Probabilistic human health risk assessment of perfluorooctane sulfonate (PFOS) by integrating in vitro, in vivo toxicity, and human epidemiological studies using a Bayesian-based dose-response assessment coupled with physiologically based pharmacokinetic (PBPK) modeling approach

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

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1315. No Dose Adjustment of Metformin with Fostemsavir Coadministration Based on Mechanistic Static and Physiologically Based Pharmacokinetic Models

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1497 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S669-S669

Author(s):

Dung N Nguyen ◽

Xiusheng Miao ◽

Mindy Magee ◽

Guoying Tai ◽

Peter D Gorycki ◽

...

Keyword(s):

Dose Adjustment ◽

Pbpk Model ◽

Systemic Exposure ◽

Multidrug Resistant ◽

Pbpk Modeling ◽

Repeat Dose ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based

Abstract Background Fostemsavir (FTR) is an oral prodrug of the first-in-class attachment inhibitor temsavir (TMR) which is being evaluated in patients with multidrug resistant HIV-1 infection. In vitro studies indicated that TMR and its 2 major metabolites are inhibitors of organic cation transporters (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs). To assess the clinical relevance, of OCT and MATE inhibition, mechanistic static DDI prediction with calculated Imax,u/IC50 ratios was below the cut-off limits for a DDI flag based on FDA guidelines and above the cut-off limits for MATEs based on EMA guidelines. Methods Metformin is a commonly used probe substrate for OCT1, OCT2 and MATEs. To predict the potential for a drug interaction between TMR and metformin, a physiologically based pharmacokinetic (PBPK) model for TMR was developed based on its physicochemical properties, in vitro and in vivo data. The model was verified and validated through comparison with clinical data. The TMR PBPK model accurately described AUC and Cmax within 30% of the observed data for single and repeat dose studies with or without food. The SimCYP models for metformin and ritonavir were qualified using literature data before applications of DDI prediction for TMR Results TMR was simulated at steady state concentrations after repeated oral doses of FTR 600 mg twice daily which allowed assessment of the potential OCT1, OCT2, and MATEs inhibition by TMR and metabolites. No significant increase in metformin systemic exposure (AUC or Cmax) was predicted with FTR co-administration. In addition, a sensitivity analysis was conducted for either hepatic OCT1 Ki, or renal OCT2 and MATEs Ki values. The model output indicated that, a 10-fold more potent Ki value for TMR would be required to have a ~15% increase in metformin exposure Conclusion Based on mechanistic static models and PBPK modeling and simulation, the OCT1/2 and MATEs inhibition potential of TMR and its metabolites on metformin pharmacokinetics is not clinically significant. No dose adjustment of metformin is necessary when co-administered with FTR Disclosures Xiusheng Miao, PhD, GlaxoSmithKline (Employee) Mindy Magee, Doctor of Pharmacy, GlaxoSmithKline (Employee, Shareholder) Peter D. Gorycki, BEChe, MSc, PhD, GSK (Employee, Shareholder) Katy P. Moore, PharmD, RPh, ViiV Healthcare (Employee)

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

Journal of Toxicology ◽

10.1155/2012/852384 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 17

Author(s):

Jane C. Caldwell ◽

Marina V. Evans ◽

Kannan Krishnan

Keyword(s):

Risk Assessment ◽

Model Development ◽

Pbpk Modeling ◽

Human Populations ◽

Pbpk Models ◽

Modeling Process ◽

Physiologically Based Pharmacokinetic ◽

State Of The Science

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 betweenin vitroexposures,in vivophysiologic 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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The use of in vitro metabolic parameters and physiologically based pharmacokinetic (PBPK) modeling to explore the risk assessment of trichloroethylene

Environmental Toxicology and Pharmacology ◽

10.1016/s1382-6689(02)00019-4 ◽

2002 ◽

Vol 11 (3-4) ◽

pp. 259-271 ◽

Cited By ~ 12

Author(s):

Erna M. Hissink ◽

Jan J.P. Bogaards ◽

Andreas P. Freidig ◽

Jan N.M. Commandeur ◽

Nico P.E. Vermeulen ◽

...

Keyword(s):

Risk Assessment ◽

Metabolic Parameters ◽

Pbpk Modeling ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based

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Physiologically Based Pharmacokinetic Modeling of Salivary Concentrations for Noninvasive Biomonitoring of 2,4-Dichlorophenoxyacetic Acid (2,4-D)

Toxicological Sciences ◽

10.1093/toxsci/kfz206 ◽

2019 ◽

Vol 172 (2) ◽

pp. 330-343

Author(s):

Alice A Han ◽

Charles Timchalk ◽

Zana A Carver ◽

Thomas J Weber ◽

Kimberly J Tyrrell ◽

...

