Translational Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Oxaliplatin and Irinotecan in Colorectal Cancer

Abstract

Despite the recent advances in this field, there are limited methods for translating organoid-based study results to clinical response. The goal of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to facilitate the translation, using oxaliplatin and irinotecan treatments with colorectal cancer (CRC) as examples. The PK models were developed using qualified oxaliplatin and irinotecan PK data from the literature. The PD models were developed based on antitumor efficacy data of SN-38 and oxaliplatin evaluated in vitro using tumor organoids. To predict the clinical response, translational scaling of the models was established by incorporating predicted ultrafiltration platinum in plasma or SN-38 in tumors to PD models as the driver of efficacy. The final PK/PD model can predict PK profiles and responses following treatments with oxaliplatin or irinotecan. After generation of virtual patient cohorts, this model simulated their tumor shrinkages following treatments, which were used in analyzing the efficacies of the two treatments. Consistent with the published clinical trials, the model simulation suggested similar patient responses following the treatments of oxaliplatin and irinotecan with regards to the probabilities of progression-free survival (HR = 1.05, 95%CI [0.97;1.15]) and the objective response rate (OR = 1.15, 95%CI [1.00;1.32]). This proposed translational PK/PD modeling approach provides a significant tool for predicting clinical responses of different agents, which may help decision-making in drug development and guide clinical trial design.

Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities

“…Another case in point is a computational model of the MAPK signaling network developed by Kirouac et al to predict the clinical outcomes of ERK inhibition in colorectal cancer with the BRAF-V600E mutation [ 78 ], in which the authors started from in vitro cell culture data to in vivo animal response to clinical prediction using one general model framework. Another recent example is Zhu et al that constructed a translational PK/PD model using data from in vitro tumor organoids and established translational scaling of the model to predict the clinical response of oxaliplatin and irinotecan in colorectal cancer [ 96 ]. Therefore, an immediate next step is to extend our model to the clinical level and make full use of the multimodal data from published trials on HER2 + mBC (e.g., individual data from spider plots and waterfall plots, population-level ORR, PFS of different regimens) as well as original biomarker data from in-house patient samples to collectively generate a plausible and accurate virtual patient population.…”