scholarly journals Internal Threshold of Toxicological Concern (iTTC): Where We Are Today and What Is Possible in the Near Future

2021 ◽  
Vol 2 ◽  
Author(s):  
Corie A. Ellison ◽  
Anne Marie Api ◽  
Richard A. Becker ◽  
Alina Y. Efremenko ◽  
Sanket Gadhia ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Assessment Tool ◽  
Plasma Concentrations ◽  
Hepatic Metabolism ◽  
Internal Exposure ◽  
Pbpk Modeling ◽  
Pharmacokinetic Data ◽  
Stakeholder Collaboration ◽  
Threshold Of Toxicological Concern

The Threshold of Toxicological Concern (TTC) is a risk assessment tool for evaluating low-level exposure to chemicals with limited toxicological data. A next step in the ongoing development of TTC is to extend this concept further so that it can be applied to internal exposures. This refinement of TTC based on plasma concentrations, referred to as internal TTC (iTTC), attempts to convert the chemical-specific external NOAELs (in mg/kg/day) in the TTC database to an estimated internal exposure. A multi-stakeholder collaboration formed, with the aim of establishing an iTTC suitable for human safety risk assessment. Here, we discuss the advances and future directions for the iTTC project, including: (1) results from the systematic literature search for metabolism and pharmacokinetic data for the 1,251 chemicals in the iTTC database; (2) selection of ~350 chemicals that will be included in the final iTTC; (3) an overview of the in vitro caco-2 and in vitro hepatic metabolism studies currently being generated for the iTTC chemicals; (4) demonstrate how PBPK modeling is being utilized to convert a chemical-specific external NOAEL to an internal exposure; (5) perspective on the next steps in the iTTC project.

scholarly journals Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Luigi Margiotta-Casaluci ◽  
Stewart F. Owen ◽  
Belinda Huerta ◽  
Sara Rodríguez-Mozaz ◽  
Subramanian Kugathas ◽  
...  
Keyword(s):  
Predictive Power ◽  
Adverse Outcome ◽  
Plasma Concentrations ◽  
Internal Exposure ◽  
Adverse Outcome Pathway ◽  
Conceptual Tool ◽  
Fish Model ◽  
Species Specific

Abstract The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

scholarly journals Exploring Mechanistic Toxicity of Mixtures Using PBPK Modeling and Computational Systems Biology

2019 ◽  
Vol 174 (1) ◽  
pp. 38-50 ◽  
Author(s):  
Patricia Ruiz ◽  
Claude Emond ◽  
Eva D McLanahan ◽  
Shivanjali Joshi-Barr ◽  
Moiz Mumtaz
Keyword(s):  
Risk Assessment ◽  
Current Knowledge ◽  
Pbpk Modeling ◽  
Toxic Substances ◽  
Computational Systems Biology ◽  
Stream Data ◽  
Short And Long Term

Abstract Mixtures risk assessment needs an efficient integration of in vivo, in vitro, and in silico data with epidemiology and human studies data. This involves several approaches, some in current use and others under development. This work extends the Agency for Toxic Substances and Disease Registry physiologically based pharmacokinetic (PBPK) toolkit, available for risk assessors, to include a mixture PBPK model of benzene, toluene, ethylbenzene, and xylenes. The recoded model was evaluated and applied to exposure scenarios to evaluate the validity of dose additivity for mixtures. In the second part of this work, we studied toluene, ethylbenzene, and xylene (TEX)-gene-disease associations using Comparative Toxicogenomics Database, pathway analysis and published microarray data from human gene expression changes in blood samples after short- and long-term exposures. Collectively, this information was used to establish hypotheses on potential linkages between TEX exposures and human health. The results show that 236 genes expressed were common between the short- and long-term exposures. These genes could be central for the interconnecting biological pathways potentially stimulated by TEX exposure, likely related to respiratory and neuro diseases. Using publicly available data we propose a conceptual framework to study pathway perturbations leading to toxicity of chemical mixtures. This proposed methodology lends mechanistic insights of the toxicity of mixtures and when experimentally validated will allow data gaps filling for mixtures’ toxicity assessment. This work proposes an approach using current knowledge, available multiple stream data and applying computational methods to advance mixtures risk assessment.

