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https://www.readbyqxmd.com/read/28546104/development-of-a-paediatric-physiologically-based-pharmacokinetic-model-to-assess-the-impact-of-drug-drug-interactions-in-tuberculosis-co-infected-malaria-subjects-a-case-study-with-artemether-lumefantrine-and-the-cyp3a4-inducer-rifampicin
#1
Olusola Olafuyi, Michael Coleman, Raj K S Badhan
The fixed dosed combination of artemether and lumefantrine (AL) is widely used for the treatment of malaria in adults and children in sub-Sahara Africa, with lumefantrine day 7 concentrations being widely used as a marker for clinical efficacy. Both are substrates for CYP3A4 and susceptible to drug-drug interactions (DDIs); indeed, knowledge of the impact of these factors is currently sparse in paediatric population groups. Confounding malaria treatment is the co-infection of patients with tuberculosis. The concomitant treatment of AL with tuberculosis chemotherapy, which includes the CYP3A4 inducer rifampicin, increases the risk of parasite recrudescence and malaria treatment failure...
May 22, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28541457/bumped-kinase-inhibitor-gastrointestinal-exposure-is-necessary-to-treat-cryptosporidium-infection
#2
Samuel L M Arnold, Ryan Choi, Matthew A Hulverson, Deborah A Schaefer, Sumiti Vinayak, Rama S R Vidadala, Molly C McCloskey, Grant R Whitman, Wenlin Huang, Lynn K Barrett, Kayode K Ojo, Erkang Fan, Dustin J Maly, Michael W Riggs, Boris Striepen, Wesley C Van Voorhis
There is a substantial need for novel therapeutics to combat the widespread impact caused by Crytosporidium infection. However, there is a lack of knowledge on which drug pharmacokinetic characteristics are key to generate an in vivo response specifically if systemic drug exposure is crucial for in vivo efficacy. To identify which pharmacokinetic properties are correlated with in vivo efficacy, we generated physiologically based pharmacokinetic (PBPK) models to simulate systemic and gastrointestinal (GI) drug concentrations for a series of bumped kinase inhibitors (BKI) that have nearly identical in vitro potency against Cryptosporidium but display divergent pharmacokinetic properties...
May 24, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28536774/physiologically-based-pharmacokinetic-modelling-and-prediction-of-metformin-pharmacokinetics-in-renal-hepatic-impaired-young-adults-and-elderly-populations
#3
Su-Jin Rhee, Hyewon Chung, SoJeong Yi, Kyung-Sang Yu, Jae-Yong Chung
BACKGROUND AND OBJECTIVES: Physiologically based pharmacokinetic (PBPK) modelling and simulation enable researchers to overcome practical limitations for clinical trials on special populations. This study was conducted to investigate how the PBPK model describes the pharmacokinetics of metformin in young adult and elderly populations and to predict the pharmacokinetics of metformin in patients with renal or hepatic impairment in both populations. METHODS: A first-order absorption/PBPK model for metformin was built in the Simcyp simulator version 14 release 1...
May 23, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28526963/incorporation-of-the-time-varying-postprandial-increase-in-splanchnic-blood-flow-into-a-pbpk-model-to-predict-the-effect-of-food-on-the-pharmacokinetics-of-orally-administered-high-extraction-drugs
#4
Rachel H Rose, David B Turner, Sibylle Neuhoff, Masoud Jamei
Following a meal, a transient increase in splanchnic blood flow occurs that can result in increased exposure to orally administered high-extraction drugs. Typically, physiologically based pharmacokinetic (PBPK) models have incorporated this increase in blood flow as a time-invariant fed/fasted ratio, but this approach is unable to explain the extent of increased drug exposure. A model for the time-varying increase in splanchnic blood flow following a moderate- to high-calorie meal (TV-Q Splanch) was developed to describe the observed data for healthy individuals...
