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https://www.readbyqxmd.com/read/29464550/clinical-pharmacokinetics-and-pharmacodynamics-of-drugs-in-the-central-nervous-system
#1
REVIEW
Nithya Srinivas, Kaitlyn Maffuid, Angela D M Kashuba
Despite contributing significantly to the burden of global disease, the translation of new treatment strategies for diseases of the central nervous system (CNS) from animals to humans remains challenging, with a high attrition rate in the development of CNS drugs. The failure of clinical trials for CNS therapies can be partially explained by factors related to pharmacokinetics/pharmacodynamics (PK/PD), such as lack of efficacy or improper selection of the initial dosage. A focused assessment is needed for CNS-acting drugs in first-in-human studies to identify the differences in PK/PD from animal models, as well as to choose the appropriate dose...
February 20, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29463527/a-new-marker-of-echinocandins-activity-in-an-in-vitro-pk-pd-model-correlates-with-an-animal-model-of-aspergillus-fumigatus-infection
#2
Joseph Meletiadis, Maria Siopi, Athanassios Tsakris, Johan W Mouton, Spyros Pournaras
The lack of a quantifiable marker for echinocandins activity hinders in vitro PK/PD studies for Aspergillus spp. We developed an in vitro PK/PD model simulating anidulafungin pharmacokinetics and assessing its pharmacodynamics against A. fumigatus with a new easily quantifiable, sensitive and reproducible marker. Two clinical A. fumigatus isolates previously used in animals (AZN8196,V52-35) with identical anidulafungin EUCAST (0.03 μg/ml) and CLSI (0.015 μg/ml) MEC and one (AFU79728) with MEC>16 μg/ml were tested in a two-compartment PK/PD dialysis/diffusion closed model containing a dialysis membrane tube (DM) inoculated with 103 cfu/mL...
February 20, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29462473/stochastic-pharmacokinetic-pharmacodynamic-modeling-for-assessing-the-systemic-health-risk-of-perfluorooctanoate-pfoa
#3
Matteo Convertino, Timothy R Church, Geary W Olsen, Yang Liu, Eddie Doyle, Clifford R Elcombe, Anna L Barnett, Leslie M Samuel, Iain R MacPherson, Thomas R J Evans
A phase 1 dose-escalation trial assessed the chemotherapeutic potential of ammonium perfluorooctanoate (APFO). Forty-nine primarily solid-tumor cancer patients who failed standard therapy received weekly APFO doses (50mg-1200mg) for six-weeks. Clinical chemistries and plasma PFOA (anionic APFO) were measured pre-dose and weekly thereafter. Several clinical measures including total cholesterol, high-density lipoproteins (HDL), thyroid stimulating hormone (TSH), and free thyroxine (fT4), relative to PFOA concentrations, were examined by: standard statistical analyses using general estimating equations (GEE) and a probabilistic analysis using probability distribution functions (pdf) at various PFOA concentrations; and a two-compartment pharmacokinetic/pharmacodynamic (PK/PD) model to directly estimate mean changes...
February 16, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29458138/pharmacokinetic-and-pharmacodynamic-evaluation-of-5-methoxy-2-aminoindane-meai-a-new-binge-mitigating-agent
#4
Jakob A Shimshoni, Eyal Sobol, Ezekiel Golan, Yulius Ben Ari, Orit Gal
5-Methoxy-2-aminoindane (MEAI) is a novel psychoactive aminoindane derivative, exerting euphoric, alcohol-like tipsy experience and reduced desire to consume alcoholic beverages. Our previous toxicological evaluation of MEAI in rats, clearly indicated MEAI's potential to be further evaluated as a promising binge mitigating agent due to its favorable safety profile. In the light of these observations, we have determined MEAI's pharmacokinetic (PK) profile in rats and evaluated in-vitro its pharmacodynamics (PD) profile...
