The area under the effect curve as an efficacy determinant for anti-infectives

Abstract

Pharmacokinetic/pharmacodynamic (PK/PD) indices making use of area under the curve, maximum concentration, and the duration that in vivo drug concentration is maintained above a critical level are commonly applied to clinical dose prediction from animal efficacy experiments in the infectious disease arena. These indices make suboptimal use of the nonclinical data, and the prediction depends on the shape of the PK profiles in the animals, determined by the species-specific absorption, distribution, metabolism, and elimination properties, and the dosing regimen used in the efficacy experiments. Motivated by the principle that efficacy is driven by pharmacology, we conducted simulations using a generalized pathogen dynamic model, to assess the properties of an alternative efficacy predictor: the area under the effect curve (AUEC), computed using in vitro PD and in vivo PK. Across a wide range of hypothetical scenarios, the AUEC consistently showed regimen-independent strong correlation (R2 0.76–0.98) with in vivo efficacy, superior to all other indices. These findings serve as proof of concept that AUEC should be considered in practice as a translation tool for cross-species dose prediction. Using AUEC for clinical dose prediction could also potentially cut down animal use by reducing or avoiding dose fractionation experiments.