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https://www.readbyqxmd.com/read/29331382/improved-human-pharmacokinetic-prediction-of-hepatically-metabolized-drugs-with-species-specific-systemic-clearance
#1
Kana Horiuchi, Shuichi Ohnishi, Takanobu Matsuzaki, Satoko Funaki, Ayahisa Watanabe, Tohru Mizutare, Sayaka Matsumoto, Kenichi Nezasa, Hiroshi Hasegawa
Accurate prediction of human pharmacokinetics (PK) is important for the choice of promising compounds in humans. As the predictability of human PK by an empirical approach is low for drugs with species-specific PK, the utility of a physiologically based pharmacokinetic (PBPK) model was verified using 16 reference drugs hepatically metabolized. After the prediction method for total clearance (CLtot) and distribution volume at steady state (Vdss) in the conventional PBPK model had been optimized, plasma concentrations following a single oral administration of each reference drug to healthy volunteers were simulated and the prediction accuracy for human PK was compared between empirical approaches and the optimized PBPK model...
January 10, 2018: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29322928/constraint-based-perturbation-analysis-with-cluster-newton-method-a-case-study-of-personalized-parameter-estimations-with-irinotecan-whole-body-physiologically-based-pharmacokinetic-model
#2
Shun Asami, Daisuke Kiga, Akihiko Konagaya
BACKGROUND: Drug development considering individual varieties among patients becomes crucial to improve clinical development success rates and save healthcare costs. As a useful tool to predict individual phenomena and correlations among drug characteristics and individual varieties, recently, whole-body physiologically based pharmacokinetic (WB- PBPK) models are getting more attention. WB-PBPK models generally have a lot of drug-related parameters that need to be estimated, and the estimations are difficult because the observed data are limited...
December 21, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/29319897/application-of-a-physiologically-based-pharmacokinetic-model-for-the-prediction-of-bumetanide-plasma-and-brain-concentrations-in-the-neonate
#3
Maria D Donovan, Khaled Abduljalil, John F Cryan, Geraldine B Boylan, Brendan T Griffin
Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in brain is relevant from a pharmacological prospective. A physiologically-based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and pediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data...
January 10, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29297772/assessment-of-drug-drug-interaction-potential-and-pbpk-modeling-of-cc-223-a-potent-inhibitor-of-the-mammalian-target-of-rapamycin-kinase
#4
Zeen Tong, Rangaraj Narayanan, Christian Atsriku, Jim Nissel, Yan Li, Hong Liu, Xiaomin Wang, Sekhar Surapaneni
1. CC-223 was studied in vitro for metabolism and drug-drug interactions (DDI), and in clinic for interaction with ketoconazole. 2. In vitro, human metabolites of CC-223 included O-desmethyl CC-223 (M1), keto (M2), N-oxide (M3), and imine (M13), with M1 being the most prominent metabolite. 3. CC-223 was metabolized by CYP2C9 and CYP3A, while metabolism of M1 was mediated by CYP2C8 and CYP3A. Ketoconazole increased CC-223 and M1 exposure by 60-70% in healthy volunteers. 4. CC-223 (IC50 ≥ 27 µM) and M1 (IC50 ≥ 46 µM) were inhibitors of CYP2C9 and CYP2C19 in human liver microsomes...
January 3, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29289674/investigating-the-impact-of-drug-crystallinity-in-amorphous-tacrolimus-capsules-on-pharmacokinetics-and-bioequivalence-using-discriminatory-in-vitro-dissolution-testing-and-pbpk-modeling-and-simulation
#5
Hitesh S Purohit, Niraj S Trasi, Dajun D Sun, Edwin C Y Chow, Hong Wen, Xinyuan Zhang, Yi Gao, Lynne S Taylor
Delivering a drug in amorphous form in a formulated product is a strategy used to enhance the apparent solubility of a drug substance and its oral bioavailability. Drug crystallization in such products may occur during the manufacturing process or upon storage, reducing the solubility advantage of the amorphous drug. However, the impact of partial drug crystallization in the drug product on the resulting bioavailability and pharmacokinetics is unknown. In this study, dissolution testing of commercial tacrolimus capsules (which are formulated to contain amorphous drug), both fresh and those containing different amounts of crystalline drug, was conducted using both USP and non-compendial dissolution tests with different dissolution media and volumes...
