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https://www.readbyqxmd.com/read/28646408/a-mechanism-based-pk-pd-model-for-hematological-toxicities-induced-by-antibody-drug-conjugates
#1
Sihem Ait-Oudhia, Weiyan Zhang, Donald E Mager
Antibody-drug conjugates (ADCs) are complex drug platforms composed of monoclonal antibodies (mAbs) conjugated to potent cytotoxic drugs (payloads) via chemical linkers, enabling selective payload delivery to neoplastic cells, resulting in improved efficacy and reduced toxicity. Brentuximab vedotin (Adcetris®, SGN-35) and adotrastuzumab emtansine (Kadcyla®, T-DM1) are the two FDA-approved and commercially available ADCs, and both drugs exhibit ADC-related thrombocytopenia and neutropenia. A pharmacokinetic/pharmacodynamic (PK/PD) model for ADCs was developed to identify the analyte from each ADC that is most associated with the observed hematopoietic toxicities and to determine the role of the apparent in vivo payload release rate on the severity of thrombocytopenia and neutropenia...
June 23, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28645327/impact-of-growth-matrix-on-pharmacodynamics-of-antimicrobial-drugs-for-pig-pneumonia-pathogens
#2
Lucy Dorey, Peter Lees
BACKGROUND: The most widely used measure of potency of antimicrobial drugs is Minimum Inhibitory Concentration (MIC). MIC is usually determined under standardised conditions in broths formulated to optimise bacterial growth on a species-by-species basis. This ensures comparability of data between laboratories. However, differences in values of MIC may arise between broths of differing chemical composition and for some drug classes major differences occur between broths and biological fluids such as serum and inflammatory exudate...
June 23, 2017: BMC Veterinary Research
https://www.readbyqxmd.com/read/28642891/safety-tolerability-of-the-anti-semaphorin-4d-antibody-vx15-2503-in-a-randomized-phase-1-trial
#3
Christopher LaGanke, Lawrence Samkoff, Keith Edwards, Lily Jung Henson, Pavle Repovic, Sharon Lynch, Lael Stone, David Mattson, Aaron Galluzzi, Terrence L Fisher, Christine Reilly, Laurie A Winter, John E Leonard, Maurice Zauderer
OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS. METHODS: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated...
July 2017: Neurology® Neuroimmunology & Neuroinflammation
https://www.readbyqxmd.com/read/28642571/pharmacokinetic-and-pharmacodynamic-modeling-of-cyadox-against-clostridium-perfringens-in-swine
#4
Lei Yan, Shuyu Xie, Dongmei Chen, Yuanhu Pan, Yanfei Tao, Wei Qu, ZhenLi Liu, Zonghui Yuan, Lingli Huang
The purpose of this study was to evaluate the activity of cyadox against Clostridium perfringens in swine and optimize the dosage regimen using ex vivo pharmacokinetic-pharmacodynamic (PK-PD) modeling. After oral administration, the ileum fluid of pigs containing the free cyadox was collected by implanted ultrafiltration probes. The Tmax, AUC24h, and CL/F of free cyadox in the ileum fluid were 1.96 h, 106.40 μg/h/mL, and 0.27 L/kg/h, respectively. Cyadox displayed a concentration-dependent killing action against C...
June 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28642145/new-and-improved-a-review-of-novel-antibiotics-for-gram-positive-bacteria
#5
REVIEW
Mohamed Abbas, Mical Paul, Angela Huttner
BACKGROUND: The number of antibiotics in the pipeline targeting Gram-positive pathogens has increased in recent years. AIMS: This narrative review aims to provide a summary of existing evidence on efficacy, microbiologic spectrum, and safety of novel systemic antibiotics that have either recently been licenced or completed phase III trials, and possess activity predominantly against Gram-positive organisms. SOURCES: A review of the published literature via the MEDLINE database was performed...
June 19, 2017: Clinical Microbiology and Infection
https://www.readbyqxmd.com/read/28640596/drug-target-kinetics-in-drug-discovery
#6
Peter J Tonge
The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation...
