scholarly journals Physiologically Based Pharmacokinetic Modelling for Nicotine and Cotinine Clearance in Pregnant Women

2021 ◽  
Vol 12 ◽  
Author(s):  
Basile Amice ◽  
Harvey Ho ◽  
En Zhang ◽  
Chris Bullen
Keyword(s):  
Pregnant Women ◽  
Pbpk Model ◽  
Research Report ◽  
Pharmacokinetic Parameters ◽  
Nicotine Concentration ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Fetal Organs ◽  
Temporal Profiles

Introduction: Physiologically based pharmacokinetic (PBPK) models for the absorption, disposition, metabolism and excretion (ADME) of nicotine and its major metabolite cotinine in pregnant women (p-PBPK) are rare. The aim of this short research report is to present a p-PBPK model and its simulations for nicotine and cotinine clearance.Methods: The maternal-placental-fetal compartments of the p-PBPK model contain a total of 16 compartments representing major maternal and fetal organs and tissue groups. Qualitative and quantitative data of nicotine and cotinine disposition and clearance have been incorporated into pharmacokinetic parameters.Results: The p-PBPK model reproduced the higher clearance rates of nicotine and cotinine in pregnant women than non-pregnant women. Temporal profiles for their disposition in organs such as the brain were also simulated. Nicotine concentration reaches its maximum value within 2 min after an intravenous injection.Conclusion: The proposed p-PBPK model produces results consistent with available data sources. Further pharmacokinetic experiments are required to calibrate clearance parameters for individual organs, and for the fetus.

scholarly journals Application of physiologically based pharmacokinetic modeling for sertraline dosing recommendations in pregnancy

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Blessy George ◽  
Annie Lumen ◽  
Christine Nguyen ◽  
Barbara Wesley ◽  
Jian Wang ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Gestational Age ◽  
Drug Exposure ◽  
Pbpk Model ◽  
Pbpk Modeling ◽  
Quantitative Prediction ◽  
Pharmacokinetic Parameters ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
In Pregnancy

Abstract Pregnancy is a period of significant change that impacts physiological and metabolic status leading to alterations in the disposition of drugs. Uncertainty in drug dosing in pregnancy can lead to suboptimal therapy, which can contribute to disease exacerbation. A few studies show there are increased dosing requirements for antidepressants in late pregnancy; however, the quantitative data to guide dose adjustments are sparse. We aimed to develop a physiologically based pharmacokinetic (PBPK) model that allows gestational-age dependent prediction of sertraline dosing in pregnancy. A minimal physiological model with defined gut, liver, plasma, and lumped placental-fetal compartments was constructed using the ordinary differential equation solver package, ‘mrgsolve’, in R. We extracted data from the literature to parameterize the model, including sertraline physicochemical properties, in vitro metabolism studies, disposition in nonpregnant women, and physiological changes during pregnancy. The model predicted the pharmacokinetic parameters from a clinical study with eight subjects for the second trimester and six subjects for the third trimester. Based on the model, gestational-dependent changes in physiology and metabolism account for increased clearance of sertraline (up to 143% at 40 weeks gestational age), potentially leading to under-dosing of pregnant women when nonpregnancy doses are used. The PBPK model was converted to a prototype web-based interactive dosing tool to demonstrate how the output of a PBPK model may translate into optimal sertraline dosing in pregnancy. Quantitative prediction of drug exposure using PBPK modeling in pregnancy will support clinically appropriate dosing and increase the therapeutic benefit for pregnant women.

scholarly journals P01 Application of feto-placental-maternal physiologically-based pharmacokinetic model to predict tenofovir concentration during pregnancy

2019 ◽  
Vol 104 (6) ◽  
pp. e17.2-e18
Author(s):  
K Abduljalil ◽  
TN Johnson ◽  
M Jamei
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Drug Exposure ◽  
Pbpk Model ◽  
Model Parameters ◽  
List Type ◽  
Large Variability ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Fetal Organs