December 28, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29247905/the-development-of-a-pregnancy-pbpk-model-for-bisphenol-a-and-its-evaluation-with-the-available-biomonitoring-data
#6
Raju Prasad Sharma, Marta Schuhmacher, Vikas Kumar
Recent studies suggest universal fetal exposure to Bisphenol A (BPA) and its association with the adverse birth outcomes. Estimation of the fetal plasma BPA concentration from the maternal plasma BPA would be highly useful to predict its associated risk to this specific population. The objective of current work is to develop a pregnancy-physiologically based pharmacokinetic (P-PBPK) model to predict the toxicokinetic profile of BPA in the fetus during gestational growth, and to evaluate the developed model using biomonitoring data obtained from different pregnancy cohort studies...
December 13, 2017: Science of the Total Environment
https://www.readbyqxmd.com/read/29246152/linking-physiologically-based-pharmacokinetic-and-genome-scale-metabolic-networks-to-understand-estradiol-biology
#7
Joanna H Sier, Alfred E Thumser, Nick J Plant
BACKGROUND: Estrogen is a vital hormone that regulates many biological functions within the body. These include roles in the development of the secondary sexual organs in both sexes, plus uterine angiogenesis and proliferation during the menstrual cycle and pregnancy in women. The varied biological roles of estrogens in human health also make them a therapeutic target for contraception, mitigation of the adverse effects of the menopause, and treatment of estrogen-responsive tumours. In addition, endogenous (e...
December 15, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/29234936/a-generic-whole-body-physiologically-based-pharmacokinetic-model-for-therapeutic-proteins-in-pk-sim
#8
Christoph Niederalt, Lars Kuepfer, Juri Solodenko, Thomas Eissing, Hans-Ulrich Siegmund, Michael Block, Stefan Willmann, Jörg Lippert
Proteins are an increasingly important class of drugs used as therapeutic as well as diagnostic agents. A generic physiologically based pharmacokinetic (PBPK) model was developed in order to represent at whole body level the fundamental mechanisms driving the distribution and clearance of large molecules like therapeutic proteins. The model was built as an extension of the PK-Sim model for small molecules incorporating (i) the two-pore formalism for drug extravasation from blood plasma to interstitial space, (ii) lymph flow, (iii) endosomal clearance and (iv) protection from endosomal clearance by neonatal Fc receptor (FcRn) mediated recycling as especially relevant for antibodies...
December 12, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29228833/in-vitro-in-silico-approach-in-the-development-of-simvastatin-loaded-self-microemulsifying-drug-delivery-systems
#9
Zora Ćetković, Sandra Cvijić, Dragana Vasiljević
OBJECTIVE: The aims of this study were to formulate simvastatin (SV)-loaded self-microemulsifying drug delivery systems (SMEDDS), and explore the potential of these drug delivery systems to improve SV solubility, and also to identify the optimal place in the gastrointestinal (GI) tract for the release of SV using coupled in vitro/in silico approach. SIGNIFICANCE: In comparison to other published results, this study considered the extensive presystemic clearance of SV, which could significantly decrease its systemic and hepatic bioavailability if SV is delivered into the small intestine...
December 12, 2017: Drug Development and Industrial Pharmacy
https://www.readbyqxmd.com/read/29226313/model-based-assessments-of-cyp-mediated-drug-drug-interaction-risk-of-alectinib-physiologically-based-pharmacokinetic-modeling-supported-clinical-development
#10
Yumi Cleary, Michael Gertz, Peter N Morcos, Li Yu, Kuresh Youdim, Alex Phipps, Stephen Fowler, Neil Parrott
Alectinib is a selective anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. Alectinib and its major active metabolite M4 exhibited drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8 in vitro. Clinical relevance of the DDI risk was investigated as part of a rapid development program to fulfil the breakthrough therapy designation. Therefore, a strategy with a combination of physiologically based pharmacokinetic (PBPK) modeling and limited clinical trials focused on generating informative data for modeling was taken to ensure extrapolation ability of DDI risk...