February 16, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29458132/therapeutic-drug-monitoring-in-treatment-experienced-hiv-infected-patients-receiving-darunavir-based-salvage-regimens-a-case-series
#5
Sébastien Landry, Chi-Nan Chen, Nimish Patel, Alice Tseng, Richard G Lalonde, Denis Thibeault, Steven Sanche, Nancy L Sheehan
Therapeutic drug monitoring (TDM) constitutes a compelling approach for the optimization of antiretroviral therapy in treatment-experienced HIV-1 patients. While various inhibitory indices have been proposed to predict virologic outcome, there is a lack of consensus on the clinical value of TDM. Here, we report the comparative results of TDM in 14 HIV-1-infected patients who had previously received at least two different PI-based regimens and who initiated darunavir (DRV)-based salvage therapy. Pharmacokinetic/pharmacodynamics (PK/PD) parameters were calculated for each subject...
February 16, 2018: Antiviral Research
https://www.readbyqxmd.com/read/29457982/discovery-of-gdc-0853-a-potent-selective-and-non-covalent-bruton-s-tyrosine-kinase-inhibitor-in-early-clinical-development
#6
James J Crawford, Adam R Johnson, Dinah L Misner, Lisa D Belmont, Georgette M Castanedo, Regina Choy, Melis Coraggio, Liming Dong, Charles Eigenbrot, Rebecca Erickson, Nico Ghilardi, Jonathan Hau, Arna Katewa, Pawan Bir Kohli, Wendy Lee, Joseph W Lubach, Brent S McKenzie, Daniel Fred Ortwine, Leah Schutt, Suzanne Tay, Binqing Wei, Karin Reif, Lichuan Liu, Harvey Wong, Wendy B Young
Btk is a non-receptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Pre-clinical studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and pre-clinical characterization of a potent, selective, and non-covalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease, and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis...
February 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29453671/comparative-evaluation-of-pharmacokinetics-and-pharmacodynamics-of-insulin-glargine-glaritus-%C3%A2-and-lantus-%C3%A2-in-healthy-subjects-a-double-blind-randomized-clamp-study
#7
Ashima Bhatia, Shraddha Tawade, Mushtaque Mastim, Eliford Ngaimisi Kitabi, Mathangi Gopalakrishnan, Manish Shah, Sridhar Yeshamaina, Joga Gobburu, Maharaj Sahib, Dipak Thakur, K M Prasanna Kumar
AIMS: The objective of the study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of an insulin glargine formulation, Glaritus ® (test) with the innovator's formulation Lantus ® (reference) using the euglycemic clamp technique in a single-dose, double-blind, randomized, two sequences, four-period replicate crossover study in healthy volunteers (n = 40). METHODS: Subjects received subcutaneous administration of the insulin glargine (0...
February 16, 2018: Acta Diabetologica
https://www.readbyqxmd.com/read/29451404/optimizing-nbe-pk-pd-assays-using-the-gyrolab-affinity-software-conveniently-within-the-bioanalyst-s-existing-workflow
#8
Maria Myzithras, Tammy Bigwarfe, Erica Waltz, Hua Li, Jennifer Ahlberg, Irina Rybina, Sarah Low, Cynthia Hess Kenny, John Miglietta, Rachel Kroe-Barrett
AIM: The fully automated microfluidics-based Gyrolab is a popular instrument for the bioanalysis of protein therapeutics; requiring minimal sample and reagent volumes. Gyros offers affinity software for determining binding affinity in solution using a high-throughput method and miniaturized reactions. RESULTS: Using this affinity software, multiple CTGF-targeting reagents were characterized on the Gyrolab after <100% target coverage was seen in a cynomolgus pharmacokinetic/PD study dosed with anti-CTGF antibodies...
February 16, 2018: Bioanalysis
https://www.readbyqxmd.com/read/29446343/cost-utility-analysis-of-antiviral-use-under-pandemic-influenza-using-a-novel-approach-linking-pharmacology-epidemiology-and-heath-economics
#9
D B C Wu, N Chaiyakunapruk, C Pratoomsoot, K K C Lee, H Y Chong, R E Nelson, P F Smith, C M Kirkpatrick, M A Kamal, K Nieforth, G Dall, S Toovey, D C M Kong, A Kamauu, C R Rayner
Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic/pharmacodynamics (PK/PD) - dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility...
