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Toxicol Sci. 2018 Sep 1;165(1):50-60. doi: 10.1093/toxsci/kfy122.

Time-to-Event Modeling of Left- or Right-Censored Toxicity Data in Nonclinical Drug Toxicology.

Author information

1
Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, London, UK.
2
UMR 5558 Laboratoire Biométrie et de Biologie Evolutive, Equipe EMET, Université Claude Bernard Lyon1; Service de Pharmacologie Clinique et Essais Thérapeutiques, Hospices Civils de Lyon, Lyon, France.

Abstract

A time-to-event (TTE) model has been developed to characterize a histopathology toxicity that can only be detected at the time of animal sacrifice. The model of choice was a hazard model with a Weibull distribution and dose was a significant covariate. The diagnostic plots showed a satisfactory fit of the data, despite the high degree of left and right censoring. Comparison to a probabilistic logit model shows similar performance in describing the data with a slight underestimation of survival by the Logit model. However, the TTE model was found to be more predictive in extrapolating toxicity risk beyond the observation range of a truncated dataset. The diagnostic and comparison outcomes would suggest using the TTE approach as a first choice for characterizing short and long-term risk from nonclinical toxicity studies. However, further investigations are needed to explore the domain of application of this kind of approach in drug safety assessment.

PMID:
29788384
DOI:
10.1093/toxsci/kfy122

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