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AAPS J. 2016 Sep;18(5):1262-72. doi: 10.1208/s12248-016-9936-8. Epub 2016 Jun 21.

Improvement of Parameter Estimations in Tumor Growth Inhibition Models on Xenografted Animals: Handling Sacrifice Censoring and Error Caused by Experimental Measurement on Larger Tumor Sizes.

Author information

1
EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, 165 chemin du Grand Revoyet-BP 12, 69921, Oullins Cedex, France. philippe.pierrillas@gmail.com.
2
Centre de Pharmacocinétique et Métabolisme, Technologie Servier, Orléans, France. philippe.pierrillas@gmail.com.
3
EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, 165 chemin du Grand Revoyet-BP 12, 69921, Oullins Cedex, France.
4
Pharmacie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France.
5
Centre de Pharmacocinétique et Métabolisme, Technologie Servier, Orléans, France.
6
Division of Clinical Pharmacokinetics and Pharmacometrics, Institut de Recherches Internationales Servier, Suresnes, France.

Abstract

The purpose of this study was to explore the impact of censoring due to animal sacrifice on parameter estimates and tumor volume calculated from two diameters in larger tumors during tumor growth experiments in preclinical studies. The type of measurement error that can be expected was also investigated. Different scenarios were challenged using the stochastic simulation and estimation process. One thousand datasets were simulated under the design of a typical tumor growth study in xenografted mice, and then, eight approaches were used for parameter estimation with the simulated datasets. The distribution of estimates and simulation-based diagnostics were computed for comparison. The different approaches were robust regarding the choice of residual error and gave equivalent results. However, by not considering missing data induced by sacrificing the animal, parameter estimates were biased and led to false inferences in terms of compound potency; the threshold concentration for tumor eradication when ignoring censoring was 581 ng.ml(-1), but the true value was 240 ng.ml(-1).

KEYWORDS:

missing data; sacrifice censoring; stochastic simulation and estimation; upper limit of quantification; xenograft model

PMID:
27329303
DOI:
10.1208/s12248-016-9936-8
[Indexed for MEDLINE]

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