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Divya Samineni, Sandhya Girish, Chunze Li
Suboptimal treatment for monoclonal antibodies (mAbs) directed against endogenous circulating soluble targets and the shed extracellular domains (ECD) of the membrane-bound targets is an important clinical concern due to the potential impact of mAbs on the in vivo efficacy and safety. Consequently, there are considerable challenges in the determination of an optimal dose and/or dosing regimen. Areas covered: This review outlines the impact of shed antigen targets from membrane-bound proteins and soluble targets on the PK and/or PD of therapeutic mAbs that have been approved in the last decade...
October 21, 2016: Expert Review of Clinical Pharmacology
Dong-Seok Yim
In the early phase of clinical development of antihypertensive drugs, quantitative modeling to predict their dose-concentration-response relationship is important to plan future clinical development and finding optimal dosage regimen at marketing approval. Two cases of concentration-response models of antihypertensive are presented here.Case 1: Carvedilol is a α1- and nonselective β- adrenergic receptor antagonist currently used for the management of mild-to-moderate essential hypertension and congestive heart failure...
September 2016: Journal of Hypertension
Emilio Fernández-Varón, Carlos Cárceles-García, Juan Manuel Serrano-Rodríguez, Carlos M Cárceles-Rodríguez
BACKGROUND: Bacterial pneumonia in goats is usually caused by Mannheimia haemolytica and Pasteurella multocida. Another important infection disease in lactating goats is intramammary infection producing mastitis, usually associated with coagulase-negative Staphylococcus spp. However, treatment of bacterial pneumonia in goats not affected by mastitis problems should be restricted to antimicrobials with scant penetration to milk in order to avoid long withdrawal times. Ceftiofur is a third-generation cephalosporin antimicrobial with activity against various gram-positive and gram-negative, aerobic and anaerobic bacteria encountered by domestic animals...
October 13, 2016: BMC Veterinary Research
Michael Osthoff, Martin Siegemund, Gianmarco Balestra, Mohd Hafiz Abdul-Aziz, Jason A Roberts
Prolonged infusion of β-lactam antibiotics as either extended (over at least 2 hours) or continuous infusion is increasingly applied in intensive care units around the world in an attempt to optimise treatment with this most commonly used class of antibiotics, whose effectiveness is challenged by increasing resistance rates. The pharmacokinetics of β-lactam antibiotics in critically ill patients is profoundly altered secondary to an increased volume of distribution and the presence of altered renal function, including augmented renal clearance...
2016: Swiss Medical Weekly
Soo Min Han, Joonhee Park, Ji Hyun Lee, Sang Seop Lee, Hyoki Kim, Hyojun Han, Yuhnam Kim, Sojeong Yi, Joo-Youn Cho, In-Jin Jang, Min Goo Lee
Phenotypic differences in drug responses have been associated with known pharmacogenomic loci, but many remain to be characterized. We therefore developed next-generation sequencing (NGS) panels to enable broad and unbiased inspection of genes that are involved in pharmacokinetics (PK) and pharmacodynamics (PD). These panels feature repetitively optimized probes to capture up to 114 PK/PD-related genes with high coverage (99.6%) and accuracy (99.9%). Sequencing of a Korean cohort (n = 376) with the panels enabled profiling of actionable variants as well as rare variants of unknown functional consequences...
October 11, 2016: Clinical Pharmacology and Therapeutics
Hannah C Slater, Lucy C Okell, Azra C Ghani
Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used at the population level, to clear infections, provide chemoprevention, and to reduce onward transmission of infection. However, there is less clarity on the extent to which different drug properties are important for these different uses. In addition, the emergence of drug resistance poses new threats to longer-term use and highlights the need for rational drug development...
October 7, 2016: Trends in Parasitology
Kai Wu, Jianfeng Xu, Regan Fong, Xiaozhou Yao, Yanmei Xu, William Guiney, Frank Gray, Andrew Lockhart
OBJECTIVE: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). METHODS: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 - 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544...
