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https://www.readbyqxmd.com/read/28612141/deterministic-identifiability-of-population-pharmacokinetic-and-pharmacokinetic-pharmacodynamic-models
#1
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...
June 13, 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
#2
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
#3
Emmanuel Chigutsa, Amanda J Long, Johan 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 3 study comparing necitumumab in combination with gemcitabine and cisplatin versus gemcitabine and cisplatin alone in 1014 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...
May 31, 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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/27832147/model-linking-plasma-and-intracellular-tenofovir-emtricitabine-with-deoxynucleoside-triphosphates
#12
Xinhui Chen, Sharon M Seifert, Jose R Castillo-Mancilla, Lane R Bushman, Jia-Hua Zheng, Jennifer J Kiser, Samantha MaWhinney, Peter L Anderson
The coformulation of the nucleos(t)ide analogs (NA) tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC) is approved for HIV-infection treatment and prevention. Plasma TFV and FTC undergo complicated hybrid processes to form, accumulate, and retain as their active intracellular anabolites: TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP). Such complexities manifest in nonlinear intracellular pharmacokinetics (PK). In target cells, TFV-DP/FTC-TP compete with endogenous deoxynucleoside triphosphates (dNTP) at the active site of HIV reverse transcriptase, underscoring the importance of analog:dNTP ratios for antiviral efficacy...
2016: PloS One
https://www.readbyqxmd.com/read/27779354/pharmacokinetics-and-analgesic-effectiveness-of-intravenous-parecoxib-for-tonsillectomy-%C3%A2-adenoidectomy
#13
Lena Tan, Elsa Taylor, Jacqueline A Hannam, Lesley Salkeld, Sam Salman, Brian J Anderson
BACKGROUND: Few pharmacokinetic (PK) and pharmacodynamic (PD) data exist for COX-2 selective inhibitors in children. We wished to characterize the PKPD of parecoxib and its active metabolite, valdecoxib, in this population. METHODS: Children (n = 59) were randomized to parecoxib 0.25 mg·kg(-1) , 1 mg·kg(-1) , and 2 mg·kg(-1) during tonsillectomy ± adenoidectomy. Samples (4-6 per child) were obtained from indwelling cannula over 6 h. A second group of inpatient children (n = 15) given 1 mg·kg(-1) contributed PK data from 6 to 24 h...
December 2016: Paediatric Anaesthesia
https://www.readbyqxmd.com/read/27763679/theory-based-pharmacokinetics-and-pharmacodynamics-of-s-and-r-warfarin-and-effects-on-international-normalized-ratio-influence-of-body-size-composition-and-genotype-in-cardiac-surgery-patients
#14
Ling Xue, Nick Holford, Xiao-Liang Ding, Zhen-Ya Shen, Chen-Rong Huang, Hua Zhang, Jing-Jing Zhang, Zhe-Ning Guo, Cheng Xie, Ling Zhou, Zhi-Yao Chen, Lin-Sheng Liu, Li-Yan Miao
AIMS: The aims of this study are to apply a theory-based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin. METHODS: Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population PK parameter with data method was used to describe the international normalized ratio (INR) time course...
April 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27713822/population-pharmacokinetic-and-pharmacodynamic-analyses-of-safinamide-in-subjects-with-parkinson-s-disease
#15
Luca Loprete, Chiara Leuratti, Carlo Cattaneo, Mita M Thapar, Colm Farrell, Marco Sardina
Safinamide is an orally administered α-aminoamide derivative with both dopaminergic and non-dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo-controlled, double-blind efficacy studies. The aim was to estimate safinamide population PK parameters in patients with Parkinson's disease (PD) on stable levodopa therapy, and to develop a model of safinamide effect on the PD phase of normal functioning (ON-time)...
October 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/27713650/glibenclamide-population-pharmacokinetic-pharmacodynamic-modeling-in-south-african-type-2-diabetic-subjects
#16
Virendra Rambiritch, Poobalan Naidoo, Goonaseelan Pillai
AIM: To determine the effective dose of glibenclamide by quantifying the dose-response relationship in South African type 2 diabetic patients. PATIENTS AND METHODS: A total of 24 type 2 diabetic patients participated in a glibenclamide dose-escalation study during which glibenclamide, glucose, and insulin concentrations were quantified, while the dose of glibenclamide was progressively increased. All except four subjects contributed data on all dose-escalation steps; however, data from all 24 patients were included in the model-based analysis...
2016: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/27693714/the-implications-of-model-informed-drug-discovery-and-development-for-tuberculosis
#17
Morris Muliaditan, Geraint R Davies, Ulrika S H Simonsson, Stephen H Gillespie, Oscar Della Pasqua
Despite promising advances in the field and highly efficacious first-line treatment, an estimated 9.6 million people are still infected with tuberculosis (TB). Innovative methods are required to effectively transition the growing number of compounds into novel combination regimens. However, progression of compounds into patients occurs despite the lack of clear understanding of the pharmacokinetic-pharmacodynamic (PKPD) relationships. The PreDiCT-TB consortium was established in response to the existing gaps in TB drug development...
September 28, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27671925/how-to-optimise-drug-study-design-pharmacokinetics-and-pharmacodynamics-studies-introduced-to-paediatricians
#18
Eric Vermeulen, John N van den Anker, Oscar Della Pasqua, Kalle Hoppu, Johanna H van der Lee
OBJECTIVES: In children, there is often lack of sufficient information concerning the pharmacokinetics (PK) and pharmacodynamics (PD) of a study drug to support dose selection and effective evaluation of efficacy in a randomised clinical trial (RCT). Therefore, one should consider the relevance of relatively small PKPD studies, which can provide the appropriate data to optimise the design of an RCT. METHODS: Based on the experience of experts collaborating in the EU-funded Global Research in Paediatrics consortium, we aimed to inform clinician-scientists working with children on the design of investigator-initiated PKPD studies...
April 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/27638857/combining-nonclinical-experiments-with-translational-pkpd-modeling-to-differentiate-erlotinib-and-gefitinib
#19
Miro J Eigenmann, Nicolas Frances, Gerhard Hoffmann, Thierry Lavé, Antje-Christine Walz
We quantitatively compare the efficacy of two approved EGFR tyrosine kinase inhibitors, erlotinib and gefitinib, based on in vivo and in vitro data and show how a modeling approach can be used to scale from animal to humans. Gefitinib shows a higher tumor uptake in cancer patients, and we explored the potential impact on pharmacologic and antitumor activity in in vitro and in xenograft mice. Tumor growth inhibition was monitored, and the pharmacokinetics (PK) in plasma and tumor, as well as temporal changes of phospho-Erk (pErk) signals were examined in patient-derived tumor xenograft mice...
December 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27617278/summary-data-of-potency-and-parameter-information-from-semi-mechanistic-pkpd-modeling-of-prolactin-release-following-administration-of-the-dopamine-d2-receptor-antagonists-risperidone-paliperidone-and-remoxipride-in-rats
#20
Amit Taneja, An Vermeulen, Dymphy R H Huntjens, Meindert Danhof, Elizabeth C M De Lange, Johannes H Proost
We provide the reader with relevant data related to our recently published paper, comparing two mathematical models to describe prolactin turnover in rats following one or two doses of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride, "A comparison of two semi-mechanistic models for prolactin release and prediction of receptor occupancy following administration of dopamine D2 receptor antagonists in rats" (Taneja et al., 2016) [1]. All information is tabulated. Summary level data on the in vitro potencies and the physicochemical properties is presented in Table 1...
September 2016: Data in Brief
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