December 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29215597/application-of-pharmacokinetics-modelling-to-predict-human-exposure-of-a-cationic-liposomal-subunit-antigen-vaccine-system
#11
Raj K S Badhan, Swapnil Khadke, Yvonne Perrie
The pharmacokinetics of a liposomal subunit antigen vaccine system composed of the cationic lipid dimethyldioctadecylammonium bromide (DDA) and the immunostimulatory agent trehalose 6,6-dibehenate (TDB) (8:1 molar ratio) combined with the Ag85B-ESAT-6 (H1) antigen were modelled using mouse in-vivo data. Compartment modelling and physiologically based pharmacokinetics (PBPK) were used to predict the administration site (muscle) and target site (lymph) temporal concentration profiles and factors governing these...
December 7, 2017: Pharmaceutics
https://www.readbyqxmd.com/read/29209972/pbpk-pd-assessment-for-parkinson-s-disease-risk-posed-by-airborne-pesticide-paraquat-exposure
#12
Yi-Hsien Cheng, Wei-Chun Chou, Ying-Fei Yang, Chi-Wei Huang, Chun Ming How, Szu-Chieh Chen, Wei-Yu Chen, Nan-Hung Hsieh, Yi-Jun Lin, Shu-Han You, Chung-Min Liao
Exposure to several specific pesticides has led to an increase of Parkinson's disease (PD) risk. However, it is difficult to quantify the PD population risk related to certain pesticides in regions where environmental exposure data are scarce. Furthermore, the time trend of the prevalence and incidence of PD embedded in the background relationship between PD risk and pesticide exposures has not been well characterized. It has been convincingly identified that a key pesticide associated significantly with an increased risk trend of PD is paraquat (PQ)...
December 5, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/29204742/target-and-tissue-selectivity-prediction-by-integrated-mechanistic-pharmacokinetic-target-binding-and-quantitative-structure-activity-modeling
#13
Anna H C Vlot, Wilhelmus E A de Witte, Meindert Danhof, Piet H van der Graaf, Gerard J P van Westen, Elizabeth C M de Lange
Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D) and the target dissociation rate constant on target and tissue selectivity...
December 4, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29204687/a-physiologically-based-pharmacokinetic-pbpk-parent-metabolite-model-of-the-chemotherapeutic-zoptarelin-doxorubicin-integration-of-in-vitro-results-phase-i-and-phase-ii-data-and-model-application-for-drug-drug-interaction-potential-analysis
#14
Nina Hanke, Michael Teifel, Daniel Moj, Jan-Georg Wojtyniak, Hannah Britz, Babette Aicher, Herbert Sindermann, Nicola Ammer, Thorsten Lehr
PURPOSE: Zoptarelin doxorubicin is a fusion molecule of the chemotherapeutic doxorubicin and a luteinizing hormone-releasing hormone receptor (LHRHR) agonist, designed for drug targeting to LHRHR positive tumors. The aim of this study was to establish a physiologically based pharmacokinetic (PBPK) parent-metabolite model of zoptarelin doxorubicin and to apply it for drug-drug interaction (DDI) potential analysis. METHODS: The PBPK model was built in a two-step procedure...
December 4, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29196879/the-feasibility-of-physiologically-based-pharmacokinetic-modeling-in-forensic-medicine-illustrated-by-the-example-of-morphine
#15
Nadine Schaefer, Daniel Moj, Thorsten Lehr, Peter H Schmidt, Frank Ramsthaler
In forensic medicine, expert opinion is often required concerning dose and time of intake of a substance, especially in the context of fatal intoxications. In the present case, a 98-year-old man died 4 days after admission to a hospital due to a femur neck fracture following a domestic fall in his retirement home. As he had obtained high morphine doses in the context of palliative therapy and a confusion of his supplemental magnesium tablets with a diuretic by the care retirement home was suspected by the relatives, a comprehensive postmortem examination was performed...
