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https://www.readbyqxmd.com/read/28226770/a-multiscale-model-based-analysis-of-the-multi-tissue-interplay-underlying-blood-glucose-regulation-in-type-i-diabetes
#1
Federico Wadehn, Stephan Schaller, Thomas Eissing, Markus Krauss, Lars Kupfer, Federico Wadehn, Stephan Schaller, Thomas Eissing, Markus Krauss, Lars Kupfer, Federico Wadehn, Markus Krauss, Lars Kupfer, Stephan Schaller, Thomas Eissing
A multiscale model for blood glucose regulation in diabetes type I patients is constructed by integrating detailed metabolic network models for fat, liver and muscle cells into a whole body physiologically-based pharmacokinetic/pharmacodynamic (pBPK/PD) model. The blood glucose regulation PBPK/PD model simulates the distribution and metabolization of glucose, insulin and glucagon on an organ and whole body level. The genome-scale metabolic networks in contrast describe intracellular reactions. The developed multiscale model is fitted to insulin, glucagon and glucose measurements of a 48h clinical trial featuring 6 subjects and is subsequently used to simulate (in silico) the influence of geneknockouts and drug-induced enzyme inhibitions on whole body blood glucose levels...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28221813/transport-glucuronidation-classification-system-and-pbpk-modeling-new-approach-to-predict-the-impact-of-transporters-on-disposition-of-glucuronides
#2
Shufan Ge, Yingjie Wei, Taijun Yin, Beibei Xu, Song Gao, Ming Hu
Glucuronide metabolites require the action of efflux transporters to exit cells due to their hydrophilic properties. In this study, we proposed a transport-glucuronidation classification system and developed a PBPK model to predict the impact of BCRP on systemic exposure of glucuronides. The clearance by UGTs in S9 fractions and the efflux clearance of glucuronides by BCRP in human UGT1A9-overexpressing HeLa cells were incorporated in the classification system and PBPK model. Based on simulations for glucuronide AUC for theoretical compounds in the classification system, it was indicated that BCRP was more important for compounds with greater efflux clearance of their glucuronides by BCRP regardless of differences in clearance by UGTs...
February 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28215648/estimation-of-the-minimum-permeability-coefficient-in-rats-for-perfusion-limited-tissue-distribution-in-whole-body-physiologically-based-pharmacokinetics
#3
Yoo-Seong Jeong, Chang-Soon Yim, Heon-Min Ryu, Chi-Kyoung Noh, Yoo-Kyung Song, Suk-Jae Chung
The objective of the current study was to determine the minimum permeability coefficient, P, needed for perfusion-limited distribution in PBPK. Two expanded kinetic models, containing both permeability and perfusion terms for the rate of tissue distribution, were considered: The resulting equations could be simplified to perfusion-limited distribution depending on tissue permeability. Integration plot analyses were carried out with theophylline in 11 typical tissues to determine their apparent distributional clearances and the model-dependent permeabilities of the tissues...
February 12, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/28214380/application-of-the-mechpeff-model-to-predict-passive-effective-intestinal-permeability-in-the-different-regions-of-the-rodent-small-intestine-and-colon
#4
D Pade, M Jamei, A Rostami-Hodjegan, D B Turner
A major component of Physiologically-Based Pharmacokinetic (PBPK) models is prediction of the rate and extent of absorption of orally dosed drugs for which knowledge of effective passive intestinal permeability (Peff ) is essential. Single pass intestinal perfusion (SPIP) studies are used to establish effective permeability in vivo but are difficult to perform in rodents while mechanistic models to predict drug Peff in rat and mouse have not been published. This work evaluates the predictive performance of the 'MechPeff' model to predict Peff in the rodent intestine based upon knowledge of regional gut physiology and drug-specific physicochemical parameters...
