title: Evaluation of changes in oral drug absorption in preterm and term neonates for Biopharmaceutics Classification System (BCS) class I and II compounds.
abstract: OBJECTIVE
  Evidence suggests that the rate of oral drug absorption changes during early childhood. Yet, respective clinical implications are currently unclear, particularly for preterm neonates. The objective of this study was to evaluate changes in oral drug absorption after birth for different Biopharmaceutics Classification System (BCS) class I and II compounds to better understand respective implications for paediatric pharmacotherapy.
  
  
  METHODS
  Two paradigm compounds were selected for BCS class I (paracetamol (acetaminophen) and theophylline) and II (indomethacin and ibuprofen), respectively, based on the availability of clinical literature data following intravenous and oral dosing. A comparative population pharmacokinetic analysis was performed in a step-wise manner in NONMEM® 7.2 to characterize and predict changes in oral drug absorption after birth for paracetamol, theophylline and indomethacin.
  
  
  RESULTS
  A one compartment model with an age-dependent maturation function for oral drug absorption was found appropriate to characterize the pharmacokinetics of paracetamol. Our findings indicate that the rate at which a drug is absorbed from the GI tract reaches adult levels within about 1 week after birth. The maturation function for paracetamol was found applicable to theophylline and indomethacin once solubility limitations were overcome via drug formulation. The influence of excipients on solubility and, hence, oral bioavailability was confirmed for ibuprofen, a second BCS class II compound.
  
  
  CONCLUSIONS
  The findings of our study suggest that the processes underlying changes in oral drug absorption after birth are drug-independent and that the maturation function identified for paracetamol may be generally applicable to other BCS class I and II compounds for characterizing drug absorption in preterm as well as term neonates.
authors: Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
authors: Amit A
authors: AA
authors: Somani
authors: Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany.
authors: Kirstin
authors: K
authors: Thelen
authors: Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
authors: Songmao
authors: S
authors: Zheng
authors: Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
authors: Mirjam N
authors: MN
authors: Trame
authors: Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany.
authors: Katrin
authors: K
authors: Coboeken
authors: Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany.
authors: Michaela
authors: M
authors: Meyer
authors: Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany.
authors: Katrin
authors: K
authors: Schnizler
authors: Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany.
authors: Ibrahim
authors: I
authors: Ince
authors: Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany.
authors: Stefan
authors: S
authors: Willmann
authors: Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
authors: Stephan
authors: S
authors: Schmidt
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics; D000284:Administration, Oral; D001702:Biopharmaceutics / Q000379:methods; D006801:Humans; D007052:Ibuprofen / Q000493:pharmacokinetics; D007213:Indomethacin / Q000493:pharmacokinetics; D007231:Infant, Newborn / Q000378:metabolism*; D007234:Infant, Premature; D007408:Intestinal Absorption; D013806:Theophylline / Q000493:pharmacokinetics
chemical_list: D000082:Acetaminophen; D013806:Theophylline; D007052:Ibuprofen; D007213:Indomethacin
keywords: BCS class I and II; oral drug absorption; paediatrics; pharmacokinetics; preterm neonates