Allometry Is a Reasonable Choice in Pediatric Drug Development

Abstract

Pharmacokinetics (PK) plays a key role in bridging drug efficacy and safety from adults to pediatric patients. The principal purpose of projecting dosing in pediatrics is to guide trial design, not to waive the study per se. This research was designed to evaluate whether the allometric scaling (AS) approach is a satisfactory method to design PK studies in pediatric patients aged 2 years and older. We systematically evaluated drugs that had pediatric label information updated from 1998 to 2015. Only intravenous (IV) or oral administration drugs with available PK information in both children and adults from FDA-approved labels were included. The allometric scaling approach was used to extrapolate adult clearance to pediatric clearance. The relative difference between the observed and the allometric scaling approach-predicted clearance was summarized and used to evaluate the predictive power of the allometric scaling approach. A total of 36 drugs eliminated by a metabolic pathway and 10 drugs by the renal pathway after intravenous (IV) or oral administration were included. Regardless of the administration route, elimination pathway, and age group, the allometric scaling approach can predict clearance in pediatric patients within a 2-fold difference; 18 of the included drugs were predicted within a 25% difference, and 31 drugs within a 50% difference. The allometric scaling approach can adequately design PK studies in pediatric subjects 2 years and older.

Initiation of Pediatric Clinical Trials for Coagulation Factors: Application of Pharmacokinetics and Allometry to First‐in‐Pediatric Dose Selection

“…The allometric exponents widely vary and are data dependent . The rapid physiologic changes in children are nonlinear, and a single exponent cannot describe the CL vs body weight data across all age groups (neonates to adults).…”

“…This observation led Mahmood to introduce the concept of the age‐dependent exponent model for small molecules. With the introduction of the age‐dependent exponent model, a substantial improvement in the prediction of drug CL in children from neonates to adolescents was noted . In this study, the concept of the age‐dependent exponent model was not applied because the children were ≥2 years of age.…”

“…Allometric scaling is regularly used to predict PK parameters such as clearance, volume of distribution, and half-life from animals to humans (interspecies scaling). 2 The allometric principles can also be applied to predict PK parameters such as CL, volume of distribution, and half-life in pediatrics from preterm neonates to adolescents [3][4][5][6][7][8][9][10][11][12][13] and is of practical value during drug development. Allometric scaling based on body weight is easy and simple and can be done once PK information of a drug is available in adults.…”

Pharmacometric Modeling and Simulation Is Essential to Pediatric Clinical Pharmacology

“…A recent review evaluated the use of allometric scaling in pediatric patients aged 2 years and older . The authors considered drugs that had pediatric, Food and Drug Administration (FDA)‐approved labels updated between 1998 and 2015.…”

“…17 A recent review evaluated the use of allometric scaling in pediatric patients aged 2 years and older. 18 The authors considered drugs that had pediatric, Food and Drug Administration (FDA)-approved labels updated between 1998 and 2015. They found 36 drugs eliminated by metabolism and 10 drugs eliminated by urinary excretion alone, administered either intravenously or by oral routes, with available PK information in both children and adults.…”