February 18, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28195732/in-vivo-predictive-dissolution-ipd-and-biopharmaceutical-modeling-and-simulation-future-use-of-modern-approaches-and-methodologies-in-a-regulatory-context
#5
H Lennernas, A Lindahl, A Van Peer, C Ollier, T Flanagan, R Lionberger, A Nordmark, S Yamashita, L Yu, G L Amidon, V Fischer, E Sjögren, P Zane, M McAllister, B Abrahamsson
The overall objective of OrBiTo, a project within Innovative Medicines Initiative (IMI), is to streamline and optimize the development of orally administered drug products through the creation and efficient application of biopharmaceutics tools. This toolkit will include both experimental and computational models developed on improved understanding of the highly dynamic gastrointestinal (GI) physiology relevant to the GI absorption of drug products in both fasted and fed states. A part of the annual OrBiTo-meeting in 2015 was dedicated to the presentation of the most recent progress in the development of the regulatory use of PBPK in silico modeling, in vivo predictive dissolution (IPD) tests and their application to biowaivers...
February 14, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28193650/interaction-of-rifampicin-and-darunavir-ritonavir-or-darunavir-cobicistat-in-vitro
#6
Owain Roberts, Saye Khoo, Andrew Owen, Marco Siccardi
Treatment of HIV patients co-infected with tuberculosis (TB) is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and anti-TB drugs. The aim of this study was to quantify the effects of cobicistat (COBI), or ritonavir (RTV), in modulating DDIs between darunavir (DRV) and rifampicin (RIF) in a human hepatocyte-based in vitro model. Human primary hepatocyte cultures were incubated with RIF alone, or in combination with either COBI or RTV for three days, followed by co-incubation with DRV for one hour...
February 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28182434/a-model-based-approach-to-assessing-the-importance-of-intracellular-binding-sites-in-doxorubicin-disposition
#7
Ilse R Dubbelboer, Elsa Lilienberg, Erik Sjögren, Hans Lennernäs
Doxorubicin is an anticancer agent, which binds reversibly to topoisomerase I and II, intercalates to DNA base pairs, and generates free radicals. Doxorubicin has a high tissue:plasma partition coefficient and high intracellular binding to the nucleus and other subcellular compartments. The metabolite doxorubicinol has an extensive tissue distribution. This porcine study investigated whether the traditional implementation of tissue binding, described by the tissue:plasma partition coefficient (Kp,t), could be used to appropriately analyze and/or simulate tissue doxorubicin and doxorubicinol concentrations in healthy pigs, when applying a physiologically based pharmacokinetic (PBPK) model approach, or whether intracellular binding is required in the semi-PBPK model...
February 23, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28181418/mathematical-modeling-of-the-effects-of-ck2-3-on-mineralization-in-osteoporotic-bone
#8
A Lisberg, R Ellis, K Nicholson, P Moku, A Swarup, P Dhurjati, A Nohe
Osteoporosis is caused by decreased bone mineral density (BMD) and new treatments for this disease are desperately needed. Bone morphogenetic protein 2 (BMP2) is crucial for bone formation. The mimetic peptide CK2.3 acts downstream of BMP2 and increases BMD when injected systemically into the tail vein of mice. However, the most effective dosage needed to induce BMD in humans is unknown. We developed a mathematical model for CK2.3-dependent bone mineralization. We used a physiologically based pharmacokinetic (PBPK) model to derive the CK2...
February 9, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28167538/application-of-physiologically-based-pharmacokinetic-modeling-to-understanding-of-bosutinib-pharmacokinetics-prediction-of-drug-drug-and-drug-disease-interactions
#9
Chiho Ono, Poe-Hirr Hsyu, Richat Abbas, Cho-Ming Loi, Shinji Yamazaki
Bosutinib (Bosulif®) is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Ph+ chronic myelogenous leukemia. Bosutinib is predominantly metabolized by CYP3A4 as the primary clearance mechanism. The main objectives of the present study were to: 1) develop physiologically-based pharmacokinetic (PBPK) models of bosutinib, 2) verify and refine the PBPK models based upon clinical study results of bosutinib single-dose drug-drug interaction (DDI) with ketoconazole and rifampin, and single-dose drug-disease interaction (DDZI) in patients with renal and hepatic impairment, 3) apply the PBPK models to predict DDI outcome in patients with weak and moderate CYP3A inhibitors, and 4) apply the PBPK models to predict DDZI outcomes in renally and hepatically impaired patients after multiple-dose administration...