BackgroundTenofovir is a drug used in combination with other anti-HIV drugs to treat patients with HIV-1 infection. It is used during pregnancy to reduce the risk of HIV transmission to the child. The aim of this work is to use a Physiologically-Based Pharmacokinetic (PBPK) model for prediction of maternal and fetal tenofovir concentration at birth.MethodsA full Feto-Placental-Maternal PBPK model that includes placenta as a 3-comparment permeability limited organ and 14 compartments for different fetal organs was developed using physiological1,2 and drug specific parameters3 to predict tenofovir concentration in 50 virtual pregnant mothers at term after single administration of 600 mg of tenofovir disoproxil fumarate (272 mg tenofovir). The mechanistic model implemented using the Simcyp Lua interface within the Simcyp Simulator. Fetal as well as maternal tissue to plasma ratio values were predicted using the Rodgers & Rowland method with a scalar of 1.5. Predictions of tenofovir maternal and fetal plasma concentration were compared to reported observations.4ResultsIn spite of the large variability in the observed data, the model adequately replicated the maternal as well as fetal clinical observations.4 The placenta transfer by cotyledon was changed 10 times the mean reported value from perfusion experiment.5 All other model parameters were calculated using bottom-up approach.The maternal predicted-to-observed ratio for AUC24hr and Cmax was 1.13 and 1.08, respectively. The predicted fetal exposure was well predicted within the 5th and 95th percentiles and was 0.51 of maternal exposure (AUC24h), the reported value is 0.60.4ConclusionThe developed feto-placental-maternal PBPK models can be used to predict drug exposure in fetal organs during in utero growth. The inter-subject variability can be predicted incorporating both the drug physicochemical properties and system (placental, maternal and fetal) parameters.ReferencesAbduljalil, et al. Clin Pharmacokinet 2018;57(9):1149–1171.Abduljalil, et al. Clin Pharmacokinet 2019;58:235–262Gilead Sciences, Inc. Product Information: tenofovir disoproxil fumarate (VIREAD) tablets.Hirt D, et al., Clin Pharmacol Ther 2009; 85: 182–9.De Sousa Mendes, et al., Br J Clin Pharmacol 2016;81(4):646–57.Disclosure(s)Nothing to disclose

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.

scholarly journals A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
H. Siebinga ◽  
B. J. de Wit-van der Veen ◽  
J. H. Beijnen ◽  
M. P. M. Stokkel ◽  
T. P. C. Dorlo ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Pbpk Model ◽  
Somatostatin Receptor ◽  
Monte Carlo Algorithm ◽  
Whole Body ◽  
Organ Distribution ◽  
Specific Information ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Abstract Background Physiologically based pharmacokinetic (PBPK) models combine drug-specific information with prior knowledge on the physiology and biology at the organism level. Whole-body PBPK models contain an explicit representation of the organs and tissue and are a tool to predict pharmacokinetic behavior of drugs. The aim of this study was to develop a PBPK model to describe organ distribution of 68Ga-DOTATATE in a population of patients without detectable neuroendocrine tumors (NETs). Methods Clinical 68Ga-DOTATATE PET/CT data from 41 patients without any detectable somatostatin receptor (SSTR) overexpressing tumors were included. Scans were performed at 45 min (range 30–60 min) after intravenous bolus injection of 68Ga-DOTATATE. Organ (spleen, liver, thyroid) and blood activity levels were derived from PET scans, and corresponding DOTATATE concentrations were calculated. A whole-body PBPK model was developed, including an internalization reaction, receptor recycling, enzymatic reaction for intracellular degradation and renal clearance. SSTR2 expression was added for several organs. Input parameters were fixed or estimated using a built-in Monte Carlo algorithm for parameter identification. Results 68Ga-DOTATATE was administered with a median peptide amount of 12.3 µg (range 8.05–16.9 µg) labeled with 92.7 MBq (range 43.4–129.9 MBq). SSTR2 amounts for spleen, liver and thyroid were estimated at 4.40, 7.80 and 0.0108 nmol, respectively. Variability in observed organ concentrations was best described by variability in SSTR2 expression and differences in administered peptide amounts. Conclusions To conclude, biodistribution of 68Ga-DOTATATE was described with a whole-body PBPK model, where tissue distribution was mainly determined by variability in SSTR2 organ expression and differences in administered peptide amounts.

scholarly journals O05 Physiologically based pharmacokinetic modelling to characterize acetaminophen pharmacokinetics and NAPQI formation in non-pregnant and pregnant women

2019 ◽  
Vol 104 (6) ◽  
pp. e2.2-e3
Author(s):  
P Mian ◽  
JN van den Anker ◽  
K van Calsteren ◽  
P Annaert ◽  
D Tibboel ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Goodness Of Fit ◽  
First Trimester ◽  
Third Trimester ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Lack Of Information ◽  
Physiologically Based ◽  
Dose Fraction

