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https://www.readbyqxmd.com/read/29734810/theoretical-insights-into-the-retinal-dynamics-of-vegf-in-patients-treated-with-ranibizumab-based-on-an-ocular-pharmacokinetic-pharmacodynamic-model
#1
Laurence A Hutton-Smith, Eamonn A Gaffney, Helen M Byrne, Antonello Caruso, Philip K Maini, Norman Alan Mazer
Neovascular age-related macular degeneration (wet AMD) results from the pathological angiogenesis of choroidal capillaries, which leak fluid within or below the macular region of the retina. The current standard of care for treating wet AMD utilizes intravitreal injections of anti-VEGF antibodies or antibody fragments to suppress ocular VEGF levels. While VEGF suppression has been demonstrated in wet AMD patients by serial measurements of free-VEGF concentrations in aqueous humor samples, it is presumed that anti-VEGF molecules also permeate across the inner limiting membrane (ILM) of the retina as well as the retinal pigmented epithelium (RPE) and suppress VEGF-levels in the retina and/or choroidal regions...
May 7, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29675639/pharmacokinetic-pharmacodynamic-modeling-in-pediatric-drug-development-and-the-importance-of-standardized-scaling-of-clearance
#2
REVIEW
Eva Germovsek, Charlotte I S Barker, Mike Sharland, Joseph F Standing
Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects...
April 19, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29463551/prediction-of-the-optimal-dosing-regimen-using-a-mathematical-model-of-tumour-uptake-for-immunocytokine-based-cancer-immunotherapy
#3
Benjamin Ribba, Christophe Boetsch, Tapan K Nayak, Hans Peter Grimm, Jehad M Charo, Stefan Evers, Christian Klein, Jean J L Tessier, Jean Eric Charoin, Alex Phipps, Pavel Pisa, Volker Teichgräber
PURPOSE: Optimal dosing is critical for immunocytokine-based cancer immunotherapy to maximize efficacy and minimize toxicity. Cergutuzumab amunaleukin (CEA-IL2v) is a novel CEA-targeted immunocytokine. We set out to develop a mathematical model to predict intratumoral CEA-IL2v concentrations following various systemic dosing intensities. EXPERIMENTAL DESIGN: Sequential measurements of CEA-IL2v plasma concentrations in 74 patients with solid tumors were applied in a series of differential equations to devise a model that also incorporates the peripheral concentrations of IL-2 receptor-positive cell populations (i...
February 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29401079/effect-site-target-controlled-infusion-in-the-obese-model-derivation-and-performance-assessment
#4
Luis I Cortínez, Pablo Sepúlveda, Augusto Rolle, Pauline Cottin, Alexandre Guerrini, Brian J Anderson
BACKGROUND: The aim of this study is to derive a propofol pharmacokinetic (PK) pharmacodynamic (PD) model to perform effect-site target-controlled infusion (TCI) in obese patients, and to analyze its performance along with that of other available PK models. METHODS: In the first step of the study, a 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (keo) was used to fit propofol concentration-bispectral index (BIS) data...
February 2, 2018: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/29355662/biotherapeutics-in-non-clinical-development-strengthening-the-interface-between-safety-pharmacokinetics-pharmacodynamics-and-manufacturing
#5
Peter Ulrich, Guenter Blaich, Andreas Baumann, Rajni Fagg, Adam Hey, Andrea Kiessling, Sven Kronenberg, Rikke Hvid Lindecrona, Silke Mohl, Wolfgang F Richter, Jay Tibbitts, Flavio Crameri, Lucinda Weir
Biological drugs comprise a wide field of different modalities with respect to structure, pharmacokinetics and pharmacological function. Considerable non-clinical experience in the development of proteins (e.g. insulin) and antibodies has been accumulated over the past thirty years. In order to improve the efficacy and the safety of these biotherapeutics, Fc modifications (e.g. Fc silent antibody versions), combinations (antibody-drug conjugates, protein-nanoparticle combinations), and new constructs (darpins, fynomers) have been introduced...