February 15, 2018: Epidemiology and Infection
https://www.readbyqxmd.com/read/29446069/accelerated-development-of-the-dual-orexin-receptor-antagonist-act-541468-integration-of-a-microtracer-in-the-first-in-human-study
#10
Clemens Muehlan, Jules Heuberger, Pierre-Eric Juif, Marie Croft, Joop van Gerven, Jasper Dingemanse
The orexin system regulates sleep and arousal and is targeted by ACT-541468, a new dual orexin receptor antagonist (DORA). Healthy male subjects received a single oral dose of 5-200 mg, to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), mass balance, metabolism, and absolute bioavailability utilizing a14 C-labeled, orally and intravenously (i.v) administered microtracer. The drug was safe and well tolerated; the PK profile was characterized by quick absorption and elimination, with median time to reach maximum concentration (tmax ) of 0...
February 15, 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29446052/correction-to-pk-pd-compass-bringing-infectious-diseases-pharmacometrics-to-the-patient-s-bedside
#11
Catharine C Bulik, Justin C Bader, Li Zhang, Scott A Van Wart, Christopher M Rubino, Sujata M Bhavnani, Kim L Sweeney, Paul G Ambrose
The original version of this article contained incorrect Supplementary Files. The correct Supplementary Files are published with this erratum.
February 14, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29442148/population-pharmacokinetics-and-pharmacodynamics-of-ticagrelor-and-ar-c124910xx-in-chinese-healthy-male-subjects
#12
Shuaibing Liu, Ling Xue, Xiangfen Shi, Zhiyong Sun, Zhenfeng Zhu, Xiaojian Zhang, Xin Tian
BACKGROUND: Ticagrelor, the first reversible P2Y12 receptor antagonist, exhibits faster onset and offset of antiplatelet effects and more consistent platelet inhibition than clopidogrel in both healthy subjects and patients with stable coronary artery disease. OBJECTIVE: The objectives of this study were to establish a population pharmacokinetics (PK) and pharmacodynamics (PD) model of ticagrelor and to provide a theoretical basis for the optimization of ticagrelor treatment in clinic...
February 13, 2018: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29438998/hydroxychloroquine-a-physiologically-based-pharmacokinetic-model-in-the-context-of-cancer-related-autophagy-modulation
#13
Keagan P Collins, Kristen M Jackson, Daniel L Gustafson
Hydroxychloroquine (HCQ) is a lysosomotropic autophagy inhibitor being used in over 50 clinical trials either alone or in combination with chemotherapy. Pharmacokinetic (PK) and pharmacodynamic (PD) studies with HCQ have shown that drug exposure in the blood does not correlate with autophagy inhibition in either peripheral blood mononuclear cells (PBMCs) or tumor tissue. To better explain this PK/PD disconnect a physiologically-based pharmacokinetic model (PBPK) was developed for HCQ describing the tissue-specific absorption, distribution, metabolism, and excretion as well as lysosome-specific sequestration...
February 8, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29436172/population-pharmacokinetic-pharmacodynamic-pk-pd-modeling-of-depot-testosterone-cypionate-in-healthy-male-subjects
#14
Youwei Bi, Paul J Perry, Michael Ellerby, Daryl J Murry
A randomized, double-blind clinical trial was conducted to investigate long-term abuse effects of testosterone cypionate. Thirty-one healthy males were randomized into a dose group of 100, 250 or 500mg/wk and received 14 weekly injections of TC. A PK-PD model was developed to characterize testosterone concentrations and link exposure to change in luteinizing hormone and spermatogenesis following long-term TC administration. A linear one-compartment model best described the concentration-time profile of total testosterone...
February 13, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29434672/pharmacokinetic-and-pharmacodynamic-comparison-of-subcutaneous-versus-intramuscular-leuprolide-acetate-formulations-in-male-subjects
#15
Daniel Saltzstein, Neal D Shore, Judd W Moul, Franklin Chu, Raoul Concepcion, Stephan de la Motte, John A McLane, Stuart Atkinson, Alex Yang, E David Crawford
Background: The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two distinct formulations of leuprolide acetate (LA); subcutaneous (SC) injection and intramuscular (IM) injection. Methods: A total of 32 healthy men were randomized to receive a single 7.5 mg injection of SC-LA ( n = 16) or IM-LA ( n = 16) in this phase I, open-label, parallel-group study. PK was assessed via LA concentrations, and PD via serum luteinizing hormone (LH) and testosterone (T) concentrations...