February 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28159656/influence-of-different-proton-pump-inhibitors-on-the-pharmacokinetics-of-voriconazole
#10
Fang Qi, Liqin Zhu, Na Li, Tingyue Ge, Gaoqi Xu, Shasha Liao
This study aimed to determine the influence of proton pump inhibitors (PPIs) on the pharmacokinetics of voriconazole and to characterise potential drug-drug interactions (DDIs) between voriconazole and various PPIs (omeprazole, esomeprazole, lansoprazole and rabeprazole). Using adjusted physicochemical data and the pharmacokinetic (PK) parameters of voriconazole and PPIs, physiologically based pharmacokinetic (PBPK) models were built and were verified in healthy subjects using GastroPlus(TM) to predict the plasma concentration-time profiles of voriconazole and PPIs...
January 31, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28155594/pbpk-modeling-a-predictive-eco-friendly-bio-waiver-tool-for-drug-research
#11
Baishakhi De, Koushik Bhandari, Ranjan Mukherjee, Prakash Katakam, Shanta K Adiki, Rohit Gundamaraju, Analava Mitra
BACKGROUND: The world has witnessed growing complexities in disease scenario influenced by the drastic changes in host-pathogen- environment triadic relation. Pharmaceutical R&Ds are in constant search of novel therapeutic entities to hasten transition of drug molecules from lab bench to patient bedside. Extensive animal studies and human pharmacokinetics are still the "gold standard" in investigational new drug research and bio-equivalency studies. Apart from cost, time and ethical issues on animal experimentation, burning questions arise relating to ecological disturbances, environmental hazards and biodiversity issues...
February 1, 2017: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/28136132/r-warfarin-clearances-from-plasma-associated-with-polymorphic-cytochrome-p450-2c19-and-simulated-by-individual-physiologically-based-pharmacokinetic-models-for-11-cynomolgus-monkeys
#12
Masahiro Utoh, Takashi Kusama, Tomonori Miura, Marina Mitsui, Mirai Kawano, Takahiro Hirano, Makiko Shimizu, Yasuhiro Uno, Hiroshi Yamazaki
1. Cynomolgus monkey cytochrome P450 2C19 (formerly known as P450 2C75), homologous to human P450 2C19, has been identified as R-warfarin 7-hydroxylase. In this study, simulations of R-warfarin clearance in individual cynomolgus monkeys genotyped for P450 2C19 p.[(Phe100Asn; Ala103Val; Ile112Leu)] were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling. 2. Pharmacokinetic parameters and absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearances for individual PBPK models were estimated for eleven cynomolgus monkeys...
January 30, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28130915/multiscale-modeling-reveals-inhibitory-and-stimulatory-effects-of-caffeine-on-acetaminophen-induced-toxicity-in-humans
#13
C Thiel, H Cordes, V Baier, L M Blank, L Kuepfer
Acetaminophen (APAP) is a widely used analgesic drug that is frequently co-administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP-induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co-medication with CAF. Therefore, drug-drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug-specific PD response data were contextualized at the cellular level...
January 28, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28122787/a-physiologically-based-pharmacokinetic-modeling-approach-to-predict-drug-drug-interactions-of-sonidegib-lde225-with-perpetrators-of-cyp3a-in-cancer-patients
#14
Heidi J Einolf, Jocelyn Zhou, Christina Won, Lai Wang, Sam Rebello
Sonidegib (Odomzo®) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed. This data was used to verify a physiologically-based pharmacokinetic (PBPK) model developed to: 1) bridge the clinical drug-drug interaction (DDI) study of sonidegib with KTZ and RIF in healthy subjects to the marketed dose (200 mg) in patients, 2) predict acute (14 days) versus long-term dosing of the perpetrators with sonidegib at steady-state, and 3) predict the effect of moderate CYP3A perpetrators on sonidegib exposure in patients...
January 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28119020/in-vitro-metabolism-of-benzo-a-pyrene-7-8-dihydrodiol-and-dibenzo-def-p-chrysene-11-12-diol-in-rodent-and-human-hepatic-microsomes
#15
Jordan N Smith, Denis Mehinagic, Subhasree Nag, Susan R Crowell, Richard A Corley
Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabolically activated by isoforms of the P450 enzyme superfamily producing benzo[a]pyrene-7,8-dihydrodiol (B[a]P diol), dibenzo[def,p]chrysene-11,12 diol (DBC diol). Each of these diols can be further metabolized by cytochrome P450 enzymes to highly reactive diol-epoxide metabolites that readily react with DNA or by phase II conjugation facilitating excretion...
