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https://www.readbyqxmd.com/read/29143334/pk-pd-modeling-of-flunixin-meglumine-in-a-kaolin-induced-inflammation-model-in-piglets
#1
O L Levionnois, T K Fosse, B Ranheim
Flunixin is marketed in several countries for analgesia in adult swine but little is known about its efficacy in piglets. Thirty-two piglets (6-8 days old) were randomized to receive placebo saline (n = 11, group CONTROL) or flunixin meglumine intravenously at 2.2 (n = 11, group MEDIUM) or 4.4 (n = 10, group HIGH) mg/kg, 10 hr after subcutaneous injection of kaolin in the left metacarpal area. A hand-held algometer was used to determine each piglet's mechanical nociceptive threshold (MNT) from both front feet up to 50 hr after treatment (cut-off value of 24...
November 16, 2017: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29127049/predicting-mutant-selection-in-competition-experiments-with-ciprofloxacin-exposed-escherichia-coli
#2
David D Khan, Pernilla Lagerbäck, Christer Malmberg, Anders N Kristoffersson, Erik Gullberg, Cao Sha, Otto Cars, Dan I Andersson, Diarmaid Hughes, Elisabet I Nielsen, Lena E Friberg
Predicting competition between antibiotic susceptible wild-type and less susceptible mutant bacteria is valuable for understanding how drug concentrations influence emergence of resistance. Pharmacokinetic-pharmacodynamic (PKPD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thereby be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PKPD model for its ability to predict in vitro mixed-population experiments with competition between E...
November 7, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/29090407/pkpd-modeling-of-acquired-resistance-to-anti-cancer-drug-treatment
#3
Miro J Eigenmann, Nicolas Frances, Thierry Lavé, Antje-Christine Walz
Non-small cell lung cancer (NSCLC) patients greatly benefit from the treatment with tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR). However, emergence of acquired resistance inevitable occurs after long-term treatment in most patients and limits clinical improvement. In the present study, resistance to drug treatment in patient-derived NSCLC xenograft mice was assessed and modeling and simulation was applied to understand the dynamics of drug resistance as a basis to explore more beneficial drug regimen...
October 31, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28961946/can-a-pharmacokinetic-pharmacodynamic-pkpd-model-be-predictive-across-bacterial-densities-and-strains-external-evaluation-of-a-pkpd-model-describing-longitudinal-in-vitro-data
#4
Elisabet I Nielsen, David D Khan, Sha Cao, Ulrika Lustig, Diarmaid Hughes, Dan I Andersson, Lena E Friberg
Background: Pharmacokinetic/pharmacodynamic (PKPD) models developed based on data from in vitro time-kill experiments have been suggested to contribute to more efficient drug development programmes and better dosing strategies for antibiotics. However, for satisfactory predictions such models would have to show good extrapolation properties. Objectives: To evaluate if a previously described mechanism-based PKPD model was able also to predict drug efficacy for higher bacterial densities and across bacterial strains...
November 1, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28888218/impact-of-non-adherence-on-the-safety-and-efficacy-of-uric-acid-lowering-therapies-in-the-treatment-of-gout
#5
Daniel Hill-McManus, Elena Soto, Scott Marshall, Steven Lane, Dyfrig Hughes
AIMS: Dual-urate lowering therapy (ULT) with xanthine oxidase inhibitor and uricosuric medications is a treatment option for severe gout. Uricosurics can cause hyperuricosuria, a risk factor for nephrolithiasis and acute uric acid nephropathy. The aims of this study were to simulate the relation between suboptimal drug adherence and efficacy, and to quantify the risk of hyperuricosuria in gout patients receiving mono and dual-ULTs. METHODS: The impact of poor medication adherence was studied using 2-compartment PK models based on published evidence and a semi-mechanistic, 4-compartment pharmacodynamic (PD) model...
September 9, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28882765/multivariate-pharmacokinetic-pharmacodynamic-pkpd-analysis-with-metabolomics-shows-multiple-effects-of-remoxipride-in-rats
#6
W J van den Brink, J Elassaiss-Schaap, B Gonzalez-Amoros, A C Harms, P H van der Graaf, T Hankemeier, E C M de Lange
The study of central nervous system (CNS) pharmacology is limited by a lack of drug effect biomarkers. Pharmacometabolomics is a promising new tool to identify multiple molecular responses upon drug treatment. However, the pharmacodynamics is typically not evaluated in metabolomics studies, although being important properties of biomarkers. In this study we integrated pharmacometabolomics with pharmacokinetic/pharmacodynamic (PKPD) modeling to identify and quantify the multiple endogenous metabolite dose-response relations for the dopamine D2 antagonist remoxipride...
