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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
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
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 a 14 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 (t max ) of 0...
February 15, 2018: Clinical Pharmacology and Therapeutics
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
Shuaibing Liu, Ling Xue, Xiangfen Shi, Zhiyong Sun, Zhenfeng Zhu, Xiaojian Zhang, Xin Tian
BACKGROUND: Ticagrelor, the first reversible P2Y 12 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
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
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
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
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
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
Dhaval K Shah, Frank Loganzo, Nahor Haddish-Berhane, Sylvia Musto, Hallie S Wald, Frank Barletta, Judy Lucas, Tracey Clark, Steve Hansel, Alison Betts
The objective of this manuscript was to establish in vitro-in vivo correlation (IVIVC) between the in vitro efficacy and in vivo efficacy of antibody drug conjugates (ADCs), using a PK/PD modeling approach. Nineteen different ADCs were used to develop IVIVC. In vitro efficacy of ADCs was evaluated using a kinetic cell cytotoxicity assay. The cytotoxicity data obtained from in vitro studies was characterized using a novel mathematical model, parameter estimates from which were used to derive an in vitro efficacy matrix for each ADC, termed as 'in vitro tumor static concentration' (TSCin vitro)...
February 8, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Xi Chen, Xiling Jiang, Rajitha Janssen R D Doddareddy, Brian Geist, Thomas McIntosh, William J Jusko, Honghui Zhou, Weirong Wang
The IL-23/Th17/IL-17 immune pathway has been identified to play an important role in the pathogenesis of psoriasis. Many therapeutic proteins targeting IL-23 or IL-17 are currently under development for the treatment of psoriasis. In the present study, a mechanistic PK/PD study was conducted to assess the target-binding and disposition kinetics of a monoclonal antibody (mAb), CNTO 3723, and its soluble target, mouse IL-23, in an IL-23-induced psoriasis-like (PsL) mouse model. A minimal physiologically-based pharmacokinetic (mPBPK) model with target-mediated drug disposition (TMDD) features was developed to quantitatively assess the kinetics and interrelationship between CNTO 3723 and exogenously administered, recombinant mouse IL-23 (rmIL-23) in both serum and lesional skin site...
February 2, 2018: Journal of Pharmacology and Experimental Therapeutics
Sherwin K B Sy, Luning Zhuang, Huiming Xia, Marie-Eve Beaudoin, Virna J Schuck, Wright W Nichols, Hartmut Derendorf
Objectives: To characterize quantitatively the effect of avibactam in potentiating ceftazidime against MDR Pseudomonas aeruginosa by developing a mathematical model to describe the bacterial response to constant concentration time-kill information and validating it using both constant and time-varying concentration-effect data from in vitro and in vivo infection systems. Methods: The time course of the bacterial population dynamics in the presence of static concentrations of ceftazidime and avibactam was modelled using a two-state pharmacokinetic/pharmacodynamic (PK/PD) model, consisting of active and resting states, to account for bactericidal activities, bacteria-mediated ceftazidime degradation and inhibition of degradation by avibactam...
February 3, 2018: Journal of Antimicrobial Chemotherapy
Laetitia Canini, Christopher Koh, Scott J Cotler, Susan L Uprichard, Mark A Winters, Ma Ai Thanda Han, David E Kleiner, Ramazan Idilman, Cihan Yurdaydin, Jeffrey S Glenn, Theo Heller, Harel Dahari
The prenylation inhibitor lonafarnib (LNF) is a potent antiviral agent providing a breakthrough for the treatment of hepatitis delta virus (HDV). The current study used a maximum likelihood approach to model LNF pharmacokinetic (PK) and pharmacodynamic (PD) parameters and predict the dose needed to achieve 99% efficacy using data from 12 patients chronically infected with HDV and treated with LNF 100 mg twice daily (bid) (group 1) or 200 mg bid (group 2) for 28 days. The LNF-PK model predicted average steady-state LNF concentrations of 860 ng/mL and 1,734 ng/mL in groups 1 and 2, respectively, with an LNF absorption rate ka = 0...
