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https://www.readbyqxmd.com/read/28532263/establishment-and-assessment-of-a-novel-in-vitro-bio-pk-pd-system-in-predicting-the-in-vivo-pharmacokinetics-and-pharmacodynamics-of-cyclophosphamide
#1
Shanshan Tong, Hong Sun, Caifu Xue, Hanmei Chen, Jing Liu, Huiying Yang, Ning Zhou, Xiaoqiang Xiang, Weimin Cai
1. A novel bio-pharmacokinetic/pharmacodynamic (PK/PD) system was established and assessed in predicting the PK parameters and PD effects of the model drug cyclophosphamide (CP) considering the interrelationships between drug metabolism, pharmacological effects and dynamic blood circulation processes in vitro. 2. The system contains a peristaltic pump, a reaction chamber with rat liver microsomes (RLMs) encapsulated in pluronic F127-acrylamide-bisacrylamide (FAB) hydrogels, an effector cell chamber and a recirculating pipeline...
May 23, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28518053/effects-of-genetic-variants-in-ugt1a1-slco1b3-abcb1-abcc2-abcg2-orm1-on-pk-pd-of-telmisartan-in-chinese-patients-with-mild-to-moderate-essential-hypertension%C3%A2
#2
Qi Pei, Liu Yang, Hong-Yi Tan, Shi-Kun Liu, Yang Liu, Lu Huang, Rong-Hui Li, Qian Wan, Jie Huang, Cheng-Xian Guo, Xiao-Cong Zuo, Jingle Li, Guo-Ping Yang
PURPOSE: This study aimed to understand the effects of single nucleotide polymorphisms (SNPs) in UGT1A1, SLCO1B3, ABCB1, ABCC2, ABCG2, and ORM1 on the pharmacokinetics (PK) (plasma concentration) and pharmacodynamics (PD) (blood pressure) of telmisartan in Chinese patients. METHODS: 58 Han Chinese patients (aged 45 - 72 years) with mild to moderate essential hypertension were included and received 80 mg/day telmisartan for 4 weeks. The plasma concentration and genetic variants were determined by LC/MS/MS and MALDI-TOF mass spectrometry, respectively...
May 18, 2017: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28516358/mechanistic-modeling-of-the-pharmacodynamic-and-pharmacokinetic-relationship-of-tissue-factor-pathway-inhibitor-neutralizing-antibody-bay-1093884-in-cynomolgus-monkeys
#3
Jian-Ming Gu, Xiao-Yan Zhao, Thomas Schwarz, Joachim Schuhmacher, Andreas Baumann, Elena Ho, Babu Subramanyan, Kathy Tran, Timothy Myles, Chandra Patel, Maria Koellnberger
BAY 1093884 is a fully human monoclonal antibody against the tissue factor pathway inhibitor (TFPI) in development as prophylaxis in patients with hemophilia with or without inhibitors. In vitro, BAY 1093884 binds to human, mouse, and monkey TFPI. The objective of this study was to find a pharmacodynamic (PD) biomarker after administration of BAY 1093884 to normal monkeys. In monkey plasma, BAY 1093884 exhibited an IC50 (concentration that inhibits 50%) of 4.65 and 6.19 nM for free TFPI and diluted prothrombin time (dPT), respectively...
May 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28510738/pharmacokinetic-pharmacodynamic-model-for-unfractionated-heparin-dosing-during-cardiopulmonary-bypass
#4
X Delavenne, E Ollier, S Chollet, F Sandri, J Lanoiselée, S Hodin, A Montmartin, J-F Fuzellier, P Mismetti, L Gergelé
Background: High-dose heparin is used during cardiopulmonary bypass (CPB) to prevent thrombosis in the circuits used for extracorporeal circulation. The aim of this study was, initially, to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to assess the variability of PK/PD parameters and their correlation with the results of the routine haemostatic test activated clotting time (ACT) and thereafter to develop a Bayesian estimator enabling an individualized dosing strategy...