September 4, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28854543/dexmedetomidine-pharmacodynamics-in-healthy-volunteers-2-haemodynamic-profile
#7
P J Colin, L N Hannivoort, D J Eleveld, K M E M Reyntjens, A R Absalom, H E M Vereecke, M M R F Struys
Background: Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, with little respiratory depression and rousability during sedations. We characterized the haemodynamic properties of dexmedetomidine by developing a pharmacokinetic-pharmacodynamic (PKPD) model with a focus on changes in mean arterial blood pressure (MAP) and heart rate. Methods: Dexmedetomidine was delivered i.v. to 18 healthy volunteers in a step-up fashion by target-controlled infusion using the Dyck model...
August 1, 2017: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/28811131/assessment-of-translational-risk-in-drug-research-role-of-biomarker-classification-and-mechanism-based-pkpd-concepts
#8
Sandra A G Visser, Tjerk J H Bueters
In 2005, Danhof and coauthors proposed a new biomarker classification in the context of the application of mechanism-based PKPD modeling. They defined the term 'biomarker' as a measure that characterizes a drug-induced response, which is on the causal path between drug administration and clinical outcome. The biomarker classification identified seven categories that provide different insights into the kinetics of drug action, such as target site distribution, target engagement, or into the impact of the drug on physiology or disease...
August 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28739794/population-pharmacokinetics-of-azd-5847-in-adults-with-pulmonary-tuberculosis
#9
Abdullah Alsultan, Jennifer J Furin, Jeannine Du Bois, Elana van Brakel, Phalkun Chheng, Amour Venter, Bonnie Thiel, Sara A Debanne, W Henry Boom, Andreas H Diacon, John L Johnson, Charles A Peloquin
AZD-5847 is a new oxazolidinone derivative under development for the treatment of tuberculosis (TB). Here we describe the population pharmacokinetics (PK) of AZD-5847 in patients with tuberculosis based on a recently completed phase II study. The study included 60 patients with drug-susceptible TB. Patients were randomized to four dosages (500 mg once daily, 1,200 mg once daily, 500 mg twice daily, and 800 mg twice daily). Patients were intensively sampled on days 1 and 14. AZD-5847 pharmacokinetics were best described with a two-compartment model with lag time (Tlag) for absorption...
October 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28612141/deterministic-identifiability-of-population-pharmacokinetic-and-pharmacokinetic-pharmacodynamic-models
#10
Vijay K Siripuram, Daniel F B Wright, Murray L Barclay, Stephen B Duffull
Identifiability is an important component of pharmacokinetic-pharmacodynamic (PKPD) model development. Structural identifiability is concerned with the uniqueness of the model parameters for a set of perfect input-output data and deterministic identifiability with the precision of parameter estimation given imperfect input-output data. We introduce two subcategories of deterministic identifiability, external and internal, and consider factors that distinguish between these forms. We define external deterministic identifiability as a function of externally controllable variables, i...
October 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28596836/characterizing-qt-interval-prolongation-in-early-clinical-development-a-case-study-with-methadone
#11
Vincent F S Dubois, Meindert Danhof, Oscar Della Pasqua
Recently, we have shown how pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to assess the probability of QT interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate nonclinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of dromotropic drug effects in humans. ECG and drug concentration data from a safety pharmacology study in dogs were analyzed using nonlinear mixed effects modeling...
February 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28569042/exposure-response-analysis-of-necitumumab-efficacy-in-squamous-non-small-cell-lung-cancer-patients
#12
E Chigutsa, A J Long, J E Wallin
We sought to describe the exposure-response relationship of necitumumab efficacy in squamous non-small cell lung cancer patients and evaluate intrinsic and extrinsic patient descriptors that may guide dosing. SQUIRE was a phase III study comparing necitumumab in combination with gemcitabine and cisplatin vs. gemcitabine and cisplatin alone in 1,014 patients. An integrated model for tumor size dynamics and overall survival was developed, where reduction in tumor size results in a decrease in survival hazard...
August 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28508378/population-pharmacokinetic-and-pharmacodynamic-modeling-of-etelcalcetide-in-patients-with-chronic-kidney-disease-and-secondary-hyperparathyroidism-receiving-hemodialysis
#13
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/28289389/understanding-physiology-in-the-continuum-integration-of-information-from-multiple-omics-levels
#14
Kubra Kamisoglu, Alison Acevedo, Richard R Almon, Susette Coyle, Siobhan Corbett, Debra C Dubois, Tung T Nguyen, William J Jusko, Ioannis P Androulakis
In this paper, we discuss approaches for integrating biological information reflecting diverse physiologic levels. In particular, we explore statistical and model-based methods for integrating transcriptomic, proteomic and metabolomics data. Our case studies reflect responses to a systemic inflammatory stimulus and in response to an anti-inflammatory treatment. Our paper serves partly as a review of existing methods and partly as a means to demonstrate, using case studies related to human endotoxemia and response to methylprednisolone (MPL) treatment, how specific questions may require specific methods, thus emphasizing the non-uniqueness of the approaches...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28213092/prediction-of-thyroid-c-cell-carcinogenicity-after-chronic-administration-of-glp1-r-agonists-in-rodents
#15
Willem van den Brink, Annette Emerenciana, Francesco Bellanti, Oscar Della Pasqua, Jan Willem van der Laan
Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products...
