scholarly journals Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery

2021 ◽  
Vol 9 ◽  
Author(s):  
Paola Mian ◽  
Bridget Nolan ◽  
John N. van den Anker ◽  
Kristel van Calsteren ◽  
Karel Allegaert ◽  
...  
Keyword(s):  
Clinical Studies ◽  
In Silico ◽  
Pbpk Model ◽  
Umbilical Vein ◽  
Whole Body ◽  
Model Parameters ◽  
Drug Transfer ◽  
Physiologically Based Pharmacokinetic ◽  
Perfusion Model ◽  
Physiologically Based

Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure.

scholarly journals A Physiologically Based Pharmacokinetic Model of Rifampin in Mice

2013 ◽  
Vol 57 (4) ◽  
pp. 1763-1771 ◽  
Author(s):  
Michael A. Lyons ◽  
Brad Reisfeld ◽  
Raymond S. H. Yang ◽  
Anne J. Lenaerts
Keyword(s):  
Pbpk Model ◽  
Oral Absorption ◽  
Whole Body ◽  
Model Parameters ◽  
Mathematical Framework ◽  
Physiologically Based Pharmacokinetic ◽  
Starting Point ◽  
Physiologically Based ◽  
Multiple Drugs

ABSTRACTOne problem associated with regimen-based development of antituberculosis (anti-TB) drugs is the difficulty of a systematic and thoroughin vivoevaluation of the large number of possible regimens that arise from consideration of multiple drugs tested together. A mathematical model capable of simulating the pharmacokinetics and pharmacodynamics of experimental combination chemotherapy of TB offers a way to mitigate this problem by extending the use of available data to investigate regimens that are not initially tested. In order to increase the available mathematical tools needed to support such a model for preclinical anti-TB drug development, we constructed a preliminary whole-body physiologically based pharmacokinetic (PBPK) model of rifampin in mice, using data from the literature. Interindividual variability was approximated using Monte Carlo (MC) simulation with assigned probability distributions for the model parameters. An MC sensitivity analysis was also performed to determine correlations between model parameters and plasma concentration to inform future model development. Model predictions for rifampin concentrations in plasma, liver, kidneys, and lungs, following oral administration, were generally in agreement with published experimental data from multiple studies. Sensitive model parameters included those descriptive of oral absorption, total clearance, and partitioning of rifampin between blood and muscle. This PBPK model can serve as a starting point for the integration of rifampin pharmacokinetics in mice into a larger mathematical framework, including the immune response toMycobacterium tuberculosisinfection, and pharmacokinetic models for other anti-TB drugs.

Plasma concentration profiles for hepatotoxic pyrrolizidine alkaloid senkirkine in humans extrapolated from rat data sets using a simplified physiologically based pharmacokinetic model

2021 ◽  
Vol 15 ◽  
Author(s):  
Yusuke Kamiya ◽  
Tomonori Miura ◽  
Airi Kato ◽  
Norie Murayama ◽  
Makiko Shimizu ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Human Plasma ◽  
In Silico ◽  
Pbpk Model ◽  
Pyrrolizidine Alkaloid ◽  
Water Soluble ◽  
Food Plants ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Aim: The main aim of the current study was to obtain forward dosimetry assessments of pyrrolizidine alkaloid senkirkine plasma and liver concentrations by setting up a human physiologically based pharmacokinetic (PBPK) model based on the limited information available. Background: The risks associated with plant-derived pyrrolizidine alkaloids as natural toxins have been assessed. Objective: The pyrrolizidine alkaloid senkirkine was investigated because it was analyzed in a European transcriptomics study of natural hepatotoxins and in a study of the alkaloidal constituents of traditional Japanese food plants Petasites japonicus. The in silico human plasma and liver concentrations of senkirkine were modeled using doses reported for acute-term toxicity in humans. Methods: Using a simplified PBPK model established using rat pharmacokinetic data, forward dosimetry was conducted. Since in vitro rat and human intrinsic hepatic clearances were similar; an allometric scaling approach was applied to rat parameters to create a human PBPK model. Results: After oral administration of 1.0 mg/kg in rats in vivo, water-soluble senkirkine was absorbed and cleared from plasma to two orders of magnitude below the maximum concentration in 8 h. Human in silico senkirkine plasma concentration curves were generated after virtual daily oral administrations of 3.0 mg/kg senkirkine (the dose involved in an acute fatal hepatotoxicity case). A high concentration of senkirkine in the culture medium caused in vitro hepatotoxicity as evidenced by lactate dehydrogenase leakage from human hepatocyte-like HepaRG cells. Conclusion: Higher virtual concentrations of senkirkine in human liver and plasma than those in rat plasma were estimated using the current rat and human PBPK models. Current simulations suggest that if P. japonicus (a water-soluble pyrrolizidine alkaloid-producing plant) is ingested daily as food, hepatotoxic senkirkine could be continuously present in human plasma and liver.

