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https://www.readbyqxmd.com/read/28437278/pharmacodynamic-and-kinetic-behavior-of-low-intermediate-and-high-dose-landiolol-during-long-term-infusion-in-caucasians
#1
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
#2
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
#3
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
https://www.readbyqxmd.com/read/28414146/tissue-distribution-of-a-therapeutic-monoclonal-antibody-determined-by-large-pore-microdialysis
#4
Satyawan B Jadhav, Vipada Khaowroongrueng, Matthias Fueth, Michael B Otteneder, Wolfgang Richter, Hartmut Derendorf
Therapeutic monoclonal antibodies (mAbs) exhibit limited distribution to the target tissues. Determination of target tissue interstitial concentration of mAbs is an important aspect in the assessment of their pharmacokinetic/pharmacodynamics (PK/PD) relationship especially for mAbs targeting membrane bound receptors. The pharmacokinetics of R7072, a full length mAb (IgG) targeting human insulin like growth factor-1 receptor (IGF-1R) was evaluated following a single intravenous (IV) dose at 1, 6.25 and 25 mg/kg in healthy female SCID-beige mice...
April 13, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28409203/the-role-of-infection-models-and-pk-pd-modelling-for-optimising-care-of-critically-ill-patients-with-severe-infections
#5
REVIEW
T Tängdén, V Ramos Martín, T W Felton, E I Nielsen, S Marchand, R J Brüggemann, J B Bulitta, M Bassetti, U Theuretzbacher, B T Tsuji, D W Wareham, L E Friberg, J J De Waele, V H Tam, Jason A Roberts
Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens...
April 13, 2017: Intensive Care Medicine
https://www.readbyqxmd.com/read/28407419/antibiotic-treatment-of-biofilm-infections
#6
REVIEW
Oana Ciofu, Estrella Rojo-Molinero, María D Macià, Antonio Oliver
Bacterial biofilms are associated with a wide range of infections, from those related to exogenous devices, such as catheters or prosthetic joints, to chronic tissue infections such as those occurring in the lungs of cystic fibrosis patients. Biofilms are recalcitrant to antibiotic treatment due to multiple tolerance mechanisms (phenotypic resistance). This causes persistence of biofilm infections in spite of antibiotic exposure which predisposes to antibiotic resistance development (genetic resistance). Understanding the interplay between phenotypic and genetic resistance mechanisms acting on biofilms, as well as appreciating the diversity of environmental conditions of biofilm infections which influence the effect of antibiotics are required in order to optimize the antibiotic treatment of biofilm infections...
April 2017: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
https://www.readbyqxmd.com/read/28407418/pharmacokinetics-and-acid-suppressant-efficacy-of-esomeprazole-after-intravenous-oral-and-subcutaneous-administration-to-healthy-beagle-dogs
#7
J-H Hwang, J-W Jeong, G-H Song, T-S Koo, K-W Seo
BACKGROUND: Esomeprazole is an S-enantiomer of omeprazole that has favorable pharmacokinetics and efficacious acid suppressant properties in humans. However, the pharmacokinetics and effects on intragastric pH of esomeprazole in dogs have not been reported. OBJECTIVE: To determine the pharmacokinetics of esomeprazole administered via various routes (PK study) and to investigate the effect of esomeprazole on intragastric pH with a Bravo pH monitoring system (PD study)...
April 13, 2017: Journal of Veterinary Internal Medicine
https://www.readbyqxmd.com/read/28401480/target-mediated-drug-disposition-pharmacokinetic-pharmacodynamic-model-of-bosentan-and-endothelin-1
#8
Anke-Katrin Volz, Andreas Krause, Walter Emil Haefeli, Jasper Dingemanse, Thorsten Lehr
BACKGROUND AND OBJECTIVES: Bosentan is a competitive antagonist on endothelin receptor A and B (ETA and ETB), displacing the endogenous binding partner endothelin-1 (ET-1) from its binding sites. After administration of escalating single doses of 10-750 mg as an intravenous (i.v.) infusion, bosentan showed dose-dependent pharmacokinetics (PK). The aim of this analysis was to develop a PK model of bosentan after i.v. administration including competitive antagonism with ET-1 and to analyze its influence on blood pressure and heart rate with a combined pharmacokinetic/pharmacodynamic (PK/PD) model...
