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DOI10.1007/s10928-015-9424-2
Identifiability of PBPK models with applications to dimethylarsinic acid exposure
Garcia, Ramon I.1; Ibrahim, Joseph G.1; Wambaugh, John F.3; Kenyon, Elaina M.2; Setzer, R. Woodrow3
发表日期2015-12-01
ISSN1567-567X
卷号42期号:6页码:591-609
英文摘要

Any statistical model should be identifiable in order for estimates and tests using it to be meaningful. We consider statistical analysis of physiologically-based pharmacokinetic (PBPK) models in which parameters cannot be estimated precisely from available data, and discuss different types of identifiability that occur in PBPK models and give reasons why they occur. We particularly focus on how the mathematical structure of a PBPK model and lack of appropriate data can lead to statistical models in which it is impossible to estimate at least some parameters precisely. Methods are reviewed which can determine whether a purely linear PBPK model is globally identifiable. We propose a theorem which determines when identifiability at a set of finite and specific values of the mathematical PBPK model (global discete identifiability) implies identifiability of the statistical model. However, we are unable to establish conditions that imply global discrete identifiability, and conclude that the only safe approach to analysis of PBPK models involves Bayesian analysis with truncated priors. Finally, computational issues regarding posterior simulations of PBPK models are discussed. The methodology is very general and can be applied to numerous PBPK models which can be expressed as linear time-invariant systems. A real data set of a PBPK model for exposure to dimethyl arsinic acid (DMA(V)) is presented to illustrate the proposed methodology.


英文关键词PBPK Models;Identifiability;Gibbs sampling;Metropolis-Hasting algorithm;Dimethyl arsinic acid
语种英语
WOS记录号WOS:000363982800001
来源期刊JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
来源机构美国环保署
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/58744
作者单位1.Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA;
2.US EPA, Natl Hlth & Environm Effects Lab, Res Triangle Pk, NC 27711 USA;
3.US EPA, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA
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GB/T 7714
Garcia, Ramon I.,Ibrahim, Joseph G.,Wambaugh, John F.,et al. Identifiability of PBPK models with applications to dimethylarsinic acid exposure[J]. 美国环保署,2015,42(6):591-609.
APA Garcia, Ramon I.,Ibrahim, Joseph G.,Wambaugh, John F.,Kenyon, Elaina M.,&Setzer, R. Woodrow.(2015).Identifiability of PBPK models with applications to dimethylarsinic acid exposure.JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS,42(6),591-609.
MLA Garcia, Ramon I.,et al."Identifiability of PBPK models with applications to dimethylarsinic acid exposure".JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS 42.6(2015):591-609.
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