scholarly journals Physiologically Based Pharmacokinetic Modeling in Risk Assessment: Case Study With Pyrethroids

2020 ◽  
Vol 176 (2) ◽  
pp. 460-469
Author(s):  
Pankajini Mallick ◽  
Gina Song ◽  
Alina Y Efremenko ◽  
Salil N Pendse ◽  
Moire R Creek ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Life Stage ◽  
Internal Exposure ◽  
Target Tissue ◽  
Important Conclusion ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Physiologically Based ◽  
Age Dependent

Abstract The assessment of potentially sensitive populations is an important application of risk assessment. To address the concern for age-related sensitivity to pyrethroid insecticides, life-stage physiologically based pharmacokinetic (PBPK) modeling supported by in vitro to in vivo extrapolation was conducted to predict age-dependent changes in target tissue exposure to 8 pyrethroids. The purpose of this age-dependent dosimetry was to calculate a Data-derived Extrapolation Factor (DDEF) to address age-related pharmacokinetic differences for pyrethroids in humans. We developed a generic human PBPK model for pyrethroids based on our previously published rat model that was developed with in vivo rat data. The results demonstrated that the age-related differences in internal exposure to pyrethroids in the brain are largely determined by the differences in metabolic capacity and in physiology for pyrethroids between children and adults. The most important conclusion from our research is that, given an identical external exposure, the internal (target tissue) concentration is equal or lower in children than in adults in response to the same level of exposure to a pyrethroid. Our results show that, based on the use of the life-stage PBPK models with 8 pyrethroids, DDEF values are essentially close to 1, resulting in a DDEF for age-related pharmacokinetic differences of 1. For risk assessment purposes, this indicates that no additional adjustment factor is necessary to account for age-related pharmacokinetic differences for these pyrethroids.

scholarly journals Development and Application of a Life-Stage Physiologically Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans

2019 ◽  
Vol 173 (1) ◽  
pp. 86-99 ◽  
Author(s):  
Pankajini Mallick ◽  
Marjory Moreau ◽  
Gina Song ◽  
Alina Y Efremenko ◽  
Salil N Pendse ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pbpk Model ◽  
Life Stage ◽  
Internal Exposure ◽  
Target Tissue ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Physiologically Based

Abstract To address concerns around age-related sensitivity to pyrethroids, a life-stage physiologically based pharmacokinetic (PBPK) model, supported by in vitro to in vivo extrapolation (IVIVE) was developed. The model was used to predict age-dependent changes in target tissue exposure of 8 pyrethroids; deltamethrin (DLM), cis-permethrin (CPM), trans-permethrin, esfenvalerate, cyphenothrin, cyhalothrin, cyfluthrin, and bifenthrin. A single model structure was used based on previous work in the rat. Intrinsic clearance (CLint) of each individual cytochrome P450 or carboxylesterase (CES) enzyme that are active for a given pyrethroid were measured in vitro, then biologically scaled to obtain in vivo age-specific total hepatic CLint. These IVIVE results indicate that, except for bifenthrin, CES enzymes are largely responsible for human hepatic metabolism (>50% contribution). Given the high efficiency and rapid maturation of CESs, clearance of the pyrethroids is very efficient across ages, leading to a blood flow-limited metabolism. Together with age-specific physiological parameters, in particular liver blood flow, the efficient metabolic clearance of pyrethroids across ages results in comparable to or even lower internal exposure in the target tissue (brain) in children than that in adults in response to the same level of exposure to a given pyrethroid (Cmax ratio in brain between 1- and 25-year old = 0.69, 0.93, and 0.94 for DLM, bifenthrin, and CPM, respectively). Our study demonstrated that a life-stage PBPK modeling approach, coupled with IVIVE, provides a robust framework for evaluating age-related differences in pharmacokinetics and internal target tissue exposure in humans for the pyrethroid class of chemicals.

MAPPING IN VITRO AND IN VIVO DERIVED CYP2C9 AND CYP2C19 ONTOGENY FUNCTIONS: A CRITICAL COMPARISON BETWEEN VARIOUS ONTOGENY MODELS

2015 ◽  
Vol 101 (1) ◽  
pp. e1.38-e1 ◽  
Author(s):  
Farzaneh Salem ◽  
Trevor Johnson ◽  
Amin Rostami-Hodjegan
Keyword(s):  
Literature Review ◽  
Microsomal Protein ◽  
Critical Comparison ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Physiologically Based ◽  
Age Range ◽  
Best Fit

In vivo derived ontogeny profiles for CYP1A2 and CYP3A4, show improved clearance (CL) predictions within a paediatric physiologically based pharmacokinetic (p-PBPK) model1. The aim of this study is to derive ontogeny functions (OF) for CYP2C9 and CYP2C19 based on age related CL data on ibuprofen and pantoprazole & lansoprazole, respectively.A literature review was undertaken to collect age related CL data for these probes, the values were deconvoluted back to intrinsic CL values (per mg of liver microsomal protein) as described previously. The 'best-fit' algorithm for ratio of paediatric to mean adult intrinsic CL with age was determined in Graphpad Prism5 to obtain in vivo OF for CYP2C9 and CYP2C19. These were compared for performance with previously established ‘in vitro' OF in Simcyp Paediatric simulator (v14) using validation datasets.CYP2C9 and CYP2C19 enzyme activities showed an increase with age to values higher than adults by ages 2 and 1 month respectively, maximum values were reached at 1.5 years and 6 months, respectively before declining to typical adult levels by around 25 years.The CYP2C9 in vivo derived OF led to improved predictions of diclofenac and S-Warfarin CL compared to in vitro derived OF across the age range. For CYP2C19 there is a dearth of suitable validation compounds due to lack of clinical data with a possibility of using omeprazole or voriconazole. The reasons for discrepancy between in vitro and in vivo derived OF require further investigation.

scholarly journals Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 813
Author(s):  
Yoo-Seong Jeong ◽  
Min-Soo Kim ◽  
Nora Lee ◽  
Areum Lee ◽  
Yoon-Jee Chae ◽  
...  
Keyword(s):  
Gastric Acid ◽  
Pbpk Model ◽  
Pbpk Modeling ◽  
Drug Candidate ◽  
Metabolite Formation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

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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