April 11, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28398628/population-pharmacokinetics-and-target-engagement-of-natalizumab-in-patients-with-multiple-sclerosis
#9
Kumar Kandadi Muralidharan, Geoffrey Kuesters, Tatiana Plavina, Meena Subramanyam, Daniel D Mikol, Sreeja Gopal, Ivan Nestorov
Natalizumab (humanized immunoglobulin G4 antibody targeting alpha-4 integrins) is a highly efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) that has been in clinical use since 2006. However, natalizumab pharmacokinetic (PK) characteristics and concentration alpha-4 integrin saturation relationships have not been well described in the scientific literature. Therefore, clinical data from 11 studies were pooled and analyzed to characterize the PK and pharmacodynamic (PD) properties of natalizumab in RRMS subjects...
April 11, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28398597/results-from-the-first-in-human-study-with-ozanimod-a-novel-selective-sphingosine-1-phosphate-receptor-modulator
#10
Jonathan Q Tran, Jeffrey P Hartung, Robert J Peach, Marcus F Boehm, Hugh Rosen, Heather Smith, Jennifer L Brooks, Gregg A Timony, Allan D Olson, Sheila Gujrathi, Paul A Frohna
The sphingosine-1-phosphate 1 receptor (S1P1R ) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P1R and S1P5R receptors in clinical development for the treatment of chronic immune-mediated, inflammatory diseases. This first-in-human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose-escalation regimen...
April 11, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28396549/in-vivo-pharmacokinetics-and-pharmacodynamics-of-zti-01-fosfomycin-for-injection-in-the-neutropenic-murine-thigh-infection-model-against-e-coli-k-pneumoniae-and-p-aeruginosa
#11
Alexander J Lepak, Miao Zhao, Brian VanScoy, Daniel S Taylor, Evelyn Ellis-Grosse, Paul G Ambrose, David R Andes
Fosfomycin is a broad-spectrum agent with activity against gram-positive and gram-negative bacteria, including drug-resistant strains, such as extended spectrum beta-lactamase (ESBL)-producing and carbapenem-resistant (CR) gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5 E. coli (EC), 3 K. pneumoniae (KPN), and 2 P. aeruginosa (PSA) strains, including a subset with ESBL and CR phenotype...
April 10, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28395759/a-multicenter-phase-ii-study-of-personalized-folfiri-cetuximab-for-safe-dose-intensification
#12
Michèle Boisdron-Celle, Jean Philippe Metges, Olivier Capitain, Antoine Adenis, Jean Luc Raoul, Thierry Lecomte, You Heng Lam, Roger Faroux, Claude Masliah, Anne Lise Poirier, Virginie Berger, Alain Morel, Erick Gamelin
We conducted a multicenter proof of concept phase II trial in patients with advanced colorectal cancer receiving FOLFIRI-cetuximab regimens to explore individual drug tailoring using pharmacogenetics and pharmacokinetics (PK) monitoring. Patients were stratified by their pharmacogenetic/phenotypic status: the irinotecan dose was adjusted according to the number of TA tandem repeats in the UGT1A1 promoter, while the 5-fluorouracil (5-FU) dose was initially adjusted according to dihydropyrimidine dehydrogenase (DPD) activity at initial screening (5-FU(ODPM Tox)) followed by PK-guided dose optimization (5-FU(ODPM Protocol))...
February 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/28393694/peptide-drug-conjugate-a-novel-drug-design-approach
#13
Liang Ma, Chao Wang, Zihao He, Biao Cheng, Ling Zheng, Kun Huang
More than 100 years ago, German physician Paul Ehrlich first proposed the concept of selectively delivering "magic bullets" to tumors through targeting agents. The targeting therapy with antibody-drug conjugates (ADCs) and peptide-drug conjugate (PDCs), which are usually composed of monoclonal antibodies or peptides, toxic payloads and cleavage/noncleavage linkers, has been extensively studied for decades. The conjugates enable selective delivery of cytotoxic payloads to target cells, which result in improved efficacy, reduced systemic toxicity and improved pharmacokinetics (PK)/pharmacodynamics (PD) compared with traditional chemotherapy...
April 4, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28382498/assessing-the-relative-potency-of-s-and-r-warfarin-with-a-new-pk-pd-model-in-relation-to-vkorc1-genotypes
#14
Myriam Ferrari, Vittorio Pengo, Massimiliano Barolo, Fabrizio Bezzo, Roberto Padrini
PURPOSE: The purpose of this study is to develop a new pharmacokinetic-pharmacodynamic (PK-PD) model to characterise the contribution of (S)- and (R)-warfarin to the anticoagulant effect on patients in treatment with rac-warfarin. METHODS: Fifty-seven patients starting warfarin (W) therapy were studied, from the first dose and during chronic treatment at INR stabilization. Plasma concentrations of (S)- and (R)-W and INRs were measured 12, 36 and 60 h after the first dose and at steady state 12-14 h after dosing...