April 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28074396/target-mediated-drug-disposition-with-drug-drug-interaction-part-ii-competitive-and-uncompetitive-cases
#16
Gilbert Koch, William J Jusko, Johannes Schropp
We present competitive and uncompetitive drug-drug interaction (DDI) with target mediated drug disposition (TMDD) equations and investigate their pharmacokinetic DDI properties. For application of TMDD models, quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are necessary to reduce the number of parameters. To realize those approximations of DDI TMDD models, we derive an ordinary differential equation (ODE) representation formulated in free concentration and free receptor variables. This ODE formulation can be straightforward implemented in typical PKPD software without solving any non-linear equation system arising from the QE or QSS approximation of the rapid binding assumptions...
February 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27934627/characterization-and-prediction-of-cardiovascular-effects-of-fingolimod-and-siponimod-using-a-systems-pharmacology-modeling-approach
#17
Nelleke Snelder, Bart A Ploeger, Olivier Luttringer, Dean F Rigel, Randy L Webb, David Feldman, Fumin Fu, Michael Beil, Liang Jin, Donald R Stanski, Meindert Danhof
Sphingosine 1-phosphate (S1P) receptor agonists are associated with cardiovascular effects in humans. This study aims to develop a systems pharmacology model to identify the site of action (i.e., primary hemodynamic response variable) of S1P receptor agonists, and to predict, in a quantitative manner, the cardiovascular effects of novel S1P receptor agonists in vivo. The cardiovascular effects of once-daily fingolimod (0, 0.1, 0.3, 1, 3, and 10 mg/kg) and siponimod (3 and 15 mg/kg) were continuously recorded in spontaneously hypertensive rats and Wistar-Kyoto rats...
February 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27931193/coagulase-negative-staphylococcal-sepsis-in-neonates-do-we-need-to-adapt-vancomycin-dose-or-target
#18
Helgi Padari, Kersti Oselin, Tõnis Tasa, Tuuli Metsvaht, Krista Lõivukene, Irja Lutsar
BACKGROUND: Despite differences in types of infection and causative organisms, pharmacokinetic-pharmacodynamic (PKPD) targets of vancomycin therapy derived from adult studies are suggested for neonates. We aimed to identify doses needed for the attainment of AUC/MIC > 400 and AUC/MIC > 300 in neonates with sepsis and correlate these targets with recommended doses and treatment outcome. METHODS: Neonates who had Vancomycin therapeutic drug monitoring (TDM) performed between January 1, 2010 and December 31, 2012 were studied...
December 8, 2016: BMC Pediatrics
https://www.readbyqxmd.com/read/27927703/pharmacokinetics-and-pharmacodynamics-of-oral-mecamylamine-development-of-a-nicotinic-acetylcholine-receptor-antagonist-cognitive-challenge-test-using-modelling-and-simulation
#19
Ricardo Alvarez-Jimenez, Anne Catrien Baakman, Jasper Stevens, Sebastiaan C Goulooze, Ellen P Hart, Robert Rissmann, Joop Ma van Gerven, Geert Jan Groeneveld
A pharmacologic challenge model with a nicotinic antagonist could be an important tool not only to understand the complex role of the nicotinic cholinergic system in cognition, but also to develop novel compounds acting on the nicotinic acetylcholine receptor. The objective was to develop a pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed effects (NLME) methods to quantitate the pharmacokinetics of three oral mecamylamine doses (10, 20 and 30 mg) and correlate the plasma concentrations to the pharmacodynamic effects on a cognitive and neurophysiologic battery of tests in healthy subjects...
December 7, 2016: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/27836941/target-site-investigation-for-the-plasma-prolactin-response-mechanism-based-pharmacokinetic-pharmacodynamic-analysis-of-risperidone-and-paliperidone-in-the-rat
#20
Shinji Shimizu, Sandra M den Hoedt, Victor Mangas-Sanjuan, Sinziana Cristea, Jana K Geuer, Dirk-Jan van den Berg, Robin Hartman, Francisco Bellanti, Elizabeth C M de Lange
To understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semiphysiologically based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was developed to describe prolactin responses to risperidone (RIS) and its active metabolite paliperidone (PAL). We performed a microdialysis study in rats to obtain detailed plasma, brain extracellular fluid (ECF), and cerebrospinal fluid (CSF) concentrations of PAL and RIS. To assess the impact of P-glycoprotein (P-gp) functioning on brain distribution, we performed experiments in the absence or presence of the P-gp inhibitor tariquidar (TQD)...
February 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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