January 21, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28108402/using-pharmacokinetic-modelling-to-improve-prescribing-practices-of-intravenous-aminophylline-in-childhood-asthma-exacerbations
#16
Lewis Cooney, Antonia McBride, Andrew Lilley, Ian Sinha, Trevor N Johnson, Daniel B Hawcutt
OBJECTIVE: To evaluate physiologically based pharmacokinetic modelling (PBPK) software in paediatric asthma patients using intravenous aminophylline. METHODS: Prospective clinical audit of children receiving iv aminophylline (July 2014 to June 2016), and in-silico modelling using Simcyp software. RESULTS: Thirty-eight admissions (25 children) were included. Children with aminophylline levels ≥10 mg/l had equivalent clinical outcomes compared to those <10 mg/L, and adverse effects occurred in 57%...
January 17, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28104414/dissolution-failure-of-solid-oral-drug-products-in-field-alert-reports
#17
Dajun Sun, Meng Hu, Mark Browning, Rick L Friedman, Wenlei Jiang, Liang Zhao, Hong Wen
From 2005 to 2014, 370 data entries of dissolution failures of solid oral drug products were assessed with respect to the solubility of drug substances, dosage forms [immediate release (IR) vs. modified release (MR)], and manufacturers (brand name vs. generic). The study results show that the solubility of drug substances does not play a significant role in dissolution failures; however, MR drug products fail dissolution tests more frequently than IR drug products. When multiple variables were analyzed simultaneously, poorly water-soluble IR drug products failed the most dissolution tests, followed by poorly soluble MR drug products and very soluble MR drug products...
January 17, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28092496/the-effect-of-contrast-material-on-radiation-dose-at-ct-part-i-incorporation-of-contrast-material-dynamics-in-anthropomorphic-phantoms
#18
Pooyan Sahbaee, W Paul Segars, Daniele Marin, Rendon C Nelson, Ehsan Samei
Purpose To develop a method to incorporate the propagation of contrast material into computational anthropomorphic phantoms for estimation of organ dose at computed tomography (CT). Materials and Methods A patient-specific physiologically based pharmacokinetic (PBPK) model of the human cardiovascular system was incorporated into 58 extended cardiac-torso (XCAT) patient phantoms. The PBPK model comprised compartmental models of vessels and organs unique to each XCAT model. For typical injection protocols, the dynamics of the contrast material in the body were described according to a series of patient-specific iodine mass-balance differential equations, the solutions to which provided the contrast material concentration time curves for each compartment...
January 13, 2017: Radiology
https://www.readbyqxmd.com/read/28089685/evaluation-of-drug-drug-interaction-potential-between-sacubitril-valsartan-lcz696-and-statins-using-a-physiologically-based-pharmacokinetic-model
#19
Wen Lin, Tao Ji, Heidi Einolf, Surya Ayalasomayajula, Tsu-Han Lin, Imad Hanna, Tycho Heimbach, Christopher Breen, Venkateswar Jarugula, Handan He
Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of OATPs. In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and AUC by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A PBPK modelling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the PK profiles of either analyte in the absence or presence of LCZ696...
January 12, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28074615/a-database-of-optimized-proteomic-quantitative-methods-for-284-human-drug-disposition-related-proteins-for-applications-in-pbpk-modeling
#20
Marc Vrana, Dale Whittington, Vivek Nautiyal, Bhagwat Prasad
The aim of this study was to create an open access repository of validated LC-MS/MS (MRM) methods for quantifying 284 important proteins associated with drug absorption, distribution, metabolism and excretion (ADME). Various in silico and experimental approaches were used to select surrogate peptides and optimize instrument parameters for LC-MS/MS quantification of the selected proteins. The final methods were uploaded to an online public database (ADME QPrOmics(TM); www.qpromics.uw.edu/qpromics/assay/) which provides essential information for facile method development in triple quadrupole MS instruments...
January 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
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