Methodological approaches to the population analysis of toxicity data

Citation
L. Aarons et G. Graham, Methodological approaches to the population analysis of toxicity data, TOX LETT, 120(1-3), 2001, pp. 405-410
Citations number
9
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
TOXICOLOGY LETTERS
ISSN journal
0378-4274 → ACNP
Volume
120
Issue
1-3
Year of publication
2001
Pages
405 - 410
Database
ISI
SICI code
0378-4274(20010331)120:1-3<405:MATTPA>2.0.ZU;2-5
Abstract
Toxicokinetics is the assessment of systemic exposure in toxicity studies, in which pharmacokinetic data are generated, either as an integral componen t in the conduct of the nonclinical toxicity studies or in specially design ed supportive studies, in order to assess systemic exposure. The data may b e used in the interpretation of toxicity findings and contribute to the ass essment of the relevance of these findings to clinical safety. Data may be obtained from all animals in a toxicity study, in representative subgroups, in satellite groups or in separate studies. Applying a mixed effects model ling approach in toxicokinetics offers many advantages over the current app roach of having satellite groups. Sparse samples for measuring drug/metabol ite concentration are collected in all main animals in the majority of stud ies where toxicological findings al e obtained. Such sampling is unlikely t o distress the animals, disturb the conduct of a toxicological study or aff ect the outcome of the study. Many of the outcome measures in toxicological studies are categorical in nature. For example, lesions may be scored on a one to four scale. from none to severe. The analysis of such data is usual ly carried out using a general mixed modelling approach. We have implemente d such models in a nonlinear mixed effects modelling framework which allows us to relate pharmacokinetic response to outcome. A case study is used to illustrate the principles of general mixed effects modelling in toxicokinet ics. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.