scholarly journals O36 Physiologically based pharmacokinetic models to predict fetal exposure to antiviral drugs

2019 ◽  
Vol 104 (6) ◽  
pp. e16.1-e16
Author(s):  
X Liu ◽  
J Momper ◽  
N Rakhmanina ◽  
J van den Anker ◽  
D Green ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Drug Exposure ◽  
Pbpk Model ◽  
Ex Vivo ◽  
Antiviral Drugs ◽  
List Type ◽  
Fetal Exposure ◽  
Pbpk Models ◽  
Physiologically Based

BackgroundPhysiologic changes associated with pregnancy may have a large impact on drug disposition. The goal of this study was to build PBPK maternal-fetal models to predict the fetal exposure to antiviral drugs including emtricitabine and acyclovir.MethodsPBPK models were built in the Open Systems Pharmacology Software Suite version 7.3 (www.open-systems-pharmacology.org). The maternal-fetal PBPK model structure was developed in MoBi and exported to PK-Sim for population simulations. Placental transfer was parameterized based on data from ex vivo cotyledon perfusion experiments. The predictive performance of the PBPK models was evaluated via comparison with in vivo data. The pregnancy data for those drugs were from in vivo maternal and fetal blood samples taken at delivery.ResultsIn the acyclovir ex vivo experimental data simulation, the fitted was 0.056 L/h (95% confidence interval: 0.043 - 0.069 L/h) and the fitted was 0.49 (95% confidence interval: 0.39 - 0.59). The predicted ratio between acyclovir in vivo concentrations in the umbilical vein plasma and the maternal plasma ranged from 0.37 - 0.77, whereas the observed ratios were slightly higher and ranged from 0.61 - 1.1.1 The previously published, and CLpl (1.49 1/h) parameters2 were applied to the emtricitabine maternal-fetal PBPK model, and the emtricitabine concentrations in the umbilical cord were adequately predicted.ConclusionThese results increase the confidence in applying PBPK models to predict maternal and fetal drug exposure. Improved maternal-fetal PBPK models may streamline and accelerate the performance of pharmacokinetic and safety studies for drugs in pregnant women.ReferencesFrenkel LM, et al. Pharmacokinetics of acyclovir in the term human pregnancy and neonate. Am J Obstet Gynecol 1991;164:569–76.De Sousa Mendes M, et al. Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models. Brit J Clin Pharmacol 2016;81:646–57.Disclosure(s)The opinions expressed in this article are those of the authors and should not be interpreted as the position of the U.S. Food and Drug Administration or of the National Institutes of Health. The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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

Methodological Approaches to Evaluate Fetal Drug Exposure

2019 ◽  
Vol 25 (5) ◽  
pp. 496-504 ◽  
Author(s):  
Naïm Bouazza ◽  
Frantz Foissac ◽  
Déborah Hirt ◽  
Saïk Urien ◽  
Sihem Benaboud ◽  
...  
Keyword(s):  
Cord Blood ◽  
Drug Exposure ◽  
Placental Transfer ◽  
Ex Vivo ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pbpk Models ◽  
Drug Concentrations ◽  
Fetal Drug Exposure

Background: Drug prescriptions are usual during pregnancy, however, women and their fetuses still remain an orphan population with regard to drugs efficacy and safety. Most xenobiotics diffuse through the placenta and some of them can alter fetus development resulting in structural abnormalities, growth or functional deficiencies. Methods: To summarize the different methodologies developed towards the prediction of fetal drug exposure. Results: Neonatal cord blood concentration is the most specific measurement of the transplacental drug transfer at the end of pregnancy. Using the cord blood and mother drug concentrations altogether, drug exchanges between the mother and fetus can be modeled and quantified via a population pharmacokinetic analysis. Thereafter, it is possible to estimate the fetus exposure and the fetus-to-mother exposure ratio. However, the prediction of placental transfer before any administration to pregnant women is desirable. Animal studies remain difficult to interpret due to structural and functional inter-species placenta differences. The ex-vivo perfusion of the human placental cotyledon is the method of reference to study the human placental transfer of drugs because it is thought to mimic the functional placental tissue. However, extrapolation of data to in vivo situation remains difficult. Some research groups have extensively worked on physiologically based models (PBPK) to predict fetal drug exposure and showed very encouraging results. Conclusion: PBPK models appeared to be a very promising tool in order to predict fetal drug exposure in-silico. However, these models mainly picture the end of pregnancy and knowledge regarding both, development of the placental permeability and transporters is strongly needed.