May 19, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28522410/a-global-human-health-risk-assessment-for-octamethylcyclotetrasiloxane-d4
#5
Robinan Gentry, Allison Franzen, Cynthia Van Landingham, Tracy Greene, Kathy Plotzke
Octamethylcyclotetrasiloxane (D4) is a low-molecular-weight volatile cyclic siloxane, primarily used as an intermediate in the production of some widely-used industrial and consumer silicone based polymers and may be present as a component in a variety of consumer products. A global "harmonized" risk assessment was conducted to meet requirements for substance-specific risk assessments conducted by regulatory agencies such as USEPA's Integrated Risk Information System (IRIS), Health Canada's Chemical Management Program (CMP) and various independent scientific committees of the European Commission (e...
May 15, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28514845/in-vivo-mercury-demethylation-in-marine-fish
#6
Xun Wang, Fengchang Wu, Wen-Xiong Wang
Mercury (Hg) in fish has attracted public attention for decades, and methylmercury (MeHg) is the predominant form in fish. However, the in vivo MeHg demethylation and its influence on Hg status in fish have not been well addressed. The present study investigated the in vivo demethylation process in a marine fish (black seabream, Acanthopagrus schlegeli) under dietary MeHg exposure and depuration, and quantified the biotransformation and inter-organ transportation of MeHg by developing a physiologically based pharmacokinetic (PBPK) model...
May 18, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28511864/metabolism-and-disposition-of-14-c-methycyclosiloxanes-in-rats
#7
Jeanne Y Domoradzki, Christopher M Sushynski, Jacob M Sushynski, Debra A McNett, Cynthia Van Landingham, Kathleen P Plotzke
Octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) are low molecular weight cyclic volatile methyl siloxanes (cVMSs) primarily used as intermediates or monomers in the production of high molecular weight silicone polymers. The use of D4 as a direct ingredient in personal care products has declined significantly over the past 10 years, although it may be present as a residual impurity in a variety of consumer products. D5 is still used as an intentional ingredient in cosmetics, consumer products and in dry cleaning...
May 13, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28506866/non-maturational-covariates-for-dynamic-systems-pharmacology-models-in-neonates-infants-and-children-filling-the-gaps-beyond-developmental-pharmacology
#8
Karel Allegaert, Sinno H P Simons, Dick Tibboel, Elke Krekels, Catherijne Knibbe, John van den Anker
Pharmacokinetics and -dynamics show important changes throughout childhood. Studies on the different maturational processes that influence developmental pharmacology have been used to create population PK/PD models that can yield individualized pediatric drug dosages. These models were subsequently translated to semi-physiologically or physiology-based PK (PBPK) models that support predictions in pediatric patient cohorts and other special populations. Although these translational efforts are crucial, these models should be further improved towards individual patient predictions by including knowledge on non-maturational covariates...
May 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28495568/quantitative-analyses-of-the-influence-of-parameters-governing-rate-determining-process-of-hepatic-elimination-of-drugs-on-the-magnitudes-of-drug-drug-interactions-via-hepatic-oatps-and-cyp3a-using-physiologically-based-pharmacokinetic-models
#9
Takashi Yoshikado, Maeda Kazuya, Hiroyuki Kusuhara, Ken-Ichi Furihata, Yuichi Sugiyama
Physiologically-based pharmacokinetic (PBPK) models were constructed for hepatic organic anion transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) substrates (bosentan, repaglinide, clarithromycin, and simeprevir), a CYP3A probe substrate (midazolam), and selective inhibitors for OATPs (rifampicin) and CYP3A (itraconazole), though the role of OATPs in the hepatic uptake of clarithromycin is unclear. The pharmacokinetic data were obtained from our previous clinical drug-drug interaction (DDI) study...
May 8, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28495566/the-constraints-construction-and-verification-of-a-strain-specific-physiologically-based-pharmacokinetic-rat-model
#10
H Musther, M D Harwood, J Yang, D B Turner, A Rostami-Hodjegan, M Jamei
The use of in vitro-in vivo extrapolation (IVIVE) techniques, mechanistically incorporated within Physiologically-Based Pharmacokinetic (PBPK) models, can harness in vitro drug data and enhance understanding of in vivo pharmacokinetics. This study's objective was to develop a user-friendly rat (250g, male Sprague-Dawley) IVIVE linked PBPK model. A 13-compartment PBPK model including mechanistic absorption models was developed, with required system data (anatomical, physiological and relevant IVIVE scaling factors) collated from literature and analysed...