June 22, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28637670/a-randomised-double-blind-trial-to-demonstrate-bioequivalence-of-gp2013-and-reference-rituximab-combined-with-methotrexate-in-patients-with-active-rheumatoid-arthritis
#7
Josef S Smolen, Stanley B Cohen, Hans-Peter Tony, Morton Scheinberg, Alan Kivitz, Andra Balanescu, Juan Gomez-Reino, Liyi Cen, Peijuan Zhu, Tamas Shisha
OBJECTIVES: The aim of this report is to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence as well as similar efficacy, safety and immunogenicity between GP2013, a biosimilar rituximab, and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitor (TNFi) treatment. METHODS: In this multinational, randomised, double-blind, parallel-group study, 312 patients with active disease despite prior TNFi therapy were randomised to receive GP2013 or either the EU (RTX-EU) or the US (RTX-US) reference product, along with methotrexate (MTX) and folic acid...
June 21, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28636208/a-phase-i-trial-of-prn1008-a-novel-reversible-covalent-inhibitor-of-bruton-s-tyrosine-kinase-in-healthy-volunteers
#8
Patrick F Smith, Janakan Krishnarajah, Philip A Nunn, Ron J Hill, Dane Karr, D Tam, Mohammad Masjedizadeh, Jens O Funk, Steve G Gourlay
AIM: To evaluate the safety, tolerability, and PK/PD of PRN1008, a novel BTK inhibitor, in healthy volunteers, and thus determine the dose range for future clinical studies. METHODS: This was a two-part randomized, placebo controlled study in healthy volunteers using a liquid formulation. Part I was a single ascending dose design with dose levels of 50 to 1200 mg (n=6 active, 2 placebo per cohort); Part II was a multiple ascending dose design, with dose regimens ranging from 300 mg to 900 mg daily, either qd or bd for 10 days...
June 21, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28629344/antiresorptive-effect-of-a-cathepsin-k-inhibitor-ono-5334-and-its-relationship-to-bmd-increase-in-a-phase-ii-trial-for-postmenopausal-osteoporosis
#9
Makoto Tanaka, Yoshitaka Hashimoto, Chihiro Hasegawa, Steve Deacon, Richard Eastell
BACKGROUND: ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain. METHODS: Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship...
June 19, 2017: BMC Musculoskeletal Disorders
https://www.readbyqxmd.com/read/28624123/population-pharmacokinetic-pharmacodynamics-modeling-of-ibutilide-in-chinese-healthy-volunteers-and-patients-with-atrial-fibrillation-af-and-or-atrial-flutter-afl
#10
Zhijun Zeng, Li Wang, Lu Hua, Juanjuan Jiang, Huimin Pang, Yiling Huang, Yishi Li, Lei Tian
PURPOSE: The goal of this study was to develop a population pharmacokinetic (PK) and PK/pharmacodynamics (PD) model for ibutilide, to evaluate the time course of its effect on QT interval in Chinese. METHODS: The population PK and PK/PD model were developed using data from 40 Chinese healthy volunteers using nonlinear mixed-effects modeling, and the final population PK/PD model was applied on 100 patients with atrial fibrillation (AF) and/or atrial flutter (AFL)...
June 14, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28623849/population-pharmacokinetics-pharmacodynamics-of-3-4-diaminopyridine-free-base-in-patients-with-lambert-eaton-myasthenia
#11
Nilay Thakkar, Jeffrey T Guptill, Kathy Aleš, David Jacobus, Laura Jacobus, Charles Peloquin, Michael Cohen-Wolkowiez, Daniel Gonzalez
Lambert-Eaton Myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4-diaminopyridine free base (3,4-DAP) is an investigational orphan drug used to treat LEM-related weakness. We performed a population PK/PD analysis using 3,4-DAP and metabolite concentrations collected from a phase 2 study in LEM patients. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1270 PK samples (49 patients) and 1091 3TUG data points (32 randomized patients) were included in the PK/PD analysis...
