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AAPS J. 2016 Mar;18(2):404-15. doi: 10.1208/s12248-015-9862-1. Epub 2016 Jan 12.

Improvement of Parameter Estimations in Tumor Growth Inhibition Models on Xenografted Animals: a Novel Method to Handle the Interval Censoring Caused by Measurement of Smaller Tumors.

Author information

1
EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, 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, Oullins, 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 interval censoring induced by caliper measurements on smaller tumors during tumor growth experiments in preclinical studies and to show its impact on parameter estimations. A new approach, the so-called interval-M3 method, is proposed to specifically handle this type of data. Thereby, the interval-M3 method was challenged with different methods (including classical methods for handling below quantification limit values) using Stochastic Simulation and Estimation process to take into account the censoring. In this way, 1000 datasets were simulated under the design of a typical of tumor growth study in xenografted mice, and then, each method was used for parameter estimation on the simulated datasets. Relative bias and relative root mean square error (relative RMSE) were consequently computed for comparison purpose. By not considering the censoring, parameter estimations appeared to be biased and particularly the cytotoxic effect parameter, k 2 , which is the parameter of interest to characterize the efficacy of a compound in oncology. The best performance was noted with the interval-M3 method which properly takes into account the interval censoring induced by caliper measurement, giving overall unbiased estimations for all parameters and especially for the antitumor effect parameter (relative bias = 0.49%, and relative RMSE = 4.06%).

KEYWORDS:

below quantification limit; interval censoring; interval-M3 method; simultaneous modeling continuous and categorical data; xenograft model

PMID:
26757730
PMCID:
PMC4779108
DOI:
10.1208/s12248-015-9862-1
[Indexed for MEDLINE]
Free PMC Article

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