May 1, 2017: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/28508378/population-pharmacokinetic-and-pharmacodynamic-modeling-of-etelcalcetide-in-patients-with-chronic-kidney-disease-and-secondary-hyperparathyroidism-receiving-hemodialysis
#5
Ping Chen, Adimoolam Narayanan, Benjamin Wu, Per Olsson Gisleskog, John P Gibbs, Andrew T Chow, Murad Melhem
INTRODUCTION: Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). METHODS: To assess titrated dosing regimens, population pharmacokinetic (PK) and PK/pharmacodynamic (PKPD) modeling of etelcalcetide was performed using NONMEM 7.2. In this analysis, plasma etelcalcetide, serum parathyroid hormone (PTH) and calcium (Ca) concentration-time data were collected from five phase I, II, and III clinical trials following single or multiple intravenous doses of etelcalcetide ranging from 2...
May 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28507715/a-quantitative-mechanistic-pk-pd-model-directly-connects-btk-target-engagement-and-in-vivo-efficacy
#6
Fereidoon Daryaee, Zhuo Zhang, Kayla R Gogarty, Yong Li, Jonathan Merino, Stewart L Fisher, Peter J Tonge
Correlating target engagement with in vivo drug activity remains a central challenge in efforts to improve the efficiency of drug discovery. Previously we described a mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model that used drug-target binding kinetics to successfully predict the in vivo efficacy of antibacterial compounds in models of Pseudomonas aeruginosa and Staphylococcus aureus infection. In the present work we extend this model to quantitatively correlate the engagement of Bruton's tyrosine kinase (Btk) by the covalent inhibitor CC-292 with the ability of this compound to reduce ankle swelling in an animal model of arthritis...
May 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28507117/pharmacokinetics-of-levofloxacin-in-multidrug-and-extensively-drug-resistant-tuberculosis-patients
#7
Natasha Van't Boveneind-Vrubleuskaya, Tatiana Seuruk, Kai van Hateren, Tridia van der Laan, Jos G W Kosterink, Tjip S van der Werf, Dick van Soolingen, Susan van den Hof, Alena Skrahina, Jan-Willem C Alffenaar
Pharmacodynamics are important in treatment of especially multidrug- and extensively resistant tuberculosis (M/XDR-TB). The free area under the concentration time curve in relation to minimal inhibitory concentration (fAUC/MIC) is the most relevant pharmacokinetic (PK)-pharmacodynamic (PD) parameter to predict the efficacy of levofloxacin (LFX). The objective of our study was to assess LFX PK variability in M/XDR-TB patients and its potential consequence for fAUC/MIC ratios. Patients with pulmonary M/XDR-TB received LFX as part of treatment regimen at a dose of 15 mg/kg once daily...
May 15, 2017: Antimicrobial Agents and Chemotherapy
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/28502671/integrating-clinical-metabolomics-based-biomarker-discovery-and-clinical-pharmacology-to-enable-precision-medicine
#9
Isabelle Kohler, Thomas Hankemeier, Piet H van der Graaf, Catherijne A J Knibbe, J G Coen van Hasselt
Novel developments in biomarkers discovery are essential in modern health care, notably in treatment individualization and precision medicine. Clinical metabolomics, which aims to identify small molecule metabolites present in patient-derived samples, has attracted much attention to support discovery of novel biomarkers. However, the step from discriminatory features of disease states towards biomarkers that can truly individualize treatments is challenging. Biomarkers used for treatment individualization can either be dynamic or static prognostic biomarkers...
May 11, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28497320/accelerating-drug-development-by-efficiently-using-emerging-pk-pd-data-from-an-adaptable-entry-into-human-trial-example-of-lumretuzumab
#10
Georgina Meneses-Lorente, Christine McIntyre, Joy C Hsu, Marlene Thomas, Wolfgang Jacob, Celine Adessi, Martin Weisser
PURPOSE: This study aimed at evaluating if pharmacokinetic and pharmacodynamic data from the first few patients treated with an investigational monoclonal antibody in a dose-escalation study can be used to guide the early initiation of potentially more efficacious combination regimens. METHODS: Emerging pharmacokinetic and pharmacodynamic data from the first nine patients treated with lumretuzumab (a glycoengineered anti-HER3 monoclonal antibody) monotherapy at doses from 100 to 400 mg q2w were used along with a pharmacokinetic model that incorporated target-mediated drug disposition to guide the selection of the starting dose for use in combination regimens...