May 8, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28487698/physiologically-based-simulations-of-deuterated-glucose-for-quantifying-cell-turnover-in-humans
#11
Julio Lahoz-Beneytez, Stephan Schaller, Derek Macallan, Thomas Eissing, Christoph Niederalt, Becca Asquith
In vivo [6,6-(2)H2]-glucose labeling is a state-of-the-art technique for quantifying cell proliferation and cell disappearance in humans. However, there are discrepancies between estimates of T cell proliferation reported in short (1-day) versus long (7-day) (2)H2-glucose studies and very-long (9-week) (2)H2O studies. It has been suggested that these discrepancies arise from underestimation of true glucose exposure from intermittent blood sampling in the 1-day study. Label availability in glucose studies is normally approximated by a "square pulse" (Sq pulse)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28483778/mechanisms-and-predictions-of-drug-drug-interactions-of-the-hepatitis-c-virus-3-direct-acting-antiviral-3d-regimen-paritaprevir-ritonavir-ombitasvir-and-dasabuvir
#12
Mohamad Shebley, Jinrong Liu, Olga Kavetskaia, Jens Sydor, Sonia M de Morais, Volker Fischer, Marjoleen Jma Nijsen, Daniel Aj Bow
To assess drug-drug interaction (DDI) potential for the 3 direct-acting antiviral (3D) regimen of ombitasvir, dasabuvir and paritaprevir, in vitro studies profiled drug metabolizing enzyme and transporter interactions. Using mechanistic static and dynamic models, DDI potential was predicted for CYP3A, CYP2C8, UGT1A1, OATP1B1/1B3, BCRP and P-gp. Perpetrator static model DDI predictions for metabolizing enzymes were within 2-fold of the clinical observations but for drug transporters, additional PBPK modeling was necessary to achieve the same...
May 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28479356/quantitative-analysis-of-complex-drug-drug-interactions-between-repaglinide-and-cyclosporin-a-gemfibrozil-using-physiologically-based-pharmacokinetic-models-with-in-vitro-transporter-enzyme-inhibition-data
#13
Soo-Jin Kim, Kota Toshimoto, Yoshiaki Yao, Takashi Yoshikado, Yuichi Sugiyama
Quantitative analysis of transporter- and enzyme-mediated complex drug-drug interactions (DDIs) is challenging. Repaglinide (RPG) is transported into the liver by OATP1B1 and then is metabolized by CYP2C8 and CYP3A4. The purpose of this study is to describe the complex DDIs of RPG quantitatively based on unified physiologically-based pharmacokinetic (PBPK) models using in vitro Ki values for OATP1B1, CYP3A4, and/or CYP2C8. Cyclosporin A (CsA) or gemfibrozil (GEM) increased the blood concentrations of RPG. The time profiles of RPG and the inhibitors were analyzed by PBPK models, considering the inhibition of OATP1B1 and CYP3A4 by CsA, or OATP1B1 inhibition by GEM and its glucuronide and the mechanism-based inhibition of CYP2C8 by GEM glucuronide...
May 4, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28474821/application-of-physiologically-based-pharmacokinetic-modeling-to-predict-drug-disposition-in-pregnant-populations
#14
Vamshi Krishna Jogiraju, Suvarchala Avvari, Rakesh Gollen, David R Taft
Pregnancy is associated with numerous physiologic changes that influence absorption, distribution, metabolism and excretion. Moreover, the magnitude of these effects changes as pregnancy matures. For most medications, there is limited information available about changes in drug disposition that can occur in pregnant patients, yet most women are prescribed one or more medications during pregnancy. In this investigation, PBPK modeling was used to assess the impact of pregnancy on the pharmacokinetic profiles of three medications (metformin, tacrolimus, oseltamivir) using the Simcyp® Simulator...
May 5, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28456730/usefulness-of-pbpk-modeling-in-incorporation-of-clinical-conditions-in-personalized-medicine
#15
REVIEW
Niloufar Marsousi, Jules A Desmeules, Serge Rudaz, Youssef Daali
Personalized medicine aims to determine the most adequate treatment and dose regimen to obtain the maximum efficacy and minimum side effect by taking into account patients' characteristics. For numerous reasons one being ethical and methodological hurdles in including specific populations in clinical trials, innovative methods for optimization of drugs safety and efficacy in such patients have received increasing interest recently. Physiologically-Based PharmacoKinetic (PBPK) modeling has emerged as a promising approach in designing adequate clinical trials and quantifying anticipated changes in unknown clinical situations...