BackgroundLittle is known about the pharmacokinetics (PK) of acetaminophen during different stages of pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen PK throughout pregnancy.MethodsPBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen PK were considered. The models were evaluated using goodness-of-fit-plots and through comparison of predicted PK profiles with in-vivo PK data. Predictions were performed to illustrate the concentrations at steady state (Css-mean), used as indicator for efficacy of acetaminophen achieved following 1000 mg q6h. Furthermore, as measurement for potential hepatotoxicity, the molar dose fraction of acetaminophen converted to NAPQI was estimated.ResultsPBPK models successfully predicted the PK of acetaminophen and its metabolites in populations of non-pregnant and pregnant women. Predictions resulted in lowest Css-mean in the third trimester (4.5 mg/L), while Css-mean was 6.7, 5.6 and 4.9 mg/L in non-pregnant, first and second trimester populations, respectively. Assuming a constant increased activity of CYP2E1 throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first (11.0%), followed by second (9.0%) and third trimester (8.2%), compared to non-pregnant women (7.1%).ConclusionRisk for drug related hepatotoxicity in pregnant women might be increased as more NAPQI is produced during pregnancy compared to non-pregnant women, especially during the first trimester. However, lack of information on the detoxifying capacity precludes any strong conclusions.Disclosure(s)Paola Mian received a Short term Minor (STM-2017) grant from the Stichting Sophia Kinderziekenhuis fonds to conduct this research.

scholarly journals A Physiologically Based Pharmacokinetic Model for Naphthalene With Inhalation and Skin Routes of Exposure

2020 ◽  
Vol 177 (2) ◽  
pp. 377-391
Author(s):  
Dustin F Kapraun ◽  
Paul M Schlosser ◽  
Leena A Nylander-French ◽  
David Kim ◽  
Erin E Yost ◽  
...  
Keyword(s):  
Pbpk Model ◽  
Human Health Risk ◽  
Blood Concentrations ◽  
Exposure Study ◽  
Skin Exposure ◽  
Human Data ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Abstract Naphthalene, a volatile organic compound present in moth repellants and petroleum-based fuels, has been shown to induce toxicity in mice and rats during chronic inhalation exposures. Although simpler default methods exist for extrapolating toxicity points of departure from animals to humans, using a physiologically based pharmacokinetic (PBPK) model to perform such extrapolations is generally preferred. Confidence in PBPK models increases when they have been validated using both animal and human in vivo pharmacokinetic (PK) data. A published inhalation PBPK model for naphthalene was previously shown to predict rodent PK data well, so we sought to evaluate this model using human PK data. The most reliable human data available come from a controlled skin exposure study, but the inhalation PBPK model does not include a skin exposure route; therefore, we extended the model by incorporating compartments representing the stratum corneum and the viable epidermis and parameters that determine absorption and rate of transport through the skin. The human data revealed measurable blood concentrations of naphthalene present in the subjects prior to skin exposure, so we also introduced a continuous dose-rate parameter to account for these baseline blood concentration levels. We calibrated the three new parameters in the modified PBPK model using data from the controlled skin exposure study but did not modify values for any other parameters. Model predictions then fell within a factor of 2 of most (96%) of the human PK observations, demonstrating that this model can accurately predict internal doses of naphthalene and is thus a viable tool for use in human health risk assessment.

scholarly journals Physiologically Based Pharmacokinetic Modeling of Cefadroxil in Mouse, Rat, and Human to Predict Concentration–Time Profile at Infected Tissue

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhongxia Tan ◽  
Youxi Zhang ◽  
Chao Wang ◽  
Le Sun
Keyword(s):  
Plasma Concentration ◽  
Pbpk Model ◽  
Oral Absorption ◽  
Time Profile ◽  
Infected Tissue ◽  
Dose Selection ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based

The aim of this study was to develop physiologically based pharmacokinetic (PBPK) models capable of simulating cefadroxil concentrations in plasma and tissues in mouse, rat, and human. PBPK models in this study consisted of 14 tissues and 2 blood compartments. They were established using measured tissue to plasma partition coefficient (Kp) in mouse and rat, absolute expression levels of hPEPT1 along the entire length of the human intestine, and the transporter kinetic parameters. The PBPK models also assumed that all the tissues were well-stirred compartments with perfusion rate limitations, and the ratio of the concentration in tissue to the unbound concentration in plasma is identical across species. These PBPK models were validated strictly by a series of observed plasma concentration–time profile data. The average fold error (AFE) and absolute average fold error (AAFE) values were all less than 2. The models’ rationality and accuracy were further demonstrated by the almost consistent Vss calculated by the PBPK model and noncompartmental method, as well as the good allometric scaling relationship of Vss and CL. The model suggests that hPEPT1 is the major transporter responsible for the oral absorption of cefadroxil in human, and the plasma concentration–time profiles of cefadroxil were not sensitive to dissolution rate faster than T85% = 2 h. The cefadroxil PBPK model in human is reliable and can be used to predict concentration–time profile at infected tissue. It may be useful for dose selection and informative decision-making during clinical trials and dosage form design of cefadroxil and provide a reference for the PBPK model establishment of hPEPT1 substrate.

