Use of pharmacokinetic versus pharmacodynamic endpoints to support human dose predictions: implications for rational drug design and early clinical development

The predicted human dose regimen of new chemical entities represents the most holistic and clinically relevant measure of drug-likeness upon which to base decisions in drug design and selection of candidate molecules for further development. Likewise, the predicted human dose regimen for efficacy and safety provides critical insight into clinical development planning. As such, human dose predictions are commonly generated in early stages of research and continually revisited as new data are generated through development. In this work, the authors illustrate scenarios where conventional approaches based on discrete pharmacokinetic metrics are inappropriate and propose a generalizable approach leveraging a predicted average pharmacodynamic effect rather than pharmacokinetic metrics. Preclinical and clinical data of a JAK inhibitor, tofacitinib, were used to illustrate the relative value of this approach to human dose prediction. Due to the simplicity of implementation, pharmacokinetic-based approaches which target a discrete maximal, average, or minimum concentration have been widely used across the pharmaceutical industry. However, in emphasizing only one point on the overall exposure-time profile, such approaches can be misleading in terms of the expected pharmacodynamic effect. For future projections, the authors recommend using the average pharmacodynamic effect-based approach to calculate human efficacious dose.