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

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
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.

scholarly journals Pharmacokinetic Interaction between Nevirapine and Nortriptyline in Rats: Inhibition of Nevirapine Metabolism by Nortriptyline

2014 ◽  
Vol 58 (12) ◽  
pp. 7041-7048 ◽  
Author(s):  
Iris Usach ◽  
Virginia Melis ◽  
Patricia Gandía ◽  
José-Esteban Peris
Keyword(s):  
Plasma Concentrations ◽  
Pharmacokinetic Interaction ◽  
Hepatic Metabolism ◽  
Transcriptase Inhibitor ◽  
Tricyclic Antidepressant ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Hepatic Microsomes

ABSTRACTOne of the most frequent comorbidities of HIV infection is depression, with a lifetime prevalence of 22 to 45%. Therefore, it was decided to study a potential pharmacokinetic interaction between the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) and the tricyclic antidepressant nortriptyline (NT). NVP and NT were administered to rats either orally, intraduodenally, or intravenously, and the changes in plasma levels and pharmacokinetic parameters were analyzed. Experiments with rat and human hepatic microsomes were carried out to evaluate the inhibitory effects of NT on NVP metabolism. NVP plasma concentrations were significantly higher when this drug was coadministered with NT. The maximum plasma concentrations of NVP were increased 2 to 5 times and the total plasma clearance was decreased 7-fold in the presence of NT. However, statistically significant differences in the pharmacokinetic parameters of NT in the absence and presence of NVP were not found.In vitrostudies with rat and human hepatic microsomes confirmed the inhibition of NVP hepatic metabolism by NT in a concentration-dependent way, with the inhibition being more intense in the case of rat microsomes. In conclusion, a pharmacokinetic interaction between NVP and NT was detected. This interaction was a consequence of the inhibition of hepatic metabolism of NVP by NT.In vivohuman studies are required to evaluate the effects of this interaction on the pharmacokinetics of NVP before it can be taken into account for patients receiving NVP.

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

2002 ◽  
Vol 11 (3-4) ◽  
pp. 259-271 ◽  
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

scholarly journals Nitrones: not only extraordinary spin traps, but also good nitric oxide sources in vivo

2015 ◽  
Vol 65 (4) ◽  
pp. 413-426 ◽  
Author(s):  
Mircea Dumitru Croitoru ◽  
Hermina Iulia Petkes ◽  
Ibolya Fülöp ◽  
Remus Cotârlan ◽  
Oana Elena Şerban ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Spin Trap ◽  
Nitrate Concentration ◽  
Plasma Concentrations ◽  
Hepatic Metabolism ◽  
Nitric Oxide Production ◽  
Spin Traps ◽  
Oxide Production

Abstract Free radicals are involved in the development of reperfusion injuries. Using a spin trap, the intensity of such lesions can be reduced. Nitrones (effective in vivo spin traps) were tried in this work as in vivo nitric oxide donors. Nitrite and nitrate concentration values (rabbit blood) were used as biomarkers of nitric oxide production. Most nitrones did not increase plasma concentrations of nitrite and nitrate; on the contrary, reduced plasma concentrations of these indicators were noted. However, glyoxal isopropyldinitrone, in a dose of 50 mg kg-1, was highly effective in increasing nitric oxide production. At the same time, nitrones do not react with hepatic homogenates, proving that the release of nitric oxide takes place in the tissues and is not related to hepatic metabolism. Before using nitrones in vivo, they were tested in vitro for the ability to release nitric oxide following a reaction with the hydroxyl radical.

scholarly journals Optimization of Personalized Amlodipine Dosing Strategies for Children Based on Pharmacokinetic Data from Chinese Male Adults and PBPK Modeling

Children ◽  
2021 ◽  
Vol 8 (11) ◽  
pp. 950
Author(s):  
Xiaolu Han ◽  
Xiaoxuan Hong ◽  
Xianfu Li ◽  
Yuxi Wang ◽  
Zengming Wang ◽  
...  
Keyword(s):  
Pbpk Model ◽  
Plasma Concentrations ◽  
Pbpk Modeling ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Optimal Dosage ◽  
Continuous Administration ◽  
Dosing Strategies ◽  
Chinese Male ◽  
Enzyme Metabolism

For children, a special population who are continuously developing, a reasonable dosing strategy is the key to clinical therapy. Accurate dose predictions can help maximize efficacy and minimize pain in pediatrics. Methods: This study collected amlodipine pharmacokinetics (PK) data from 236 Chinese male adults and established a physiological pharmacokinetic (PBPK) model for adults using GastroPlus™. A PBPK model of pediatrics is constructed based on hepatic-to-body size and enzyme metabolism, used similar to the AUC0-∞ to deduce the optimal dosage of amlodipine for children aged 1–16 years. A curve of continuous administration for 2-, 6-, 12-, 16-, and 25-year-olds and a personalized administration program for 6-year-olds were developed. Results: The results show that children could not establish uniform allometric amplification rules. The optimal doses were 0.10 mg·kg−1 for ages 2–6 years and −0.0028 × Age + 0.1148 (mg/kg) for ages 7–16 years, r = 0.9941. The trend for continuous administration was consistent among different groups. In a 6-year-old child, a maintenance dose of 2.30 mg was used to increase the initial dose by 2.00 mg and the treatment dose by 1.00 mg to maintain stable plasma concentrations. Conclusions: A PBPK model based on enzyme metabolism can accurately predict the changes in the pharmacokinetic parameters of amlodipine in pediatrics. It can be used to support the optimization of clinical treatment plans in pediatrics.

scholarly journals Advancing Chemical Risk Assessment through Human Physiology-Based Biochemical Process Modeling