February 2018: Therapeutic Advances in Urology
https://www.readbyqxmd.com/read/29433693/pharmacocin%C3%A3-tique-et-pharmacodynamie-des-antibiotiques-est-ce-diff%C3%A3-rent-en-n%C3%A3-onatologie
#16
R Cohen, M Tauzin, S Béchet, L Caeymaex
Pharmacokinetic and pharmacodynamics (PK/PD) data on antimicrobial agents enable physicians to optimize their use in clinical practice. Neonates exhibit a large inter-individual variability in antibiotic levels due to immaturity and maturational changes in the first weeks of life. This variability explains the large therapeutic margins needed to ensure an optimal efficacy of antibiotics. These pharmacokinetic characteristics have to be taken into account when treating neonatal sepsis, along with pharmacodynamics targets for each antibiotic and notably minimal inhibitory concentration for usual causes of neonatal bacterial infections (group B streptococcus and Escherichia coli)...
December 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
https://www.readbyqxmd.com/read/29431542/obesity-and-drug-pharmacology-a-review-of-the-influence-of-obesity-on-pharmacokinetic-and-pharmacodynamic-parameters
#17
Cornelis Smit, Sjoerd De Hoogd, Roger J M Brüggemann, Catherijne A J Knibbe
The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on how to adapt the dose may not always be known. Areas covered: In this review, physiological changes associated with obesity are discussed. An overview is provided on the alterations in absorption, distribution, drug metabolism and clearance in (morbid) obesity focusing on general principles that can be extracted from pharmacokinetic studies...
February 12, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29429038/pharmacodynamic-modeling-of-cardiac-biomarkers-in-breast-cancer-patients-treated-with-anthracycline-and-trastuzumab-regimens
#18
Aurelia H M de Vries Schultink, Annelies H Boekhout, Jourik A Gietema, Artur M Burylo, Thomas P C Dorlo, J G Coen van Hasselt, Jan H M Schellens, Alwin D R Huitema
Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure-response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab...
February 10, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29427293/development-of-a-nomogram-for-the-estimation-of-long-term-adherence-to-clozapine-therapy-using-neutrophil-fluorescence
#19
W H Man, A Pérez-Pitarch, I Wilting, E R Heerdink, W W van Solinge, A C G Egberts, A D R Huitema
AIMS: Previously, we have reported an association between clozapine use and elevated FL3 neutrophil fluorescence, a flow-cytometric parameter for cell viability. Here, we developed and evaluated a PK/PD model relating FL3-fluorescence to clozapine exposure and derived a nomogram for estimation of long-term adherence. METHODS: Data from 27 patients initiating clozapine were analyzed using non-linear mixed effects modelling. A previously described PK model for clozapine was coupled to a FL3 fluorescence model...
February 9, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29425834/population-pharmacokinetics-pharmacodynamics-of-linezolid-in-sepsis-patients-with-and-without-continuous-renal-replacement-therapy
#20
Takeshi Ide, Yoshio Takesue, Kazuro Ikawa, Norifumi Morikawa, Takashi Ueda, Yoshiko Takahashi, Kazuhiko Nakajima, Kenta Takeda, Shinichi Nishi
PURPOSE: The purpose of this study was to identify the optimum dosing regimen of linezolid in sepsis patients with and without renal dysfunction and sepsis patients on low-dose continuous renal replacement therapy (CRRT) using a pharmacokinetics/pharmacokinetics (PK/PD) approach. METHODS: Sepsis patients with and without renal dysfunction (creatinine clearance < 50 mL/min), and sepsis patients on low-dose CRRT (dose: 800 mL/h) were studied. The PK data were modeled using a two-compartment model, and then used for simulation...
February 6, 2018: International Journal of Antimicrobial Agents
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