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Multiscale systems pharmacological analysis of everolimus action in hepatocellular carcinoma

Original Paper
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Abstract

Dysregulation of mTOR pathway is common in hepatocellular carcinoma (HCC). A translational quantitative systems pharmacology (QSP), pharmacokinetic (PK), and pharmacodynamic (PD) model dissecting the circuitry of this pathway was developed to predict HCC patients’ response to everolimus, an mTOR inhibitor. The time course of key signaling proteins in the mTOR pathway, HCC cells viability, tumor volume (TV) and everolimus plasma and tumor concentrations in xenograft mice, clinical PK of everolimus and progression free survival (PFS) in placebo and everolimus-treated patients were extracted from literature. A comprehensive and multiscale QSP/PK/PD model was developed, qualified, and translated to clinical settings. Model fittings and simulations were performed using Monolix software. The S6-kinase protein was identified as critical in the mTOR signaling pathway for describing everolimus lack of efficacy in HCC patients. The net growth rate constant (kg) of HCC cells was estimated at 0.02 h−1 (2.88%RSE). The partition coefficient of everolimus into the tumor (kp) was determined at 0.06 (12.98%RSE). The kg in patients was calculated from the doubling time of TV in naturally progressing HCC patients, and was determined at 0.004 day−1. Model-predicted and observed PFS were in good agreement for placebo and everolimus-treated patients. In conclusion, a multiscale QSP/PK/PD model elucidating everolimus lack of efficacy in HCC patients was successfully developed and predicted PFS reasonably well compared to observed clinical findings. This model may provide insights into clinical response to everolimus-based therapy and serve as a valuable tool for the clinical translation of efficacy for novel mTOR inhibitors.

Keywords

Quantitative systems pharmacology Hepatocellular carcinoma Everolimus 

Notes

Compliance with ethical standards

Conflict of Interest

The authors declare that there is no conflict of interest.

Supplementary material

10928_2018_9590_MOESM1_ESM.docx (403 kb)
Supplementary material 1 (DOCX 397 kb)

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of PharmacyUniversity of FloridaOrlandoUSA

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