| The cynomolgus monkey as a model for developmental toxicity studies: variability of pregnancy losses, statistical power estimates, and group size considerations. | |
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MedLine Citation:
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PMID: 20544806 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: This work evaluates pregnancy and infant loss in 1,069 vehicle-treated cynomolgus monkeys from 78 embryo-fetal development (EFD) studies and 14 pre-postnatal development (PPND) studies accrued during 1981-2007. METHODS: Losses were analysed by survival function and hazard ratio using logistic regression for influence of year, study type (e.g., dose duration), and test item route of administration (ig, im, iv, sc). RESULTS: Neither study type nor route of dosing affected pregnancy outcome. Losses were higher pre-1990 (104 losses/347 pregnancies) compared to 1990 onwards (94 losses/722 pregnancies). Losses were greatest before gestation day 50 and at parturition. Using post-1989 data, Monte-Carlo simulations of pregnancy outcomes were created. The power associated with the comparison of vehicle survival curves and simulated adverse survival curves was examined. This showed that EFD studies with initial vehicle group sizes of 16 and 20 have an 80% probability of having 13 and 16 ongoing pregnancies at gestational day 100, respectively. For PPND studies with initial vehicle group sizes of 16, 20, or 28, there is an 80% likelihood of having 9, 11, or 16 infants at day 7 post-partum, respectively. A PPND study initiated with group size 20 could detect a threefold increase of test item-related pregnancy or infant loss. CONCLUSIONS: For designing and managing primate developmental toxicity studies, this type of analysis provides an objective tool to facilitate decisions either by supplementing groups with additional pregnant animals or stopping a group because an adverse effect on offspring survival has already been adequately revealed. |
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Authors:
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Philip Jarvis; Shiela Srivastav; Elvira Vogelwedde; Jane Stewart; Terri Mitchard; Gerhard F Weinbauer |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Birth defects research. Part B, Developmental and reproductive toxicology Volume: 89 ISSN: 1542-9741 ISO Abbreviation: Birth Defects Res. B Dev. Reprod. Toxicol. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-21 Completed Date: 2010-09-20 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101155115 Medline TA: Birth Defects Res B Dev Reprod Toxicol Country: United States |
Other Details:
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Languages: eng Pagination: 175-87 Citation Subset: IM |
Affiliation:
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AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, United Kingdom. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Animals, Newborn Computer Simulation Embryo Loss / chemically induced* Embryonic Development* Female Kaplan-Meiers Estimate Macaca fascicularis / embryology* Models, Animal* Models, Statistical* Monte Carlo Method Postpartum Period Pregnancy Pregnancy Outcome Proportional Hazards Models Toxicity Tests* |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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