scholarly journals A computational investigation of the ventilation structure and maximum rate of metabolism for a physiologically based pharmacokinetic (PBPK) model of inhaled xylene

BIOMATH ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 1901067
Author(s):  
Karen A Yokley ◽  
Jaclyn Ashcraft ◽  
Nicholas S Luke
Keyword(s):  
Inverse Problems ◽  
Blood Concentration ◽  
Maximum Rate ◽  
Pbpk Model ◽  
Simulated Data ◽  
Parameter Estimates ◽  
Computational Investigation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Physiologically based pharmacokinetic (PBPK) models are systems of ordinary differential equations that estimate internal doses following exposure to toxicants. Most PBPK models use standard equations to describe inhalation and concentrations in blood. This study extends previous work investigating the effect of the structure of air and blood concentration equations on PBPK predictions. The current study uses an existing PBPK model of xylene to investigate if different values for the maximum rate of toxicant metabolism can result in similar compartmental predictions when used with different equations describing inhalation. Simulations are performed using values based on existing literature. Simulated data is also used to determine specific values that result in similar predictions from different ventilation structures. Differences in ventilation equation structure may affect parameter estimates found through inverse problems, although further investigation is needed with more complicated models.

Development of a Physiologically-Based Pharmacokinetic (PBPK) Model of Nebulized Hydroxychloroquine for Pulmonary Delivery to COVID-19 Patients

Drug Research ◽  
2020 ◽  
Author(s):  
Nasir Idkaidek ◽  
Feras Hawari ◽  
Yasmeen Dodin ◽  
Nour Obeidat
Keyword(s):  
Plasma Levels ◽  
Pbpk Model ◽  
Model Building ◽  
Drug Disposition ◽  
Virus Disease ◽  
Pulmonary Delivery ◽  
Pharmacokinetic Parameters ◽  
Alveolar Cells ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

AbstractDespite inconclusive evidence, chloroquine (CQ) and hydroxychloroquine (HCQ)are commonly used for the treatment of Corona virus Disease 2019(COVID-19) in critically ill patients.It was hypothesized that HCQ as an aerosol application can reach the antiviral concentration of ~1–5 μM in the alveolar cells which has been proven effective in vitro. A physiologically-based pharmacokinetic (PBPK) model of nebulized HCQ for pulmonary delivery to COVID-19 patients using the Nasal-Pulmonary Module in GastroPlus® V9.7 simulator, in order to calculate the necessary inhalation dose regimen of HCQ, was developed. The physiological, drug disposition, and pharmacokinetic parameters were obtained from the literature and used during model building after optimization using Optimization Module, while oral data was used for validation. The 25 mg BID inhalation dosing was predicted to lead to alveolar HCQ levels of 7 µM (above EC50 of ~1–5 µM), and small plasma levels of 0.18 µM (as compared to plasma levels of 3.22 µM after 200 mg BID oral dosing). However, average contact time (>1 µM) is around 0.5 h in lung parts, suggesting indirect exposure response effect of HCQ.The developed PBPK model herein predicted HCQ levels in plasma and different lung parts of adults after multiple inhalation dosing regimens for 5 days. This in-silico work needs to be tested in vivo on healthy subjects and COVID-19 patients using 12.5 mg BID and 25 mg BID inhalation doses.

scholarly journals Proof of Concept in Assignment of Within-Subject Variability During Virtual Bioequivalence Studies: Propagation of Intra-Subject Variation in Gastrointestinal Physiology Using Physiologically Based Pharmacokinetic Modeling

2022 ◽  
Vol 24 (1) ◽  
Author(s):  
Margareta Bego ◽  
Nikunjkumar Patel ◽  
Rodrigo Cristofoletti ◽  
Amin Rostami-Hodjegan
Keyword(s):  
Systemic Exposure ◽  
Physiological Parameters ◽  
Pharmacokinetic Parameters ◽  
Proof Of Concept ◽  
Release Formulation ◽  
Current Case ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

AbstractWhile the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as ‘not plausible’. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations.

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