June 2017: Hepatology Communications
Zhixin Lei, Qianying Liu, Shuaike Yang, Bing Yang, Haseeb Khaliq, Kun Li, Saeed Ahmed, Abdul Sajid, Bingzhou Zhang, Pin Chen, Yinsheng Qiu, Jiyue Cao, Qigai He
The aims of the present study were to establish optimal doses and provide an alternate COPD for florfenicol against Streptococcus suis based on pharmacokinetic-pharmacodynamic integration modeling. The recommended dose (30 mg/kg b.w.) were administered in healthy pigs through intramuscular and intravenous routes for pharmacokinetic studies. The main pharmacokinetic parameters of Cmax, AUC0-24h, AUC, Ke, t1/2ke, MRT, Tmax, and Clb, were estimated as 4.44 μg/ml, 88.85 μg⋅h/ml, 158.56 μg⋅h/ml, 0.048 h-1, 14...
2018: Frontiers in Pharmacology
D C Richter, A Heininger, T Brenner, M Hochreiter, M Bernhard, J Briegel, S Dubler, B Grabein, A Hecker, W A Kruger, K Mayer, M W Pletz, D Storzinger, N Pinder, T Hoppe-Tichy, S Weiterer, S Zimmermann, A Brinkmann, M A Weigand, C Lichtenstern
The mortality of patients with sepsis and septic shock is still unacceptably high. An effective calculated antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality; therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed infection and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account during the selection of anti-infective treatment...
January 30, 2018: Der Anaesthesist
Zhipeng Wang, Davit A Potoyan, Peter G Wolynes
BACKGROUND: Transfection of NF κB synthetic decoy Oligodeoxynucleotides (ODNs) has been proposed as a promising therapeutic strategy for a variety of diseases arising from constitutive activation of the eukaryotic transcription factor NF κB. The decoy approach faces some limitations under physiological conditions notably nuclease-induced degradation. RESULTS: In this work, we show how a systems pharmacology model of NF κB regulatory networks displaying oscillatory temporal dynamics, can be used to predict quantitatively the dependence of therapeutic efficacy of NF κB synthetic decoy ODNs on dose, unbinding kinetic rates and nuclease-induced degradation rates...
January 30, 2018: BMC Systems Biology
Jee Hyun Park, William Craig, Karen Marchillo, David B Huang, David R Andes
The neutropenic, murine thigh infection model was used to define the PK/PD index linked to efficacy of iclaprim against S. aureus ATCC 29213 and S. pneumoniae ATCC 10813. The 24h AUC/MIC index was most closely linked to efficacy for S. aureus (R2=0.65), while both the 24h AUC/MIC and the %T>MIC were both strongly associated with effect (R2=0.86 for both parameters) for S. pneumoniae.
January 29, 2018: Antimicrobial Agents and Chemotherapy
Miao Zhao, Alexander J Lepak, Brian VanScoy, Justin C Bader, Karen Marchillo, Jamie Vanhecker, Paul G Ambrose, David R Andes
APX001 is the prodrug of APX001A, which is a first in class small molecule with a unique mechanism of action that inhibits the fungal enzyme (Gwt1) in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The goal of the present study was to determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy in the murine disseminated candidiasis model for Candida albicans (n=5), C. glabrata (n=5) and C. auris (n=4). MIC values ranged from 0.002 to 0.03 mg/L for C...
January 29, 2018: Antimicrobial Agents and Chemotherapy
Marilena Tsala, Sophia Vourli, Panagiota-Christina Georgiou, Spyros Pournaras, Athanasios Tsakris, George L Daikos, Johan W Mouton, Joseph Meletiadis
Objectives: Because the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of colistin against Enterobacteriaceae are not well explored, we studied the activity of colistin against K. pneumoniae in an in vitro PK/PD model simulating different dosing regimens. Methods: Three clinical isolates of K. pneumoniae with MICs of 0.5, 1 and 4 mg/L were tested in an in vitro PK/PD model following a dose-fractionation design over a period of 24 h. A high and low inoculum of 107 and 104 cfu/mL with and without a heteroresistant subpopulation, respectively, were used...
January 25, 2018: Journal of Antimicrobial Chemotherapy
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