June 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28496463/antibacterial-loaded-spray-dried-chitosan-polyelectrolyte-complexes-as-dry-powder-aerosol-for-the-treatment-of-lung-infections
#11
Brahmeshwar Mishra, Madhusmita Mishra, Sarita Kumari Yadav
Inhalation delivery of aerosolized antibacterials is preferred over conventional methods of delivery for targeting lung infection. The present study is concerned with the development and characterization of a novel, spray dried, aerosolized, chitosan polyelectrolyte complex (PEC) based microparticles containing antibacterials for the treatment of lung infections. Chitosan polyelectrolyte complex microparticles were formulated by spray drying process. Prepared spray dried chitosan PEC microparticles were studied for surface morphology, drug encapsulation efficiency, moisture content, Carr's index, solid state interaction by XRD, aerosolization behaviour and in-vitro drug release...
2017: Iranian Journal of Pharmaceutical Research: IJPR
https://www.readbyqxmd.com/read/28476536/translational-pharmacokinetic-pharmacodynamic-analysis-in-the-pharmaceutical-industry-an-iq-consortium-pk-pd-discussion-group-perspective
#12
Harvey Wong, Tonika Bohnert, Valeriu Damian-Iordache, Christopher Gibson, Cheng-Pang Hsu, Anu Shilpa Krishnatry, Bianca M Liederer, Jing Lin, Qiang Lu, Jerome T Mettetal, Daniel R Mudra, Marjoleen J M A Nijsen, Patricia Schroeder, Edgar Schuck, Satyendra Suryawanshi, Patrick Trapa, Alice Tsai, Haiqing Wang, Fan Wu
With inadequate efficacy being the primary cause for the attrition of drug candidates in clinical development, the need to better predict clinical efficacy earlier in the drug development process has increased in importance in the pharmaceutical industry. Here, we review current applications of translational pharmacokinetic-pharmacodynamic (PK-PD) modeling of preclinical data in the pharmaceutical industry, including best practices. Preclinical translational PK-PD modeling has been used in many therapeutic areas and has been impactful to drug development...
May 2, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28472247/pharmacodynamics-of-isavuconazole-for-invasive-mold-disease-role-of-galactomannan-for-real-time-monitoring-of-therapeutic-response
#13
Laura L Kovanda, Ruwanthi Kolamunnage-Dona, Michael Neely, Johan Maertens, Misun Lee, William W Hope
Background.: The ability to make early therapeutic decisions when treating invasive aspergillosis using changes in biomarkers as a surrogate for therapeutic response could significantly improve patient outcome. Methods.: Cox proportional hazards model and logistic regression were used to correlate early changes in galactomannan index (GMI) to mortality and overall response, respectively, from patients with positive baseline GMI (≥0.5) and serial GMI during treatment from a phase 3 clinical trial for the treatment of invasive mold disease...
June 1, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/28470723/pharmacokinetics-milk-penetration-and-pk-pd-analysis-by-monte-carlo-simulation-of-marbofloxacin-after-intravenous-and-intramuscular-administration-to-lactating-goats
#14
A M Lorenzutti, N J Litterio, M A Himelfarb, M D P Zarazaga, M I San Andrés, J J De Lucas
The main objectives of this study were (i) to evaluate the serum pharmacokinetic behaviour and milk penetration of marbofloxacin (MFX; 5 mg/kg), after intravenous (IV) and intramuscular (IM) administration in lactating goats and simulate a multidose regimen on steady-state conditions, (ii) to determine the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of coagulase negative staphylococci (CNS) isolated from caprine mastitis in Córdoba, Argentina and (iii) to make a PK/PD analysis by Monte Carlo simulation from steady-state pharmacokinetic parameters of MFX by IV and IM routes to evaluate the efficacy and risk of the emergence of resistance...
May 4, 2017: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28470147/assessment-of-urinary-pharmacokinetics-and-pharmacodynamics-of-orbifloxacin-in-healthy-dogs-with-ex-vivo-modelling
#15
Takae Shimizu, Kazuki Harada, Saki Manabe, Taku Tsukamoto, Norihiko Ito, Yoshiaki Hikasa
PURPOSE: The aim of this study was to investigate the urinary pharmacokinetics (PK) of orbifloxacin (OBFX) administered at 5 mg kg-1 in six healthy dogs. A further aim was to use an ex vivo model to evaluate the urinary PK and pharmacodynamics (PD) of OBFX to determine its urinary bactericidal titre (UBT), which represents the maximal dilution of urine allowing bactericidal activity. METHODOLOGY: Fourteen urinary tract infection (UTI) pathogenic strains of five bacterial species (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis and Staphylococcuspseudintermedius) were used...