June 17, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28619503/clinical-pharmacokinetics-of-levornidazole-in-elderly-subjects-and-dosing-regimen-evaluation-using-pharmacokinetic-pharmacodynamic-analysis
#12
Beining Guo, Gaoli He, Xiaojie Wu, Jicheng Yu, Guoying Cao, Yi Li, Yaxin Fan, Yuancheng Chen, Yaoguo Shi, Yingyuan Zhang, Jing Zhang
PURPOSE: Levornidazole, the levo-isomer of ornidazole, is a third-generation nitroimidazole derivative newly developed after metronidazole, tinidazole, and ornidazole. An open-label, parallel-controlled, single-dose study was conducted for the investigation of the pharmacokinetic (PK) profile of levornidazole and its metabolites in healthy elderly Chinese subjects, and for the evaluation of 2 dosing regimens in the elderly. METHODS: Levornidazole was intravenously administered at 500 mg to healthy elderly (aged 60-80 years) or young subjects (aged 19-45 years)...
June 12, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28619095/integrated-pharmacokinetic-pharmacodynamic-pk-pd-model-to-evaluate-the-in-vivo-antimicrobial-activity-of-marbofloxacin-against-pasteurella-multocida-in-piglets
#13
Qing Lin Zeng, Xian Mei, Jia Su, Xiao Hong Li, Wen Guang Xiong, Yan Lu, Zhen Ling Zeng
BACKGROUND: Marbofloxacin is a veterinary fluoroquinolone with high activity against Pasteurella multocida. We evaluated it's in vivo activity against P. multocida based on in vivo time-kill data in swine using a tissue-cage model. A series of dosages ranging from 0.15 to 2.5 mg/kg were administered intramuscularly after challenge with P. multocida type B, serotype 2. RESULTS: The ratio of the 24 h area under the concentration-time curve divided by the minimum inhibitory concentration (AUC24TCF/MIC) was the best PK/PD index correlated with the in vivo antibacterial effectiveness of marbofloxacin (R2 = 0...
June 15, 2017: BMC Veterinary Research
https://www.readbyqxmd.com/read/28616684/influence-of-ethanol-on-darunavir-hepatic-clearance-and-intracellular-pk-pd-in-hiv-infected-monocytes-and-cyp3a4-darunavir-interactions-using-inhibition-and-in-silico-binding-studies
#14
Narasimha M Midde, Yuqing Gong, Theodore J Cory, Junhao Li, Bernd Meibohm, Weihua Li, Santosh Kumar
PURPOSE: Although the prevalence of alcohol consumption is higher in HIV+ people than general public, limited information is available on how alcohol affects the metabolism and bioavailability of darunavir (DRV). METHODS: DRV was quantified by using LC-MS/MS method. All in vitro experiments were performed using human liver microsomes and HIV-infected monocytic cells. CYP3A4 and DRV/Ritonavir (RTV) docking was performed using GOLD suite 5.8. RESULTS: Ethanol (20 mM) significantly decreased apparent half-life and increased degradation rate constant of RTV-boosted DRV but not for DRV alone...