October 10, 2016: International Journal of Clinical Pharmacology and Therapeutics
Richard Burdick, Todd Coffey, Hiten Gutka, Gyöngyi Gratzl, Hugh D Conlon, Chi-Ting Huang, Michael Boyne, Henriette Kuehne
Protein therapeutics have unique critical quality attributes (CQAs) that define their purity, potency, and safety. The analytical methods used to assess CQAs must be able to distinguish clinically meaningful differences in comparator products, and the most important CQAs should be evaluated with the most statistical rigor. High-risk CQA measurements assess the most important attributes that directly impact the clinical mechanism of action or have known implications for safety, while the moderate- to low-risk characteristics may have a lower direct impact and thereby may have a broader range to establish similarity...
October 5, 2016: AAPS Journal
Masato Fukae, Yoshimasa Shiraishi, Takeshi Hirota, Yuka Sasaki, Mika Yamahashi, Koichi Takayama, Yoichi Nakanishi, Ichiro Ieiri
PURPOSE: Docetaxel is used to treat many cancers, and neutropenia is the dose-limiting factor for its clinical use. A population pharmacokinetic-pharmacodynamic (PK-PD) model was introduced to predict the development of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer (NSCLC). METHODS: Forty-seven advanced or recurrent Japanese patients with NSCLC were enrolled. Patients received 50 or 60 mg/m(2) docetaxel as monotherapy, and blood samples for a PK analysis were collected up to 24 h after its infusion...
October 5, 2016: Cancer Chemotherapy and Pharmacology
Xi-Ling Jiang, Hong-Wu Shen, Donald E Mager, Stephan Schmidt, Ai-Ming Yu
We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control...
September 2016: Acta Pharmaceutica Sinica. B
Amélie Le Bihan, Ruben de Kanter, Iñigo Angulo-Barturen, Christoph Binkert, Christoph Boss, Reto Brun, Ralf Brunner, Stephan Buchmann, Jeremy Burrows, Koen J Dechering, Michael Delves, Sonja Ewerling, Santiago Ferrer, Christoph Fischli, Francisco Javier Gamo-Benito, Nina F Gnädig, Bibia Heidmann, María Belén Jiménez-Díaz, Didier Leroy, Maria Santos Martínez, Solange Meyer, Joerg J Moehrle, Caroline L Ng, Rintis Noviyanti, Andrea Ruecker, Laura María Sanz, Robert W Sauerwein, Christian Scheurer, Sarah Schleiferboeck, Robert Sinden, Christopher Snyder, Judith Straimer, Grennady Wirjanata, Jutta Marfurt, Ric N Price, Thomas Weller, Walter Fischli, David A Fidock, Martine Clozel, Sergio Wittlin
BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented...
October 2016: PLoS Medicine
P Singh, H Rong, T Gordi, J Bosley, I Bhattacharya
Suppression of the myostatin (GDF-8) pathway has emerged as an important therapeutic paradigm for muscle-wasting disorders. In this study, we conducted a translational pharmacokinetic/pharmacodynamic (PK/PD) analysis of MYO-029, an anti-myostatin monoclonal antibody, using PK data in mice, rats, monkeys, humans, mouse tissue distribution data with (125) I-labeled MYO-029, muscle weight increase in SCID mice, and muscle circumference changes in monkeys. This analysis revealed significant in vivo potency shift between mice and monkeys (72 nM vs...
October 4, 2016: Clinical and Translational Science
Morris Muliaditan, Geraint R Davies, Ulrika S H Simonsson, Stephen H Gillespie, Oscar Della Pasqua
Despite promising advances in the field and highly effective first-line treatment, an estimated 9.6 million people are still infected with tuberculosis (TB). Innovative methods are required to effectively transition the growing number of compounds into novel combination regimens. However, progression of compounds into patients occurs despite the lack of clear understanding of the pharmacokinetic-pharmacodynamic (PK/PD) relations. The PreDiCT-TB consortium was established in response to the existing gaps in TB drug development...
September 28, 2016: Drug Discovery Today
Q Shan, J Wang
Increasing prevalence of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae (K. pneumoniae) is of clinical concern. The objective of our study was to examine the in vivo activity of cefquinome against ESBL-producing K. pneumoniae strain using a neutropenic mouse thigh infection model. Cefquinome kinetics and protein binding in infected neutropenic mice were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Dose-fractionation studies over a 24-h dose range of 2.5-320 mg/kg were administered every 3, 6, 12, or 24 h...