April 5, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28378945/translational-pharmacometric-evaluation-of-typical-antibiotic-broad-spectrum-combination-therapies-against-staphylococcus-aureus-exploiting-in-vitro-information
#15
Sebastian G Wicha, Wilhelm Huisinga, Charlotte Kloft
Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid or vancomycin combined with meropenem against Staphylococcus aureus as the most frequent causative pathogen of severe infections. A semi-mechanistic PK-PD model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of linezolid, vancomycin and meropenem alone and in dual combinations...
April 5, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28378544/effects-of-cyp2c19-genetic-polymorphisms-on-pk-pd-responses-of-omeprazole-in-korean-healthy-volunteers
#16
Sunny Park, Yang Jin Hyun, Yu Ran Kim, Ju Hyun Lee, Sunae Ryu, Jeong Mi Kim, Woo Yong Oh, Han Sung Na, Jong Gu Lee, Doo Won Seo, In Yeong Hwang, Zewon Park, In Jin Jang, Jaeseong Oh, Seung Eun Choi
The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS)...
May 2017: Journal of Korean Medical Science
https://www.readbyqxmd.com/read/28375030/aminoglycosides-against-carbapenem-resistant-enterobacteriaceae-in-the-critically-ill-the-pitfalls-of-aminoglycoside-susceptibility
#17
Alexandre P Zavascki, Brandon O Klee, Jürgen B Bulitta
The emergence of carbapenem-resistant Enterobacteriaceae (CRE) has brought aminoglycosides to the frontline since an aminoglycoside may be the only antimicrobial to which CRE isolates show in vitro susceptibility. The appropriateness of aminoglycoside-based therapies for severe infections by CRE is discussed considering the current breakpoints and recent pharmacokinetic (PK) studies in critically ill patients. Areas covered: Many aminoglycoside-susceptible CRE isolates present minimal inhibitory concentrations (MICs) at or slightly below the breakpoint of amikacin or gentamicin...
April 17, 2017: Expert Review of Anti-infective Therapy
https://www.readbyqxmd.com/read/28374319/application-of-a-pk-pd-modeling-and-simulation-based-strategy-for-clinical-translation-of-antibody-drug-conjugates-a-case-study-with-trastuzumab-emtansine-t-dm1
#18
Aman P Singh, Dhaval K Shah
Successful clinical translation of antibody-drug conjugates (ADCs) can be challenging due to complex pharmacokinetics and differences between preclinical and clinical tumors. To facilitate this translation, we have developed a general pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation (M&S)-based strategy for ADCs. Here we present the validation of this strategy using T-DM1 as a case study. A previously developed preclinical tumor disposition model for T-DM1 (Singh and Shah, AAPSJ. 2015; 18(4):861-875) was used to develop a PK-PD model that can characterize in vivo efficacy of T-DM1 in preclinical tumor models...
April 3, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28371693/pharmacokinetic-pharmacodynamic-modeling-of-benazepril-and-benazeprilat-after-administration-of-intravenous-and-oral-doses-of-benazepril-in-healthy-horses
#19
Juan Manuel Serrano-Rodríguez, Manuel Gómez-Díez, María Esgueva, Cristina Castejón-Riber, Antonio Mena-Bravo, Feliciano Priego-Capote, Nahúm Ayala, Juan Manuel Serrano Caballero, Ana Muñoz
Pharmacokinetic and pharmacodynamic (PK/PD) properties of the angiotensin-converting enzyme inhibitor (ACEI) benazeprilat have not been evaluated in horses. This study was designed to establish PK profiles for benazepril and benazeprilat after intravenous (IV) and oral (PO) administration of benazepril using a PK/PD model. This study also aims to determine the effects of benazeprilat on serum angiotensin converting enzyme (ACE), selecting the most appropriate dose that suppresses ACE activity. Six healthy horses in a crossover design received IV benazepril at 0...
March 28, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28363695/in-vitro-anaerobic-pharmacokinetic-pharmacodynamic-model-to-simulate-the-bactericidal-activity-of-levornidazole-against-bacteroides-fragilis
#20
Jiali Hu, Jing Zhang, Yuancheng Chen, Wang Liang, Shi Wu
PURPOSE: This study was designed to correlate the pharmacokinetic/pharmacodynamic (PK/PD) parameters with PD indices of levornidazole against Bacteroides fragilis and to calculate the PK/PD target value for levornidazole to attain its expected maximal bactericidal effect using an in vitro anaerobic dynamic PK/PD model. METHODS: An anaerobic dynamic PK/PD model was developed in vitro. The scheme for PK modeling was designed according to the PK parameters of levornidazole in the human body...
March 28, 2017: Clinical Therapeutics
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