June 14, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28611739/the-pk-pd-relationship-and-resistance-development-of-danofloxacin-against-mycoplasma-gallisepticum-in-an-in-vivo-infection-model
#15
Nan Zhang, Yuzhi Wu, Zilong Huang, Lihua Yao, Longfei Zhang, Qinren Cai, Xiangguang Shen, Hongxia Jiang, Huanzhong Ding
Mycoplasma gallisepticum is the causative agent of chronic respiratory disease (CRD), a prevalent disease of poultry, which is responsible for significant economic losses in farms. Although several antimicrobial agents are currently recommended for the treatment and prevention of M. gallisepticum infections, investigations of M. gallisepticum have been hampered by their fastidious growth requirements and slow growth rate. As such, little work has been conducted concerning the PK/PD relationship and mechanisms of antibiotic resistance between antimicrobials against M...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28609567/safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-the-novel-crth2-antagonist-bi-1021958-at-single-oral-doses-in-healthy-men-and-multiple-oral-doses-in-men-and-women-with-well-controlled-asthma
#16
Andy Fowler, Rüdiger Koenen, James Hilbert, Jon Blatchford, Dominik Kappeler, Ewald Benediktus, Chester Wood, Abhya Gupta
BI 1021958, a novel antagonist of the chemoattractant-receptor-homologous molecule (CRTH2), targets airway inflammation in asthma by inhibiting prostaglandin binding to CRTH2 receptors. Two phase 1 studies assessed BI 1021958 safety/tolerability and pharmacokinetics (PK)/pharmacodynamics (PD) following single doses in healthy men and multiple doses in men/women with well-controlled asthma. Studies 1 had 2 parts: a placebo-controlled, fixed-sequence, single-blind, single-rising-dose part (n = 56) and a randomized, 2-way crossover, open-label, repeated-dose part studying the food effect on PK/PD (n = 12)...
June 13, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28600397/semi-mechanistic-bone-marrow-exhaustion-pharmacokinetic-pharmacodynamic-model-for-chemotherapy-induced-cumulative-neutropenia
#17
Andrea Henrich, Markus Joerger, Stefanie Kraff, Ulrich Jaehde, Wilhelm Huisinga, Charlotte Kloft, Zinnia Patricia Parra-Guillen
Paclitaxel is a commonly used cytotoxic anticancer drug with potentially life-threatening toxicity at therapeutic doses and high interindividual pharmacokinetic variability. Thus, drug and effect monitoring is indicated to control dose-limiting neutropenia. A dose individualization algorithm was developed by Joerger et al. based on a pharmacokinetic/pharmacodynamic (PK/PD) model describing paclitaxel and neutrophil concentrations. Further, the algorithm was prospectively compared in a clinical trial against standard dosing (CEPAC-TDM study, npatients=365, ncycles=720) but did not substantially improve neutropenia...
June 9, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28571114/population-modelling-integrating-pharmacokinetics-pharmacodynamics-pharmacogenetics-and-clinical-outcome-in-sunitinib-treated-cancer-patients
#18
M H Diekstra, A Fritsch, F Kanefendt, J J Swen, Djar Moes, F Sörgel, M Kinzig, C Stelzer, D Schindele, T Gauler, S Hauser, D Houtsma, M Roessler, B Moritz, K Mross, L Bergmann, E Oosterwijk, L A Kiemeney, H J Guchelaar, U Jaehde
The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics. Inter-individual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic and pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662 and the soluble VEGF receptors sVEGFR-2 and sVEGFR-3 were measured in 26 mRCC patients within the EuroTARGET project and 21 metastasized colorectal cancer (mCRC) patients from the C-II-005 study...
June 1, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28561730/pharmacokinetic-pharmacodynamic-modeling-for-drug-development-in-oncology
#19
Elena Garralda, Rodrigo Dienstmann, Josep Tabernero
High drug attrition rates remain a critical issue in oncology drug development. A series of steps during drug development must be addressed to better understand the pharmacokinetic (PK) and pharmacodynamic (PD) properties of novel agents and, thus, increase their probability of success. As available data continues to expand in both volume and complexity, comprehensive integration of PK and PD information into a robust mathematical model represents a very useful tool throughout all stages of drug development...
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28559256/aerosolized-polymyxin-b-for-treatment-of-respiratory-tract-infections-determination-of-pharmacokinetic-pharmacodynamic-indices-for-aerosolized-polymyxin-b-against-pseudomonas-aeruginosa-in-a-mouse-lung-infection-model
#20
Yu-Wei Lin, Qi Tony Zhou, Nikolas J Onufrak, Veronika Wirth, Ke Chen, Jiping Wang, Alan Forrest, Hak-Kim Chan, Jian Li
Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD) and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were conducted in neutropenic infected mice and the data were analyzed by a population PK model...
May 30, 2017: Antimicrobial Agents and Chemotherapy
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