September 29, 2016: Journal of Veterinary Pharmacology and Therapeutics
Martin Soehle, Christina F Wolf, Melanie J Priston, Georg Neuloh, Christian G Bien, Andreas Hoeft, Richard K Ellerkmann
BACKGROUND: During awake craniotomy, the patient's language centers are identified by neurological testing requiring a fully awake and cooperative patient. Hence, anesthesia aims for an unconscious patient at the beginning and end of surgery but an awake and responsive patient in between. We investigated the plasma (Cplasma) and effect-site (Ceffect-site) propofol concentration as well as the related Bispectral Index (BIS) required for intraoperative return of consciousness and begin of neurological testing...
September 27, 2016: Journal of Neurosurgical Anesthesiology
M J Melchers, E Mavridou, A C van Mil, C Lagarde, J W Mouton
Ceftolozane is a new broad-spectrum cephalosporin and combined with tazobactam to broaden its activity against strains producing extended spectrum beta-lactamases (ESBL). We determined the pharmacodynamics (PD) of the combination in the neutropenic mouse thigh model to determine the optimal exposure of tazobactam. Treatment was started in CD-1 neutropenic mice 2h after infection with ceftolozane q2h alone or in combination with tazobactam using different dose frequencies for 24h and cfu determined in the thighs before and after treatment...
September 26, 2016: Antimicrobial Agents and Chemotherapy
Xiaofen Liu, Miao Zhao, Yuancheng Chen, Xingchen Bian, Yunfei Li, Jun Shi, Jing Zhang
Carbapenem-resistant Acinetobacter baumannii (CRAB) is an important clinical threat. Combination therapy that exerts a synergistic effect has become a potential solution to combat CRAB. However, choosing an optimal combination regimen is challenging. A dynamic in vitro pharmacokinetic/pharmacodynamic (PK/PD) model that can simulate the pharmacokinetic profiles of antibiotics provides a powerful tool to compare antibacterial responses to different clinical dosage regimens. In this study, the synergistic effect of the combination of meropenem and colistin was tested in 12 clinical CRAB isolates from Chinese patients using the chequerboard technique...
September 8, 2016: International Journal of Antimicrobial Agents
Jung-Min Lee, Cody J Peer, Minshu Yu, Lauren Amable, Nicolas Gordon, Christina M Annunziata, Nicole Houston, Andrew K L Goey, Tristan M Sissung, Bernard Parker, Lori Minasian, Victoria Chiou, Robert F Murphy, Brigitte C Widemann, William D Figg, Elise C Kohn
PURPOSE: Our preclinical studies showed the PARP inhibitor, olaparib prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic/pharmacodynamic (PK/PD) effects, safety and activity of the combination. PATIENTS AND METHODS: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200mg bid, days1-7) in a 3+3 dose escalation with carboplatin AUC4 or 5 q21 days, up to eight cycles, followed by olaparib maintenance...
September 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sihem Ait-Oudhia, Meric Ayse Ovacik, Donald E Mager
Pharmacokinetic (PK) and pharmacodynamic (PD) models seek to describe the temporal pattern of drug exposures and their associated pharmacological effects produced at micro- and macro-scales of organization. Antibody-based drugs have been developed for a large variety of diseases, with effects exhibited through a comprehensive range of mechanisms of action. Mechanism-based PK/PD and systems pharmacology models can play a major role in elucidating and integrating complex antibody pharmacological properties, such as nonlinear disposition and dynamical intracellular signaling pathways triggered by ligation to their cognate targets...
September 23, 2016: MAbs
Spencer B Jones, Lance A Pfeifer, Thomas J Bleisch, Thomas J Beauchamp, Jim D Durbin, V Joseph Klimkowski, Norman E Hughes, Christopher J Rito, Yen Dao, Joseph M Gruber, Hai Bui, Mark G Chambers, Srinivasan Chandrasekhar, Chaohua Lin, Denis J McCann, Daniel R Mudra, Jennifer L Oskins, Craig A Swearingen, Kannan Thirunavukkarasu, Bryan H Norman
In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship...
September 8, 2016: ACS Medicinal Chemistry Letters
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