scholarly journals 1396. Predictions of Isavuconazonium Sulfate Dosage in Patients Aged 6 Months: <18 Years by Physiologically Based Pharmacokinetic Modeling

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S429-S430 ◽  
Author(s):  
Amit Desai ◽  
Laura Kovanda ◽  
Christopher Lademacher ◽  
William Hope ◽  
Michael Neely ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Steady State ◽  
Allometric Scaling ◽  
Pbpk Model ◽  
Whole Body ◽  
Target Range ◽  
Independent Contractor ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Research Grant

Abstract Background Best practice to establish dosage regimens for “first-in-pediatric” clinical trials requires knowledge of efficacious and safe exposures in adults. Methods Pediatric equivalent doses were predicted for patients aged 6 months and &lt;18 years using physiologically based pharmacokinetic (PBPK) modeling, and compared with predictions by allometric scaling. All simulations were completed using PK-Sim®, which implements a whole-body PBPK model with 15 organs and appropriate maturation of anatomical and physiological parameters for children. The adult PBPK model was built using knowledge of drug physico-chemistry and clearance partitioning (CYP3A4, CYP3A5, glomerular filtration). PK data following IV (40, 80, 160 mg 60-minute infusion) and oral (100, 200, 400 mg capsule) doses in adults were used for initial model development. This model was validated by matching observed adult concentrations after multiple oral 200 mg doses. From this adult model, a virtual pediatric population (n = 4,600) from 6 months to &lt;18 years was created. Simulations with the pediatric model assessed optimal doses of isavuconazonium sulfate based on age and weight to achieve at least a median steady-state daily area under the curve (AUCss) of 100 mg hour/L, and the majority below 230 mg hour/L. These targets were derived from efficacy and safety data in clinical trials with adults. Results As shown in the figure, an isavuconazonium sulfate dose of 10 mg/kg is expected to result in AUCss within the target range for the majority of patients &gt;1 year old, in agreement with that predicted by allometry for patients aged 2–17 years. For patients aged 6 months to 1 year, a dose of 6 mg/kg predicts comparable exposures. Conclusion A proposed isavuconazonium sulfate dose of 10 mg/kg administered every 8 hours for the first 2 days and once daily thereafter is predicted to result in safe and efficacious steady state exposures in patients aged 1–17 years, similar to predictions from allometric scaling for patients aged 2–17 years. For subjects aged 6 months to 1 year, a dose of 6 mg/kg is predicted to achieve similar exposures. These doses should be tested in clinical trials to confirm. Disclosures A. Desai, Astellas Pharma, Inc.: Employee, Salary. L. Kovanda, Astellas Pharma, Inc.: Employee, Salary. C. Lademacher, Astellas Pharma, Inc.: Employee, Salary. W. Hope, F2G: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Astellas: Grant Investigator and Investigator, Grant recipient and Research grant. Pfizer: Grant Investigator, Research support. Gilead: Consultant and Scientific Advisor, Consulting fee. P. Bonate, Astellas Pharma, Inc.: Employee, Salary. A. Edginton, Astellas Pharma Global Development, Inc.: Independent Contractor, Consulting fee.

scholarly journals Physiologically Based Pharmacokinetic Modeling of Rosuvastatin to Predict Transporter-Mediated Drug-Drug Interactions

2021 ◽  
Author(s):  
Nina Hanke ◽  
José David Gómez-Mantilla ◽  
Naoki Ishiguro ◽  
Peter Stopfer ◽  
Valerie Nock
Keyword(s):  
Drug Interactions ◽  
Pbpk Model ◽  
Open Systems ◽  
Whole Body ◽  
Good Prediction ◽  
Active Efflux ◽  
Physiologically Based Pharmacokinetic ◽  
Positron Emission ◽  
Physiologically Based

