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A Population Dynamic Energy Budget-Based Tumor Growth Inhibition Model for Etoposide Effects on Wistar Rats

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Abstract

Purpose

This work aimed to develop a population PK/PD tumor-in-host model able to describe etoposide effects on both tumor cells and host in Walker-256 tumor-bearing rats.

Methods

Etoposide was investigated on thirty-eight Wistar rats randomized in five arms: two groups of tumor-free animals receiving either placebo or etoposide (10 mg/kg bolus for 4 days) and three groups of tumor-bearing animals receiving either placebo or etoposide (5 or 10 mg/kg bolus for 8 or 4 days, respectively). To analyze experimental data, a tumor-in-host growth inhibition (TGI) model, based on the Dynamic Energy Budget (DEB) theory, was developed. Total plasma and free-interstitial tumor etoposide concentrations were assessed as driver of tumor kinetics.

Results

The model simultaneously describes tumor and host growths, etoposide antitumor effect as well as cachexia phenomena related to both the tumor and the drug treatment. The schedule-dependent inhibitory effect of etoposide is also well captured when the intratumoral drug concentration is considered as the driver of the tumor kinetics.

Conclusions

The DEB-based TGI model capabilities, up to now assessed only in mice, are fully confirmed in this study involving rats. Results suggest that well designed experiments combined with a mechanistic modeling approach could be extremely useful to understand drug effects and to describe all the dynamics characterizing in vivo tumor growth studies.

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Abbreviations

AIC:

Akaike’s information criterion

AUC:

Area under the curve

BIC:

Bayesian information criterion

BQL:

Below limit of quantification

BWL:

Body weight loss

CV:

Coefficient of variation

DEB:

Dynamic energy budget

GOF:

Goodness of fit

i.v.:

Intravenous

NPDE:

Normalized prediction distribution errors

PD:

Pharmacodynamic

PK:

Pharmacokinetic

RSE:

Residual standard error

s.c.:

Subcutaneously

TGI:

Tumor Growth Inhibition

VPC:

Visual predictive check

W256:

Walker-256

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Author notes

  1. M. C. Pigatto

    Present address: R&D Department, Eurofarma Laboratories S.A., Itapevi, SP, 06, Brazil

Authors and Affiliations

  1. Dipartimento di Ingegneria Industriale e dell’Informazione, Universita degli Studi di Pavia, I-27100, Pavia, Italy

    E. M. Tosca & P. Magni

  2. Pharmacokinetics and PK/PD Modeling Laboratory, Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90.610-000, Brazil

    M. C. Pigatto & T. Dalla Costa

Authors
  1. E. M. Tosca
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  2. M. C. Pigatto
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  3. T. Dalla Costa
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  4. P. Magni
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Correspondence to P. Magni.

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Tosca, E.M., Pigatto, M.C., Dalla Costa, T. et al. A Population Dynamic Energy Budget-Based Tumor Growth Inhibition Model for Etoposide Effects on Wistar Rats. Pharm Res 36, 38 (2019). https://doi.org/10.1007/s11095-019-2568-9

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