May 2017: Journal of Medical Microbiology
https://www.readbyqxmd.com/read/28464333/pharmacokinetic-and-pharmacodynamic-integration-and-modeling-of-acetylkitasamycin-in-swine-for-clostridium-perfringens
#16
J Nan, H Hao, S Xie, Y Pan, C Xi, F Mao, Z Liu, L Huang, Z Yuan
The aim of this study was to establish an integrated pharmacokinetic/pharmacodynamic (PK/PD) modeling approach of acetylkitasamycin for designing dosage regimens and decreasing the emergence of drug-resistant bacteria. After oral administration of acetylkitasamycin to healthy and infected pigs at the dose of 50 mg/kg body weights (bw), a rapid and sensitive LC-MS/MS method was developed and validated for determining the concentration change of the major components of acetylkitasamycin and its possible metabolite kitasamycin in the intestinal samples taken from the T-shape ileal cannula...
May 2, 2017: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28455999/pharmacokinetics-of-posaconazole-in-koalas-phascolarctos-cinereus-after-intravenous-and-oral-administration
#17
S Gharibi, B Kimble, L Vogelnest, J Barnes, C K Stadler, M Govendir
The pharmacokinetic profile of posaconazole in clinically normal koalas (n = 8) was investigated. Single doses of posaconazole were administered intravenously (i.v.; 3 mg/kg; n = 2) or orally (p.o.; 6 mg/kg; n = 6) with serial plasma samples collected over 24 and 36 hr, respectively. Plasma concentrations of posaconazole were quantified by validated high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis of data was performed. Following i.v. administration, estimates of the median (range) of plasma clearance (CL) and steady-state volume of distribution (Vss ) were 0...
April 29, 2017: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28437278/pharmacodynamic-and-kinetic-behavior-of-low-intermediate-and-high-dose-landiolol-during-long-term-infusion-in-caucasians
#18
Günther Krumpl, Ivan Ulč, Michaela Trebs, Pavla Kadlecová, Juri Hodisch, Gabriele Maurer, Bernhard Husch
PK, PD, safety, and tolerability of long-term administration of landiolol, a fast-acting cardioselective β-blocker, were investigated for the first time in Caucasian subjects in a prospective clinical trial.Blood concentrations of landiolol and its metabolites, HR, BP and ECG parameters were studied in twelve healthy volunteers receiving continuous infusions of a new 12 mg/mL formulation of landiolol using a dose-escalation regimen (10 µg/kg BW/min for 2 hr, 20 µg/kg BW/min for 2 hr, 40 µg/kg BW/min for 20 hr, 6 hr follow-up)...
April 18, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28416614/modeling-combined-immunosuppressive-and-anti-inflammatory-effects-of-dexamethasone-and-naproxen-in-rats-predicts-the-steroid-sparing-potential-of-naproxen
#19
Xiaonan Li, Debra C DuBois, Dawei Song, Richard R Almon, William J Jusko, Xijing Chen
Dexamethasone (DEX), a widely prescribed corticosteroid (CS), has long been the cornerstone for the treatment of inflammation and immunological dysfunctions in Rheumatoid Arthritis (RA). The CS are frequently used in combination with other anti-rheumatic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs) to mitigate disease symptoms and minimize unwanted effects. The steroid dose-sparing potential of the NSAID naproxen (NPX) was explored with in vitro and in vivo studies...
April 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28416552/in-vivo-pharmacodynamic-target-assessment-of-eravacycline-against-escherichia-coli-in-a-murine-thigh-infection-model
#20
Miao Zhao, Alexander J Lepak, Karen Marchillo, Jamie VanHecker, David R Andes
Eravacycline is a novel fluorocycline antibiotic with potent activity against a broad range of pathogens, including strains with tetracycline and other drug-resistance phenotypes. The goal of the studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy in the murine thigh infection model. Six E. coli were utilized for the studies. MICs were determined using CLSI methods and ranged from 0.125 to 0.25 mg/L. A neutropenic murine thigh infection model was utilized for all treatment studies...
April 17, 2017: Antimicrobial Agents and Chemotherapy
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