Abstract Purpose To build a physiologically based pharmacokinetic (PBPK) model of the clinical OATP1B1/OATP1B3/BCRP victim drug rosuvastatin for the investigation and prediction of its transporter-mediated drug-drug interactions (DDIs). Methods The Rosuvastatin model was developed using the open-source PBPK software PK-Sim®, following a middle-out approach. 42 clinical studies (dosing range 0.002–80.0 mg), providing rosuvastatin plasma, urine and feces data, positron emission tomography (PET) measurements of tissue concentrations and 7 different rosuvastatin DDI studies with rifampicin, gemfibrozil and probenecid as the perpetrator drugs, were included to build and qualify the model. Results The carefully developed and thoroughly evaluated model adequately describes the analyzed clinical data, including blood, liver, feces and urine measurements. The processes implemented to describe the rosuvastatin pharmacokinetics and DDIs are active uptake by OATP2B1, OATP1B1/OATP1B3 and OAT3, active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The available clinical rifampicin, gemfibrozil and probenecid DDI studies were modeled using in vitro inhibition constants without adjustments. The good prediction of DDIs was demonstrated by simulated rosuvastatin plasma profiles, DDI AUClast ratios (AUClast during DDI/AUClast without co-administration) and DDI Cmax ratios (Cmax during DDI/Cmax without co-administration), with all simulated DDI ratios within 1.6-fold of the observed values. Conclusions A whole-body PBPK model of rosuvastatin was built and qualified for the prediction of rosuvastatin pharmacokinetics and transporter-mediated DDIs. The model is freely available in the Open Systems Pharmacology model repository, to support future investigations of rosuvastatin pharmacokinetics, rosuvastatin therapy and DDI studies during model-informed drug discovery and development (MID3).

scholarly journals Prediction of Cyclosporin-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Model Characterizing Interplay of Drug Transporters and Enzymes

2020 ◽  
Vol 21 (19) ◽  
pp. 7023
Author(s):  
Yiting Yang ◽  
Ping Li ◽  
Zexin Zhang ◽  
Zhongjian Wang ◽  
Li Liu ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Pbpk Model ◽  
Drug Disposition ◽  
Organic Anion ◽  
Whole Body ◽  
Efflux Transporters ◽  
Cytochrome P450 Enzymes ◽  
Control Drug ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Uptake transporter organic anion transporting polypeptides (OATPs), efflux transporters (P-gp, BCRP and MRP2) and cytochrome P450 enzymes (CYP450s) are widely expressed in the liver, intestine or kidney. They coordinately work to control drug disposition, termed as “interplay of transporters and enzymes”. Cyclosporine A (CsA) is an inhibitor of OATPs, P-gp, MRP2, BCRP and CYP3As. Drug–drug interaction (DDI) of CsA with victim drugs occurs via disordering interplay of transporters and enzymes. We aimed to establish a whole-body physiologically-based pharmacokinetic (PBPK) model which predicts disposition of CsA and nine victim drugs including atorvastatin, cerivastatin, pravastatin, rosuvastatin, fluvastatin, simvastatin, lovastatin, repaglinide and bosentan, as well as drug–drug interactions (DDIs) of CsA with nine victim drugs to investigate the integrated effect of enzymes and transporters in liver, intestinal and kidney on drug disposition. Predictions were compared with observations. Most of the predictions were within 0.5–2.0 folds of observations. Atorvastatin was represented to investigate individual contributions of transporters and CYP3As to atorvastatin disposition and their integrated effect. The contributions to atorvastatin disposition were hepatic OATPs >> hepatic CYP3A > intestinal CYP3As ≈ efflux transporters (P-gp/BCRP/MRP2). The results got the conclusion that the developed PBPK model characterizing the interplay of enzymes and transporters was successfully applied to predict the pharmacokinetics of 10 OATP substrates and DDIs of CsA with 9 victim drugs.

scholarly journals Revisiting a physiologically based pharmacokinetic model for cocaine with a forensic scope

2019 ◽  
Vol 8 (3) ◽  
pp. 432-446
Author(s):  
María Elena Bravo-Gómez ◽  
Laura Nayeli Camacho-García ◽  
Luz Alejandra Castillo-Alanís ◽  
Miguel Ángel Mendoza-Meléndez ◽  
Alejandra Quijano-Mateos
Keyword(s):  
Pharmacokinetic Model ◽  
Pbpk Model ◽  
Whole Body ◽  
Physiologically Based Pharmacokinetic Model ◽  
Time Profiles ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based ◽  
Permeability Rate ◽  
Different Tissues

A whole-body permeability-rate-limited physiologically based pharmacokinetic (PBPK) model for cocaine was developed with the aim to predict the concentration–time profiles of the drug in blood and different tissues in humans.

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.

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