Amit A. Somani(1), Kirstin Thelen(2), Songmao Zheng (1), Mirjam N. Trame (1), Katrin Coboeken(2), Michaela Meyer(2), Katrin Schnizler(2), Ibrahim Ince(2), Stefan Willmann(2), Stephan Schmidt+
(1) Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida (2) Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany
Objectives: Evidence suggests that the rate of oral drug absorption changes from birth, yet, the clinical implications are currently unclear, in particular for preterm neonates. The objective of this study was to: i) better understand and quantify changes in oral drug absorption for different Biopharmaceutics Classification System (BCS) class I and II compounds and ii) to provide a rational dosing guide for orally administered drug formulations.
Methods: Following a thorough literature search, two paradigm compounds were selected from BCS class I (acetaminophen (APAP) [1, 2] & theophylline [3, 4]) and II (indomethacin [5, 6, 7, 8] & ibuprofen [9, 10]), respectively, based on the availability of clinical data following intravenous (IV) and oral dosing. A population pharmacokinetic (PopPK) analysis was performed in a step-wise fashion in NONMEM® 7.2 to characterize and predict changes in oral drug absorption from birth. Maturational changes in systemic clearance were evaluated based on IV data followed by a BCS class-specific evaluation of changes in pre-systemic events following oral dosing. Due to a lack of published PopPK study data on ibuprofen, the rate and extent of oral drug absorption for ibuprofen in preterm neonates was characterized based on published PK data.
Results: A one-compartment model with an age-dependent maturation function for the rate of absorption was found appropriate to characterize the pharmacokinetic (PK) of APAP. The maturation function for APAP was also sufficient to characterize the PK of theophylline following oral dosing in preterm neonates indicating that the underlying physiological process are drug-independent and the determined maturation function might be generally applicable. Once in solution, indomethacin, a BCS class II compound, showed a similar absorption profile as the two BCS class I compounds suggesting that the use of the maturation function can even be expanded to BCS class II compounds. Our findings further suggest that the rate of drug absorption reaches adult levels within approximately 1 week from birth and that there is a pronounced food effect which contributes to substantial between-subject variability in drug exposure.
Conclusions: For BCS class I and II drugs, age dependent changes in the rate of oral drug absorption appear to drug-independent. A respective maturation function can be applied across these drugs once solubility-related limitations are addressed via appropriate drug formulations.
References:
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Reference: PAGE 23 (2014) Abstr 3046 [www.page-meeting.org/?abstract=3046]
Poster: Drug/Disease modeling - Paediatrics