A Comparative Study Between Allometric Scaling and Physiologically Based Pharmacokinetic Modeling for the Prediction of Drug Clearance From Neonates to Adolescents

Abstract

The objective of this study was to compare the predictive performance of an allometric model with that of a physiologically based pharmacokinetic (PBPK) model to predict clearance or area under the concentration-time curve (AUC) of drugs in subjects from neonates to adolescents. From the literature, 10 studies were identified in which clearance or AUC of drugs from neonates to adolescents was predicted by PBPK models. In these published studies, drugs were given to children either by intravenous or oral route. The allometric model was an age-dependent exponent (ADE) model for the prediction of clearance across the age groups. The predicted clearance or AUC values from the PBPK and ADE models were compared with the experimental values. The acceptable prediction error was the percentage of subjects within an 0.5- to 2-fold or 0.5- to 1.5-fold prediction error. There were 73 drugs with a total of 372 observations. From PBPK and allometric models, 91.1% and 90.6% of observations were within 0.5- to 2-fold prediction error, respectively. For children ≤2 years old (n = 130), PBPK and allometric models had 89% and 87% of observations within the 0.5- to 2-fold prediction error, respectively. This study indicates that the predictive power of PBPK and allometric models was essentially similar for the prediction of clearance or AUC in pediatric subjects ranging from neonates to adolescents.

A Retrospective Evaluation of Allometry, PopulationPharmacokinetics,andPhysiologically‐Based Pharmacokineticsfor Pediatric Dosing Using Clearance as a Surrogate

“…Overall, it may be said that PBPK, allometry with ADEs, and popPK have comparable performance, consistent with what has been reported previously . However, in clinical studies where pediatric popPK models were employed for both interpolations and extrapolations, PBPK and allometry with ADEs appear to be better than popPK.…”

“…It also suggests that the exponent of 0.75 in simple allometry cannot be universal. However, the use of age‐segmented exponents in allometry has the potential to considerably improve predictions as demonstrated in this analysis.…”

“…Both PBPK and popPK models perform better than simple allometry, especially for children < 2 years of age. The lack of body‐weight correlation for the children aged < 2 years demonstrates that this subpopulation of children cannot be treated as small adults . It also suggests that the exponent of 0.75 in simple allometry cannot be universal.…”

“…used 10 compounds metabolized by Cytochrome P450 (CYP)3A4 to demonstrate the value of PBPK pediatric predictions for children < 2 years of age. Although simple allometry with a constant body‐weight exponent of 0.75 performed badly for the < 2 years children, a recent study demonstrated that allometry with age‐dependent exponents (ADEs) predicted 87% of the 130 studies evaluated within a twofold error margin, which was comparable with PBPK . Evaluation of PK‐Sim (http://www.systems-biology.com), another widely used PBPK platform for pediatric applications, has been reported .…”

Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants

“…Our recent work addresses the comparative performances of both methods for predicting infliximab PK in children between 4 and 18 years of age . In the case of small‐molecule drugs, allometric scaling and PBPK modeling often achieve predictions within 2‐fold prediction error >90% of the time for children over 2 years of age, when maturation and ontogeny do not critically influence drug disposition . Below the age of 2 years there is more uncertainty.…”