Recent developments in in vitro and in vivo models for improved translation of preclinical pharmacokinetics and pharmacodynamics data

Abstract

Improved pharmacokinetics/pharmacodynamics (PK/PD) prediction in the early stages of drug development is essential to inform lead optimization strategies and reduce attrition rates. Recently, there have been significant advancements in the development of new in vitro and in vivo strategies to better characterize pharmacokinetic properties and efficacy of drug leads. Herein, we review advances in experimental and mathematical models for clearance predictions, advancements in developing novel tools to capture slowly metabolized drugs, in vivo model developments to capture human etiology for supporting drug development, limitations and gaps in these efforts, and a perspective on the future in the field.

Keywords:

• Clearance prediction
• zebrafish
• in-vitro in-vivo extrapolation
• intrinsic clearance
• in-vivo models

Acknowledgment

Authors would like to thank Dr. Rob Foti for reviewing the IVIVE section of the manuscript.

Disclosure statement

VML is co-founder and chairman of the board of PersoMedix AB, CEO and shareholder of HepaPredict AB, and discloses consultancy work for Enginzyme AB.

Additional information

Funding

JHH is supported by a grant from National Institutes of Health [R00-ES029552]. VML is supported by the Swedish Research Council [2016-01153, 2016-01154, and 2019-01837], by the Strategic Research Programmes in Diabetes (SFO Diabetes) and Stem Cells and Regenerative Medicine (StratRegen) and by the EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN [875510]). In addition, VML acknowledges support by Merck KGaA and Eli Lilly and Company. JS was supported in part by an American Foundation for Pharmaceutical Education Predoctoral Fellowship, NIGMS [R25 GM56847], and a Louis Zeh Fellowship.