April 2018: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29302838/gpkpdsim-a-simbiology-%C3%A2-based-gui-application-for-pkpd-modeling-in-drug-development
#6
Iraj Hosseini, Anita Gajjala, Daniela Bumbaca Yadav, Siddharth Sukumaran, Saroja Ramanujan, Ricardo Paxson, Kapil Gadkar
Modeling and simulation (M&S) is increasingly used in drug development to characterize pharmacokinetic-pharmacodynamic (PKPD) relationships and support various efforts such as target feasibility assessment, molecule selection, human PK projection, and preclinical and clinical dose and schedule determination. While model development typically require mathematical modeling expertise, model exploration and simulations could in many cases be performed by scientists in various disciplines to support the design, analysis and interpretation of experimental studies...
April 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29229429/semi-mechanistic-pharmacokinetic-pharmacodynamic-modelling-of-antibiotic-drug-combinations
#7
REVIEW
M J E Brill, A N Kristoffersson, C Zhao, E I Nielsen, L E Friberg
BACKGROUND: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens...
December 8, 2017: Clinical Microbiology and Infection
https://www.readbyqxmd.com/read/29198064/claiming-desmopressin-therapeutic-equivalence-in-children-requires-pediatric-data-a-population-pkpd-analysis
#8
Robin Michelet, Lien Dossche, Charlotte Van Herzeele, Jan Van Bocxlaer, An Vermeulen, Johan Vande Walle
PURPOSE: For a new formulation of a drug, only pharmacokinetic bioequivalence with the original formulation has to be demonstrated in healthy, young adults. However, "children are not small adults," and to guarantee a safe and effective treatment, age-adapted drug development is required. Desmopressin, a vasopressin analogue prescribed for nocturnal enuresis in children, was studied as an example formulation first developed in adults and then extrapolated to a pediatric indication...
March 2018: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29161763/quantifying-the-relationship-between-inhibition-of-vegfr-2-drug-induced-blood-pressure-elevation-and-hypertension
#9
Teresa Collins, Kelly Gray, Michal Bista, Matt Skinner, Christopher Hardy, Haiyun Wang, Jerome T Mettetal, Alexander R Harmer
BACKGROUND AND PURPOSE: Several anti-angiogenic cancer drugs that inhibit VEGF receptor (VEGFR) signalling for efficacy are associated with a 15-60% incidence of hypertension. Tyrosine kinase inhibitors (TKIs) that have off-target activity at VEGFR-2 may also cause blood pressure elevation as an undesirable side effect. Therefore, the ability to translate VEGFR-2 off-target potency into blood pressure elevation would be useful in development of novel TKIs. EXPERIMENTAL APPROACH: We sought to quantify the relationship between VEGFR-2 inhibition and blood pressure elevation for a range of kinase inhibitors...
November 21, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29143334/pk-pd-modeling-of-flunixin-meglumine-in-a-kaolin-induced-inflammation-model-in-piglets
#10
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...
April 2018: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29127049/predicting-mutant-selection-in-competition-experiments-with-ciprofloxacin-exposed-escherichia-coli
#11
David D Khan, Pernilla Lagerbäck, Christer Malmberg, Anders N Kristoffersson, Erik Wistrand-Yuen, Cao Sha, Otto Cars, Dan I Andersson, Diarmaid Hughes, Elisabet I Nielsen, Lena E Friberg
Predicting competition between antibiotic-susceptible wild-type (WT) and less susceptible mutant (MT) bacteria is valuable for understanding how drug concentrations influence the emergence of resistance. Pharmacokinetic/pharmacodynamic (PK/PD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thus be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PK/PD model for its ability to predict in vitro mixed-population experiments with competition between Escherichia coli (E...
March 2018: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/29090407/pkpd-modeling-of-acquired-resistance-to-anti-cancer-drug-treatment
#12
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...
December 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
#13
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
#14
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. Uricosuric agents can cause hyperuricosuria, a risk factor for nephrolithiasis and acute uric acid nephropathy. The aims of the present study were to simulate the relationship 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 two-compartment pharmacokinetic (PK) models based on published evidence, and a semi-mechanistic four-compartment pharmacodynamic (PD) model...
January 2018: 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
#15
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...
November 15, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28854543/dexmedetomidine-pharmacodynamics-in-healthy-volunteers-2-haemodynamic-profile
#16
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
#17
REVIEW
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...
November 15, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28739794/population-pharmacokinetics-of-azd-5847-in-adults-with-pulmonary-tuberculosis
#18
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 ( T lag ) for absorption...
October 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28612141/deterministic-identifiability-of-population-pharmacokinetic-and-pharmacokinetic-pharmacodynamic-models
#19
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
#20
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
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