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

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)

scholarly journals Development of a Physiologically Based Pharmacokinetic Model for Hydroxychloroquine and Its Application in Dose Optimization in Specific COVID-19 Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Miao Zhang ◽  
Xueting Yao ◽  
Zhe Hou ◽  
Xuan Guo ◽  
Siqi Tu ◽  
...  
Keyword(s):  
Pbpk Model ◽  
Clinical Findings ◽  
Lung Model ◽  
Elderly Subjects ◽  
Distribution Data ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Drug Actions

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated in vitro anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant in vitro and in vivo experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.

scholarly journals P21 PBPK modeling in pregnancy: achievements, shortcomings and future perspectives

2019 ◽  
Vol 104 (6) ◽  
pp. e25.2-e25
Author(s):  
A Dallmann ◽  
P Mian ◽  
P Annaert ◽  
M Pfister ◽  
K Allegaert ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Pbpk Model ◽  
Multiple Pregnancy ◽  
First Trimester ◽  
Model Verification ◽  
Pbpk Modeling ◽  
Third Trimester ◽  
The Past ◽  
Pbpk Models

BackgroundPhysiologically-based pharmacokinetic (PBPK) models are considered a promising approach to better characterize and anticipate the effect of physiological changes on pharmacokinetics in pregnant women. Consequently, multiple pregnancy PBPK models have been developed and verified over the past years. Using acetaminophen (paracetamol) as example, PBPK modeling can provide specific insights into the expected pharmacokinetic changes throughout pregnancy.MethodsTo obtain an overview of pregnancy PBPK models, the scientific literature was systematically screened for publications with a focus on pharmaceutical applications using relevant keywords. Additionally, a pregnancy PBPK model for acetaminophen was developed with the Open Systems Pharmacology software suite (www.open-systems-pharmacology.org) following an established workflow. After model verification around gestational week 30, the model was scaled to earlier stages of pregnancy and molar dose fractions converted to acetaminophen metabolites were estimated for each trimester.ResultsOver the past years, more than 60 different pregnancy PBPK models for more than have 40 drugs been published. More than 70% of these models were developed for the third trimester, while few models have been applied to the first trimester. The developed PBPK model for acetaminophen indicated that the median dose fraction of acetaminophen converted to the reactive metabolite N-acetyl-p-benzoquinonimine (NAPQI) was 11%, 9.0% and 8.2% in the first, second and third trimester, respectively, while for non-pregnant women a value of 7.7% was simulated.ConclusionWhile the overall availability and quality of pregnancy PBPK models is varying considerably, the efforts to establish such models are promising in that they reflect an increased awareness of the necessity to better characterize pharmacokinetics during pregnancy. This is illustrated by the developed PBPK model for acetaminophen where information on NAPQI-formation in vivo is hitherto lacking. Although PBPK models are not a substitute for clinical trials, they constitute an important tool for clinicians in case of missing or incomplete information.Disclosure(s)Nothing to disclose

scholarly journals Direct anabolic three carbon metabolism via propionate to a six carbon metabolite occurs in human heart and in vivo across mouse tissues

2019 ◽  
Author(s):  
Mary T. Doan ◽  
Michael D. Neinast ◽  
Erika L Varner ◽  
Kenneth Bedi ◽  
David Bartee ◽  
...  
Keyword(s):  
Human Heart ◽  
Ex Vivo ◽  
Tibialis Anterior Muscle ◽  
Whole Body ◽  
List Type ◽  
Isotope Tracing ◽  
Brown Adipose ◽  
Mouse Tissues

AbstractAnabolic metabolism of carbon in mammals is mediated via the one and two carbon carriers S-adenosyl methionine and acetyl-coenzyme A (acetyl-CoA). In contrast, anabolic metabolism using three carbon units via propionate is not thought to occur. Mammals are primarily thought to oxidize the 3-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. We found that this may not be absolute and that in mammals one non-oxidative fate of two units of propionyl-CoA is to condense to a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this pathway using purified protein extracts provided limited substrates and confirmed the product with a synthetic standard. In whole-body in vivo stable isotope tracing with infusion of 13C-labeled valine achieving steady state, 2M2PE-CoA formed via propionyl-CoA in multiple murine tissues including heart, kidney, and to a lesser degree in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three to six carbon reaction conserved in humans and mice that utilizes three carbons via propionate.Highlights- Synthesis and confirmation of structure 2-methyl-2-pentenoyl-CoA- In vivo fate of valine across organs includes formation of a 6-carbon metabolite from propionyl-CoA- Ex vivo metabolism of propionate in the human heart includes direct anabolism to a 6-carbon product- In both cases, this reaction occurred at physiologically relevant concentrations of propionate and valine- In vitro this pathway requires propionyl-CoA and NADH/NADPH as substrates

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.

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