et al. Pharmacokinetics and pharmacodynamics of midazolam and metabolites in nonventilated infants after craniofacial surgery. Anesthesiology. 2006 Dec;105(6):1135-46.
. de Wildt SN, Riva L, van den Anker JN, Murray DJ. Does age alter the pharmacokinetics of midazolam and l-OH-midazolam in paediatric patients? Clin Pharmacol Ther 2000 Mar;67:104.
. de Wildt SN, de Hoog M, Vinks AA, van der Giesen E, van den Anker JN. Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. Crit Care Med. 2003 Jul;31(7):1952-8.