Wilbaux, Melanie, Demanse, David, Gu, Gary, Jullion, Astrid, Myers, Andrea, Katsanou, Vasiliki and Meille, Christophe (2022) Contribution of machine learning to tumor growth inhibition modeling for hepatocellular carcinoma patients under Roblitinib (FGF401) drug treatment. CPT: pharmacometrics & systems pharmacology. ISSN 2163-8306

Abstract

Machine learning (ML) opens new perspectives in identifying predictive factors of efficacy among a large number of patients' characteristics in oncology studies. The objective of this work was to combine ML with population pharmacokinetic/pharmacodynamic (PK/PD) modeling of tumor growth inhibition to understand the sources of variability between patients and therefore improve model predictions to support drug development decisions. Data from 127 patients with hepatocellular carcinoma enrolled in a phase I/II study evaluating once-daily oral doses of the fibroblast growth factor receptor FGFR4 kinase inhibitor, Roblitinib (FGF401), were used. Roblitinib  PKs was best described by a two-compartment model with a delayed zero-order absorption and linear elimination. Clinical efficacy using the longitudinal sum of the longest lesion diameter data was described with a population PK/PD model of tumor growth inhibition including resistance to treatment. ML, applying elastic net modeling of time to progression data, was associated with cross-validation, and allowed to derive a composite predictive risk score from a set of 75 patients' baseline characteristics. The two approaches were combined by testing the inclusion of the continuous risk score as a covariate on PD model parameters. The score was found as a significant covariate on the resistance parameter and resulted in 19% reduction of its variability, and 32% variability reduction on the average dose for stasis. The final PK/PD model was used to simulate effect of patients' characteristics on tumor growth inhibition profiles. The proposed methodology can be used to support drug development decisions, especially when large interpatient variability is observed.

Item Type:	Article
Date Deposited:	13 Jul 2022 00:45
Last Modified:	13 Jul 2022 00:45
URI:	https://oak.novartis.com/id/eprint/44264