April 26, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28444890/utilizing-pbpk-modeling-to-evaluate-the-potential-of-a-significant-drug-drug-interaction-between-clopidogrel-and-dasabuvir-a-scientific-perspective
#16
V Arya, P Zhao, K S Reynolds, P Mishra, I R Younis
Dasabuvir, a component of VIEKIRA PAK, is a substrate of CYP2C8 enzymes. Prescribing information for VIEKIRA PAK contraindicates gemfibrozil, a strong CYP2C8 inhibitor, because coadministration significantly increases dasabuvir exposures, which may increase the risk of QT prolongation. Clopidogrel may increase dasabuvir exposures primarily due to CYP2C8 inhibition by clopidogrel-acyl-β-D-glucuronide. This commentary outlines the US Food and Drug Administration (FDA) interdisciplinary review team's scientific perspective to address the potential for a significant drug-drug interaction (DDI) between clopidogrel and VIEKIRA PAK...
April 26, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28439684/impact-of-altered-endogenous-igg-on-unspecific-mab-clearance
#17
Saskia Fuhrmann, Charlotte Kloft, Wilhelm Huisinga
Immunodeficient mice are crucial models to evaluate the efficacy of monoclonal antibodies (mAbs). When studying mAb pharmacokinetics (PK), protection from elimination by binding to the neonatal Fc receptor (FcRn) is known to be a major process influencing the unspecific clearance of endogenous and therapeutic IgG. The concentration of endogenous IgG in immunodeficient mice, however is reduced, and this effect on the FcRn protection mechanism and subsequently on unspecific mAb clearance is unknown, yet of great importance for the interpretation of mAb PK data...
April 24, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28438781/transporter-mediated-disposition-clinical-pharmacokinetics-and-cholestatic-potential-of-glyburide-and-its-primary-active-metabolites
#18
Rui Li, Yi-An Bi, Anna Vildhede, Renato J Scialis, Sumathy Mathialagan, Xin Yang, Lisa D Marroquin, Jian Lin, Manthena V S Varma
Glyburide is widely used for the treatment of type 2 diabetes mellitus. We studied the mechanisms involved in the disposition of glyburide and its pharmacologically active hydroxy metabolites, M1 and M2b; and evaluated their clinical pharmacokinetics and the potential role in glyburide-induced cholestasis employing physiologically based pharmacokinetic (PBPK) modeling. Transport studies of parent and metabolites in human hepatocytes and transfected cell systems imply hepatic uptake mediated by organic anion transporting polypeptides...
April 24, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28412400/prediction-of-losartan-active-carboxylic-acid-metabolite-exposure-following-losartan-administration-using-static-and-physiologically-based-pharmacokinetic-models
#19
Hoa Q Nguyen, Jian Lin, Emi Kimoto, Ernesto Callegari, Susanna Tse, R Scott Obach
The aim of this study was to evaluate a strategy based on static and dynamic physiologically based pharmacokinetic (PBPK) modeling for the prediction of metabolite and parent drug area under the time-concentration curve ratio (AUCm/AUCp) and their PK profiles in humans using in vitro data when active transport processes are involved in disposition. The strategy was applied to losartan and its pharmacologically active metabolite carboxylosartan as test compounds. Hepatobiliary transport including transport-mediated uptake, canilicular and basolateral efflux, and metabolic clearance estimates were obtained from in vitro studies using human liver microsomes and sandwich cultured hepatocytes...
April 12, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28411400/physiologically-based-pharmacokinetic-modeling-suggests-limited-drug-drug-interaction-between-clopidogrel-and-dasabuvir
#20
Mohamad Shebley, Wentao Fu, Prajakta Badri, Daniel A J Bow, Volker Fischer
Dasabuvir, a non-nucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug-drug interaction (DDI) with clopidogrel. A physiologically-based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl-β-D glucuronide metabolite of which has been reported as a strong mechanism-based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data...
April 15, 2017: Clinical Pharmacology and Therapeutics
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