title: Prediction of Clearance in Neonates and Infants (≤ 3 Months of Age) for Drugs That Are Glucuronidated: A Comparative Study Between Allometric Scaling and Physiologically Based Pharmacokinetic Modeling.
abstract: The objective of this study was to evaluate the predictive performances of allometric models and a physiologically based pharmacokinetic model (PBPK) to predict clearance of glucuronidated drugs in neonates (≤ 3 months of age). From the literature, clearance values for 9 drugs (glucuronidated) for neonates and adults were obtained. Three allometric models were used to predict clearances of these glucuronidated drugs. A PBPK model was developed using the physicochemical, biopharmaceutical, and metabolic properties together with known pediatric physiology and enzymatic ontogeny. The model was first developed for adult subjects and then verified using external data and then applied to simulations in neonates. The predictive performances of allometric and PBPK models were evaluated by comparing the predicted values of clearance with the observed clearance values in the neonates. For 9 drugs, there were 13 age groups (preterm and term neonates) for which prediction error in mean clearance values within 0.5- to 1.5-fold was observed in 10 and 11 age groups by 2 allometric models and a PBPK model, respectively. The proposed allometric methods can predict mean clearances of glucuronidated drugs in preterm and term neonates (≤ 3 months of age) with reasonable accuracy (within 0.5- to 1.5-fold or 50% error) and are of practical value during neonatal drug development. The predicted mean clearance values of glucuronidated drugs in neonates ≤ 3 months of age by 2 allometric methods were comparable with the PBPK model.
authors.affiliation: Division of Hematology, Clinical Review Branch, Office of Blood Review & Research (OBRR), Center for Biologic Evaluation and Research, Food & Drug Administration, Silver Spring, MD, USA.
authors.forename: Iftekhar
authors.initials: I
authors.lastname: Mahmood
authors.affiliation: Pharma Professional Services, A-93 Ettawah Society, Gadap Town, Karachi, Pakistan.
authors.forename: Tasneem
authors.initials: T
authors.lastname: Ahmad
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy & Pharmaceutical Sciences, University of Karachi, Karachi, Pakistan.
authors.forename: Najia
authors.initials: N
authors.lastname: Mansoor
authors.affiliation: Pharma Professional Services, A-93 Ettawah Society, Gadap Town, Karachi, Pakistan.
authors.forename: S M
authors.initials: SM
authors.lastname: Sharib
mesh_terms: D000367:Age Factors; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011237:Predictive Value of Tests
chemical_list: D020719:Glucuronides; D004364:Pharmaceutical Preparations
keywords: Clinical Pharmacology (CPH); Drug Metabolism; Neonatology; Pediatrics (PED); Pharmaceutical Medicine (PMD)