Population PK of midazolam from preterm neonates to adults, a maturation model
I. Ince (1,2), S.N. de Wildt (1), C. Wang (2), M.Y.M. Peeters (3), J. Burggraaf (4), E. Jacqz-Aigrain (5), D. Tibboel (1), M. Danhof (2), C.A. Knibbe (2,3)
(1)ErasmusMC Sophia Children’s Hospital, Department of Paediatric Surgery and Intensive Care, Rotterdam, The Netherlands, (2)Leiden/Amsterdam Center For Drug Research, Division of Pharmacology, Leiden, The Netherlands, (3)St. Antonius Hospital, Department of Clinical Pharmacy, Nieuwegein, The Netherlands, (4)Centre for Human Drug Research, Leiden University, Leiden, the Netherlands, (5)University Diderot, Department of Paediatric Pharmacology and Pharmacogenetics, Paris, France.
Objectives: : A previous investigation showed major impact of critical illness on midazolam clearance, however no influence of age-related changes on the cytochrome P450 (CYP) 3A4/5 mediated clearance of midazolam was found in children between 1 month to 17 years of age.1 In this analysis we aimed to develop a maturation model for CYP3A4/5 enzyme activity using midazolam clearance as in vivo probe, for preterm neonates from 26 weeks gestational age (GA) onwards to adults.
Methods: : Pharmacokinetic data after intravenous midazolam were obtained from 6 previously reported studies. Subjects were 32 non-ventilated preterm neonates (26-33.5 weeks GA and 3-11 days PNA)2, 24 preterm neonates with respiratory distress syndrome (26-37 weeks GA and 0-1 days postnatal age (PNA))3, 23 children after elective major craniofacial surgery (3-23 months)4, 18 pediatric intensive care (a term) patients (2 days to 17 years)5, 18 pediatric oncology patients (3-17 years)6 and 20 healthy male adults (20-31 years)7. Population PK modeling was performed using NONMEM v6.2. In a systematic covariate analysis, the influence of PNA, GA, postmenstrual age, body weight (BW) and PELOD score (organ failure) was investigated.
Results: Upon inclusion of preterm neonate datasets, BW proved a significant covariate for clearance in a two-compartment model. The influence of BW was best described using an allometric equation with a BW-dependent maturational exponent (BWME): BWME = Coeff1 x BWexp2, in which Coeff1 is the coefficient of the exponential function, exp2 is the additional exponent of the exponential function. It was shown that BWME changed from 0.84 in preterm neonates to 0.44 in adults, with a Coeff1 of 0.8 (CV of 9.1%) and exp2 of – 0.141 (CV of 32.1%). BW was also linearly correlated with midazolam central volume of distribution.
Conclusions: A maturation model for midazolam clearance from preterm neonates to adults has been developed showing that CYP3A4/5 activity rapidly matures from (preterm) neonates up to children of 0.77-10 kg. Thereafter, maturation slows down resulting in minimal increase between 10 and 81 kg of body weight.
 Ince I et al., PAGE 19 (2010) Abstr 1819 [www.page-meeting.org/?abstract=1819]
 de Wildt SN et al., Clin Pharmacol Ther. 2001 Dec;70(6):525-31.
 Jacqz-Aigrain E et al,. Lancet. 1994 Sep 3;344(8923):646-50.
 Peeters MY et al., Anesthesiology. 2006 Dec;105(6):1135-46.
 de Wildt SN et al., Crit Care Med. 2003 Jul;31(7):1952-8.
 de Wildt SN et al., Clin Pharmacol Ther 2000 Mar;67:104.
 van Gerven JM et al., Br J Clin Pharmacol. 1997 Nov;44(5):487-93.