Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions.

Allometric scaling provides a practical framework for predicting human pharmacokinetic (PK) parameters from animal data by relating physiological processes to body size through power-law equations. Despite its simplicity and widespread use in first-in-human (FIH) dose selection, its predictive performance is limited by species-specific differences in absorption, distribution, metabolism, and excretion (ADME). This review summarizes the mathematical foundations, workflows, and diagnostics of allometric scaling, while critically examining where the approach succeeds and where it fails. Core concepts, including clearance, volume of distribution, correction factors, and the rule of exponents, are discussed alongside complementary methods: in vitro-in vivo extrapolation (IVIVE), physiologically based pharmacokinetic (PBPK) modelling, and the Wajima normalized time-course method. Historical clinical failures, including fialuridine, TGN1412, BIA 10-2474, and rofecoxib, illustrate the limits of relying solely on allometry, while thalidomide and the fenfluramine combination exemplify toxicodynamic species-selection failures. Modern advances, including the Extended Clearance Classification System (ECCS), target-mediated drug disposition, FcRn recycling, and emerging artificial intelligence and machine-learning methods, are integrated within a framework. Overall, the review treats allometric scaling as a disciplined starting hypothesis that must be triangulated with mechanistic, experimental, and regulatory evidence to support safer and more reliable human translation.