Predicting In Vivo Efficacy from In Vitro Data: Quantitative Systems Pharmacology Modeling for an Epigenetic Modifier Drug in Cancer. Issue 2 (16th January 2020)

• Record Type: Journal Article
• Authors: Bouhaddou, Mehdi; Yu, Li J.; Lunardi, Serena; Stamatelos, Spyros K.; Mack, Fiona; Gallo, James M.; Birtwistle, Marc R.; Walz, Antje‐Christine
• Is Part Of: Clinical and translational science. Volume 13:Issue 2(2020)
• Page Start: 419
• Page End: 429
• Publication Date: 2020-01-16
• Subjects: Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; 616.027
• DOI: 10.1111/cts.12727
• Languages: English
• ISSNs: 1752-8054

Abstract

Abstract : Reliably predicting in vivo efficacy from in vitro data would facilitate drug development by reducing animal usage and guiding drug dosing in human clinical trials. However, such prediction remains challenging. Here, we built a quantitative pharmacokinetic/pharmacodynamic (PK/PD) mathematical model capable of predicting in vivo efficacy in animal xenograft models of tumor growth while trained almost exclusively on in vitro cell culture data sets. We studied a chemical inhibitor of LSD1 (ORY‐1001), a lysine‐specific histone demethylase enzyme with epigenetic function, and drug‐induced regulation of target engagement, biomarker levels, and tumor cell growth across multiple doses administered in a pulsed and continuous fashion. A PK model of unbound plasma drug concentration was linked to the in vitro PD model, which enabled the prediction of in vivo tumor growth dynamics across a range of drug doses and regimens. Remarkably, only a change in a single parameter—the one controlling intrinsic cell/tumor growth in the absence of drug—was needed to scale the PD model from the in vitro to in vivo setting. These findings create a framework for using in vitro data to predict in vivo drug efficacy with clear benefits to reducing animal usage while enabling the collection of dense time course and dose response data in a highly controlled in vitro environment.