Keyword(s):

Pbpk Model ◽

Pbpk Modeling ◽

Dichlorophenoxyacetic Acid ◽

Diffusion Limited ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based ◽

Dynamic Time ◽

2,4 Dichlorophenoxyacetic Acid

Abstract Saliva has become a favorable sample matrix for biomonitoring due to its noninvasive attributes and overall flexibility in collection. To ensure measured salivary concentrations reflect the exposure, a solid understanding of the salivary transport mechanism and relationships between salivary concentrations and other monitored matrices (ie, blood, urine) is needed. Salivary transport of a commonly applied herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), was observed in vitro and in vivo and a physiologically based pharmacokinetic (PBPK) model was developed to translate observations from the cell culture model to those in animal models and further evaluate 2,4-D kinetics in humans. Although apparent differences in experimental in vitro and in vivo saliva:plasma ratios (0.034 and 0.0079) were observed, simulations with the PBPK model demonstrated dynamic time and dose-dependent saliva:plasma ratios, elucidating key mechanisms affecting salivary transport. The model suggested that 2,4-D exhibited diffusion-limited transport to saliva and was additionally impacted by protein binding saturation and permeability across the salivary gland. Consideration of sampling times post-exposure and potential saturation of transport mechanisms are then critical aspects for interpreting salivary 2,4-D biomonitoring observations. This work utilized PBPK modeling in in vitro to in vivo translation to explore benefits and limitations of salivary analysis for occupational biomonitoring.

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Probabilistic risk assessment of gold nanoparticles after intravenous administration by integrating in vitro and in vivo toxicity with physiologically based pharmacokinetic modeling

Nanotoxicology ◽

10.1080/17435390.2018.1459922 ◽

2018 ◽

Vol 12 (5) ◽

pp. 453-469 ◽

Cited By ~ 11

Author(s):

Yi-Hsien Cheng ◽

Jim E. Riviere ◽

Nancy A. Monteiro-Riviere ◽

Zhoumeng Lin

Keyword(s):

Risk Assessment ◽

Gold Nanoparticles ◽

Intravenous Administration ◽

Pharmacokinetic Modeling ◽

Physiologically Based Pharmacokinetic Modeling ◽

In Vivo Toxicity ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based

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Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats

Pharmaceutics ◽

10.3390/pharmaceutics13030373 ◽

2021 ◽

Vol 13 (3) ◽

pp. 373

Author(s):

Yoo-Kyung Song ◽

Yun-Hwan Seol ◽

Min Ju Kim ◽

Jong-Woo Jeong ◽

Hae-In Choi ◽

...

Keyword(s):

Adipose Tissue ◽

Oral Administration ◽

Dose Range ◽

Pbpk Modeling ◽

Drug Candidate ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based ◽

Intravenous And Oral Administration

Supinoxin is a novel anticancer drug candidate targeting the Y593 phospho-p68 RNA helicase, by exhibiting antiproliferative activity and/or suppression of tumor growth. This study aimed to characterize the in vitro and in vivo pharmacokinetics of supinoxin and attempt physiologically based pharmacokinetic (PBPK) modeling in rats. Supinoxin has good permeability, comparable to that of metoprolol (high permeability compound) in Caco-2 cells, with negligible net absorptive or secretory transport observed. After an intravenous injection at a dose range of 0.5–5 mg/kg, the terminal half-life (i.e., 2.54–2.80 h), systemic clearance (i.e., 691–865 mL/h/kg), and steady state volume of distribution (i.e., 2040–3500 mL/kg) of supinoxin remained unchanged, suggesting dose-independent (i.e., dose-proportional) pharmacokinetics for the dose ranges studied. After oral administration, supinoxin showed modest absorption with an absolute oral bioavailability of 56.9–57.4%. The fecal recovery following intravenous and oral administration was 16.5% and 46.8%, respectively, whereas the urinary recoveries in both administration routes were negligible. Supinoxin was mainly eliminated via NADPH-dependent phase I metabolism (i.e., 58.5% of total clearance), while UDPGA-dependent phase II metabolism appeared negligible in the rat liver microsome. Supinoxin was most abundantly distributed in the adipose tissue, gut, and liver among the nine major tissues studied (i.e., the brain, liver, kidneys, heart, lungs, spleen, gut, muscles, and adipose tissue), and the tissue exposure profiles of supinoxin were well predicted with physiologically based pharmacokinetics.

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