December 1, 2017: International Journal of Legal Medicine
https://www.readbyqxmd.com/read/29194718/prediction-of-olanzapine-exposure-in-individual-patients-using-physiologically-based-pharmacokinetic-modelling-and-simulation
#16
Thomas M Polasek, Geoffrey T Tucker, Michael J Sorich, Michael D Wiese, Titus Mohan, Amin Rostami-Hodjegan, Porntipa Korprasertthaworn, Vidya Perera, Andrew Rowland
AIM: To predict olanzapine (OLZ) exposure in individual patients using physiologically-based pharmacokinetic modelling and simulation (PBPK M&S). METHODS: A 'bottom-up' PBPK model for OLZ was constructed in Simcyp® (V14.1) and validated against pharmacokinetic studies and data from therapeutic drug monitoring (TDM). The physiological, demographic and genetic attributes of the 'healthy volunteer population' file in Simcyp® were then individualised to create 'virtual twins' of 14 patients...
November 30, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29193123/physiologically-based-pharmacokinetic-modeling-to-evaluate-the-systemic-exposure-of-gefitinib-in-cyp2d6-ultrarapid-metabolizers-and-extensive-metabolizers
#17
Yingxue Chen, Diansong Zhou, Weifeng Tang, Wangda Zhou, Nidal Al-Huniti, Eric Masson
Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase and is used for the treatment of non-small-cell lung cancer (NSCLC) with activating EGFR mutations. Gefitinib is metabolized by CYP2D6 and CYP3A4. This analysis compared the systemic exposure of gefitinib after oral administration in CYP2D6 ultrarapid metabolizers (UM) vs extensive metabolizers (EM). Physiologically based pharmacokinetic (PBPK) modeling was conducted using a population-based simulator. The model was calibrated using itraconazole-gefitinib clinical drug-drug interaction data and validated with gefitinib data in CYP2D6 EM vs poor metabolizers (PM)...
November 28, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29189141/prediction-of-tissue-to-plasma-concentration-ratios-of-drugs-in-the-rat-from-experimentally-estimated-volume-of-distribution-application-of-allometry
#18
Iftekhar Mahmood
BACKGROUND: In physiologically based pharmacokinetic (PBPK) models, the most important input parameter is tissue-to-plasma partition coefficient (Kp). Over the years, several empirical methods have been developed to predict Kp in animals. OBJECTIVES: The objective of this study was to propose two allometric methods to predict Kp from experimentally determined in-vivo volume of distribution at steady state (Vss). METHODS: In one method, Vss was allometrically predicted (using a fixed exponent 1...
November 28, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/29181592/selection-and-qualification-of-simplified-qsp-models-when-using-model-order-reduction-techniques
#19
Chihiro Hasegawa, Stephen B Duffull
Quantitative systems pharmacology (QSP) models are increasingly used in drug development to provide a deep understanding of the mechanism of action of drugs and to identify appropriate disease targets. Such models are, however, not suitable for estimation purposes due to their high dimensionality. Based on any desired and specific input-output relationship, the system may be reduced to a model with fewer states and parameters. However, any simplification process will be a trade-off between model performance and complexity...
November 27, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29176011/estimation-of-fractions-metabolized-by-hepatic-cyp-enzymes-using-a-concept-of-inter-system-extrapolation-factors-isefs-a-comparison-with-the-chemical-inhibition-method
#20
Ken-Ichi Umehara, Felix Huth, Helen Gu, Hilmar Schiller, Tycho Heimbach, Handan He
BACKGROUND: For estimation of fractions metabolized (fm) by different hepatic recombinant human CYP enzymes (rhCYP), calculation of inter-system extrapolation factors (ISEFs) has been proposed. METHODS: ISEF values for CYP1A2, CYP2C19 and CYP3A4/5 were measured. A CYP2C9 ISEF was taken from a previous report. Using a set of compounds, fractions metabolized by CYP enzymes (fm,CYP) values calculated with the ISEFs based on rhCYP data were compared with those from the chemical inhibition data...
November 27, 2017: Drug Metabolism and Personalized Therapy
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