I. Ince (1,2), S.N. de Wildt (1), M.Y.M. Peeters (3), K. Burggraaf (4), E. Jacqz-Aigrain (5), J.S. Barrett (6), M. Danhof (2), C.A.J. Knibbe (1,2,3)
1.Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands; 2.Leiden/Amsterdam Center For Drug Research, Leiden, The Netherlands; 3.St. Antonius Hospital, Nieuwegein, The Netherlands; 4.Centre for Human Drug Research, Leiden, The Netherlands; 5.University Diderot, Paris, France; 6.Children's Hospital of Philadelphia, Philadelphia, PA, USA
Objectives: A maturation model for midazolam clearance from preterm neonates to adults has been previously developed, analyzing data that were obtained after IV dosing of midazolam across the entire human age range.[1] The aim of this study was to investigate changes in oral bioavailability and absorption rate of midazolam across the pediatric age range upon oral dosing of midazolam. The results can be used for the development of evidence-based dosing of oral midazolam in children.
Methods: Pharmacokinetic (PK) data were obtained from a combined dataset of 7 previously reported studies in 52 preterm infants (26-37 weeks GA, PNA 2-13 days), 305 children (3 months-18 years) and 20 adults, who received IV and/or PO midazolam. Population PK modeling was performed using NONMEM v6.2, and the influence of postnatal age (PNA), bodyweight (BW) and study population was investigated in a systematic covariate analysis.
Results: Oral bioavailability of midazolam with a population estimate of 24% (CV of 7.5%) was negatively influenced by BW in an allometric function, resulting in a value of 67% in a preterm neonate of 0.77 kg to 17% in an adult (70 kg). Previous results on the influence of BW on midazolam CL, characterized using an allometric function with a BW dependent exponent (BDE),[1] were confirmed.
Conclusions: Oral bioavailability of midazolam decreases from preterm neonates to adults, leading to higher systemic availability of midazolam in preterm neonates (67%) compared to older children or adults (17%). While this information may aid for the development of evidence-based dosages of oral midazolam for children of different ages, further physiologically-based modeling should elucidate the exact subprocesses that contribute to the reported age related changes in oral bioavailability of midazolam.
References:
[1] Ince et al., PAGE 20 (2011) Abstr 2102 [www.page-meeting.org/?abstract=2102]
Reference: PAGE 22 () Abstr 2853 [www.page-meeting.org/?abstract=2853]
Poster: Paediatrics