Physiologically Based Pharmacokinetic Model Use in Risk Assessment—Why Being Published Is Not Enough

McLanahan, Eva D.; El‐Masri, Hisham A.; Sweeney, Lisa; Kopylev, Leonid; Clewell, Harvey J.; Wambaugh, John F.; Schlosser, Paul M.

doi:10.1093/toxsci/kfr295

Cited by 61 publications

(39 citation statements)

References 42 publications

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“…It is considered good practice to assess the quality of a model against in vivo data that were not used in the model development process and in situations where one of the parameters is altered, such as in a DDI or an alternative genotype population (International Programme on Chemical Harmonization Project, 2010;McLanahan et al, 2012;Zhao et al, 2012b;Sinha et al, 2014;Jones et al, 2015). Our analysis revealed that the PK simulations of 97% of the models were compared with pharmacokinetics in independent study populations.…”

Section: Pbpk Modeling Articles By Year and Applicationmentioning

confidence: 99%

“…The data also suggest that there is a need for more rigorous evaluation of model quality assessment during peer review. The issue of the lack of strict peer-review requirements for published models has been discussed previously in the literature (McLanahan et al, 2012) but it has not been formally addressed by the larger research community. Based on the analysis of the PBPK models used to simulate drug absorption, more stringent criteria of model assessment were used in this field, likely adapted from bioequivalence standards.…”

Section: Data Sets Used In Model Verification Included: (A) Single Domentioning

confidence: 99%

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Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

Sager

Ragueneau‐Majlessi

et al. 2015

Drug Metabolism and Disposition

413

320

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Modeling and simulation of drug disposition has emerged as an important tool in drug development, clinical study design and regulatory review, and the number of physiologically based pharmacokinetic (PBPK) modeling related publications and regulatory submissions have risen dramatically in recent years. However, the extent of use of PBPK modeling by researchers, and the public availability of models has not been systematically evaluated. This review evaluates PBPK-related publications to 1) identify the common applications of PBPK modeling; 2) determine ways in which models are developed; 3) establish how model quality is assessed; and 4) provide a list of publically available PBPK models for sensitive P450 and transporter substrates as well as selective inhibitors and inducers. PubMed searches were conducted using the terms "PBPK" and "physiologically based pharmacokinetic model" to collect published models. Only papers on PBPK modeling of pharmaceutical agents in humans published in English between 2008 and May 2015 were reviewed. A total of 366 PBPK-related articles met the search criteria, with the number of articles published per year rising steadily. Published models were most commonly used for drug-drug interaction predictions (28%), followed by interindividual variability and general clinical pharmacokinetic predictions (23%), formulation or absorption modeling (12%), and predicting age-related changes in pharmacokinetics and disposition (10%). In total, 106 models of sensitive substrates, inhibitors, and inducers were identified. An in-depth analysis of the model development and verification revealed a lack of consistency in model development and quality assessment practices, demonstrating a need for development of best-practice guidelines.

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Section: Pbpk Modeling Articles By Year and Applicationmentioning

confidence: 99%

Section: Data Sets Used In Model Verification Included: (A) Single Domentioning

confidence: 99%

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

Sager

Ragueneau‐Majlessi

et al. 2015

Drug Metabolism and Disposition

413

320

View full text Add to dashboard Cite

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“…PBPK models can also be used to test the plausibility of different dose metrics, and thus the credibility of hypothesized MOAs. Recent guidance documents and reviews (IPCS, 2010; McLanahan et al, 2012; USEPA, 2006c) provide guidance on best practices for characterizing, evaluating, and applying PBPK models. Additional extrapolation to environmentally relevant doses can be addressed with PBPK modeling.…”

Section: Low-dose Extrapolation: Transition From Defaults To Mode Of mentioning

confidence: 99%

Advancing human health risk assessment: Integrating recent advisory committee recommendations

Dourson

Becker

Haber

et al. 2013

Critical Reviews in Toxicology

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Over the last dozen years, many national and international expert groups have considered specific improvements to risk assessment. Many of their stated recommendations are mutually supportive, but others appear conflicting, at least in an initial assessment. This review identifies areas of consensus and difference and recommends a practical, biology-centric course forward, which includes: (1) incorporating a clear problem formulation at the outset of the assessment with a level of complexity that is appropriate for informing the relevant risk management decision; (2) using toxicokinetics and toxicodynamic information to develop Chemical Specific Adjustment Factors (CSAF); (3) using mode of action (MOA) information and an understanding of the relevant biology as the key, central organizing principle for the risk assessment; (4) integrating MOA information into dose–response assessments using existing guidelines for non-cancer and cancer assessments; (5) using a tiered, iterative approach developed by the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) as a scientifically robust, fit-for-purpose approach for risk assessment of combined exposures (chemical mixtures); and (6) applying all of this knowledge to enable interpretation of human biomonitoring data in a risk context. While scientifically based defaults will remain important and useful when data on CSAF or MOA to refine an assessment are absent or insufficient, assessments should always strive to use these data. The use of available 21st century knowledge of biological processes, clinical findings, chemical interactions, and dose–response at the molecular, cellular, organ and organism levels will minimize the need for extrapolation and reliance on default approaches.

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“…In this regard, the International Program on Chemical Safety (IPCS) of the World Health Organization (WHO) has recently published guidelines for characterization and purpose-specific evaluation of PBPK models [7]. A detailed description of the PBPK model evaluation process for use in risk assessment is also described in a recent publication [8]. Accordingly, if the model is to be used for conducting interspecies extrapolation for the oral route based on a particular dose metric (e.g., AUC), then the evaluation should focus on the ability of the model to provide the relevant simulations, and not on generically “validating” the model for all possible applications.…”

Section: Best Practicesmentioning

confidence: 99%

Cutting Edge PBPK Models and Analyses: Providing the Basis for Future Modeling Efforts and Bridges to Emerging Toxicology Paradigms

Caldwell

Evans

Krishnan

2012

Journal of Toxicology

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Physiologically based Pharmacokinetic (PBPK) models are used for predictions of internal or target dose from environmental and pharmacologic chemical exposures. Their use in human risk assessment is dependent on the nature of databases (animal or human) used to develop and test them, and includes extrapolations across species, experimental paradigms, and determination of variability of response within human populations. Integration of state-of-the science PBPK modeling with emerging computational toxicology models is critical for extrapolation between in vitro exposures, in vivo physiologic exposure, whole organism responses, and long-term health outcomes. This special issue contains papers that can provide the basis for future modeling efforts and provide bridges to emerging toxicology paradigms. In this overview paper, we present an overview of the field and introduction for these papers that includes discussions of model development, best practices, risk-assessment applications of PBPK models, and limitations and bridges of modeling approaches for future applications. Specifically, issues addressed include: (a) increased understanding of human variability of pharmacokinetics and pharmacodynamics in the population, (b) exploration of mode of action hypotheses (MOA), (c) application of biological modeling in the risk assessment of individual chemicals and chemical mixtures, and (d) identification and discussion of uncertainties in the modeling process.

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Physiologically Based Pharmacokinetic Model Use in Risk Assessment—Why Being Published Is Not Enough

Cited by 61 publications

References 42 publications

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

Advancing human health risk assessment: Integrating recent advisory committee recommendations

Cutting Edge PBPK Models and Analyses: Providing the Basis for Future Modeling Efforts and Bridges to Emerging Toxicology Paradigms

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