Fluids ◽  
2019 ◽  
Vol 4 (1) ◽  
pp. 4 ◽  
Author(s):  
Dimosthenis Sarigiannis ◽  
Spyros Karakitsios
Keyword(s):  
Risk Assessment ◽  
Effective Dose ◽  
High Throughput Screening ◽  
Chemical Space ◽  
Daily Intake ◽  
Adverse Outcomes ◽  
Internal Exposure ◽  
Biological Pathway ◽  
Exposure Levels

Physiology-Based BioKinetic (PBBK) models are of increasing interest in modern risk assessment, providing quantitative information regarding the absorption, metabolism, distribution, and excretion (ADME). They focus on the estimation of the effective dose at target sites, aiming at the identification of xenobiotic levels that are able to result in perturbations to the biological pathway that are potentially associated with adverse outcomes. The current study aims at the development of a lifetime PBBK model that covers a large chemical space, coupled with a framework for human biomonitoring (HBM) data assimilation. The methodology developed herein was demonstrated in the case of bisphenol A (BPA), where exposure analysis was based on European HBM data. Based on our calculations, it was found that current exposure levels in Europe are below the temporary Tolerable Daily Intake (t-TDI) of 4 μg/kg_bw/day proposed by the European Food Safety Authority (EFSA). Taking into account age-dependent bioavailability differences, internal exposure was estimated and compared with the biologically effective dose (BED) resulting from translating the EFSA temporary total daily intake (t-TDI) into equivalent internal dose and an alternative internal exposure reference value, namely biological pathway altering dose (BPAD); the use of such a refined exposure metric, showed that environmentally relevant exposure levels are below the concentrations associated with the activation of biological pathways relevant to toxicity based on High Throughput Screening (HTS) in vitro studies.

scholarly journals 1111. Therapeutic Drug Monitoring of Colistin in Cerebrospinal Fluid in the Treatment of Neurosurgical Meningitis caused by Pseudomonas aeruginosa and KPC-producing Enterobacterales

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S647-S647
Author(s):  
Mohamad Yasmin ◽  
Amir nutman ◽  
Steven Marshall ◽  
Lu Wang ◽  
Ke Chen ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
External Ventricular Drain ◽  
Plasma Concentrations ◽  
Cns Infection ◽  
Therapeutic Drug ◽  
Pharmacokinetic Data ◽  
Research Support ◽  
Cns Infections

Abstract Background Central nervous system (CNS) infections caused by carbapenem-resistant Enterobacterales (CRE) and Difficult-to-treat resistant (DTR)-P. aeruginosa (PA) present a therapeutic dilemma. Therapies are limited due to antibiotic resistance and inadequate CNS diffusion. Intraventricular polymyxins are utilized in this setting despite a lack in pharmacokinetic data after CNS injection. We describe the utilization of intravenous and intrathecal polymyxin E [colistimethate (CMS)] therapeutic drug monitoring (TDM) in 3 cases of post-neurosurgical meningitis. Methods Bacterial identification and susceptibility testing were performed using MicroScan. TDM was employed by dosing CMS at 125,000 IU (i.e., 4.1 mg CBA or 10 mg) administered via external ventricular drain twice daily and 4.5 MIU (133.2 CBA or 360 mg) CMS administered over 30 minutes IV twice daily. Four pairs of CSF and blood samples were collected for each patient (Table 1). Samples were placed on ice to minimize in-vitro conversion of CMS to Colistin. Colistin binding in plasma and CSF was measured using ultracentrifugation. Concentrations of CMS and Colistin in CSF and human plasma were determined by liquid chromatography/mass spectrometry. Patients A, B and C received 20, 15, and 12 doses of CMS, respectively, prior to TDM. Results Bacterial cultures revealed DTR PA, blaKPCE. cloacae and blaOXA-48K. pneumoniae for patients A, B and C, respectively. Colistin minimum inhibitory concentrations (MIC) were 0.5 µg/ml, 0.125 µg/ml, and 0.125 µg/ml, respectively. The measured CSF and plasma concentrations of CMS, Colistin, and binding are shown in Table 1. Clinical resolution and microbiological cure were attained in all patients. Therapeutic Drug Monitoring of Unchanged CMS and Formed Colistin in CSF samples for patient A, B, and C Therapeutic Drug Monitoring of Unchanged CMS and Formed Colistin in Plasma Samples for patient A, B, and C Conclusion Favorable concentrations of formed Colistin and CMS in CSF were achieved in 3 patients with complicated CNS infection. To the best of our knowledge, this is the first study to report the binding of Colistin in CSF in humans. A TDM method was effectively applied to demonstrate that Colistin achieves and maintains the PK/PD target (fAUC/MIC) [ratio of area under the plasma concentration curve of unbound drug to MIC] that best correlates with killing activity. Overall, our results support intraventricular polymyxins for treating DTR Gram-negative CNS infections. Disclosures Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support)

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