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Clinical pharmacokinetics

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https://www.readbyqxmd.com/read/29342358/synthesis-and-biological-characterization-of-aryl-uracil-inhibitors-of-hepatitis-c-virus-ns5b-polymerase-discovery-of-abt-072-a-trans-stilbene-analog-with-good-oral-bioavailability
#1
John Randolph, A Chris Krueger, Pamela Donner, John K Pratt, Dachun Liu, Christopher E Motter, Todd W Rockway, Mike D Tufano, Rolf Wagner, Hock B Lim, Jill M Beyer, Rubina Mondal, Neeta S Panchal, Lynn Colletti, Yaya Liu, Gennadiy Koev, Warren M Kati, Lisa E Hernandez, David W A Beno, Kenton L Longenecker, Kent D Stewart, Emily O Dumas, Akhteruzzaman Molla, Clarence Maring
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility, and provided much better pharmacokinetic properties in preclinical species...
January 17, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29342199/a-non-linear-pharmacokinetic-pharmacodynamic-relationship-of-metformin-in-healthy-volunteers-an-open-label-parallel-group-randomized-clinical-study
#2
Hyewon Chung, Jaeseong Oh, Seo Hyun Yoon, Kyung-Sang Yu, Joo-Youn Cho, Jae-Yong Chung
BACKGROUND: The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers. METHODS: A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration...
2018: PloS One
https://www.readbyqxmd.com/read/29341904/a-rapid-and-simple-lc-ms-ms-method-for-personalized-busulfan-dosing-in-pediatric-patients-undergoing-hematological-stem-cell-transplantation-hsct
#3
Yi Xiao, Xiaohan Li, Xiaowei Fu
BACKGROUND: Busulfan is commonly used as a conditioning regimen before hematological stem cell transplantation (HSCT). There is a big inter-individual variability in busulfan exposure and the narrow therapeutic index, especially in pediatric population. Therefore, to achieve therapeutic efficacy and safety concurrently, personalized busulfan dosing, guided by pharmacokinetic study with serial plasma samples, is needed a few hours afterwards. METHODS: We used liquid-chromatography-mass spectrometry (HPLC-MS/MS) to develop, validate, and implementation of a fast, sensitive, and accurate method for busulfan measurement...
January 13, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29341245/pharmacokinetic-pharmacodynamic-drug-drug-interactions-of-avatrombopag-when-co-administered-with-dual-or-selective-cyp2c9-and-cyp3a-interacting-drugs
#4
Maiko Nomoto, Cynthia A Zamora, Edgar Schuck, Peter Boyd, Min-Kun Chang, Jagadeesh Aluri, Y Amy Siu, W George Lai, Sanae Yasuda, Jim Ferry, Bhaskar Rege
AIMS: Avatrombopag, a thrombopoietin receptor agonist, is a substrate of cytochrome P450 (CYP) 2C9 and CYP3A. We assessed three drug-drug interactions of avatrombopag as a victim with dual or selective CYP2C9/3A inhibitors and inducers. METHODS: This was a 3-part, open-label study. Forty-eight healthy subjects received single 20 mg doses of avatrombopag alone or with one of 3 CYP2C9/3A inhibitors or inducers: fluconazole 400 mg once daily for 16 days, itraconazole 200 mg twice daily on Day 1 and 200 mg once daily on Days 2-16, or rifampin 600 mg once daily for 16 days...
January 16, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29341227/pet-radiometals-for-antibody-labeling
#5
Eduardo Aluicio-Sarduy, Paul A Ellison, Todd E Barnhart, Weibo Cai, Robert Jerry Nickles, Jonathan W Engle
Recent advances in molecular characterization of tumors have made possible the emergence of new types of cancer therapies where the traditional cytotoxic drugs and nonspecific chemotherapy can be complemented with targeted molecular therapies. One of the main revolutionary treatments is the use of monoclonal antibodies (mAbs) that selectively target the disseminated tumor cells while sparing normal tissues. mAbs and related therapeutics can be efficiently radiolabeled with a wide range of radionuclides to facilitate preclinical and clinical studies...
January 17, 2018: Journal of Labelled Compounds & Radiopharmaceuticals
https://www.readbyqxmd.com/read/29341192/population-pharmacokinetic-modeling-of-guselkumab-a-human-igg1%C3%AE-monoclonal-antibody-targeting-il-23-in-patients-with-moderate-to-severe-plaque-psoriasis
#6
Zhenling Yao, Chuanpu Hu, Yaowei Zhu, Zhenhua Xu, Bruce Randazzo, Yasmine Wasfi, Yang Chen, Amarnath Sharma, Honghui Zhou
Psoriasis is a common inflammatory skin disorder that requires chronic treatment and is associated with multiple comorbidities. Guselkumab, a human immunoglobulin-G1-lambda monoclonal antibody, binds to interleukin-23 with high specificity and affinity and is effective in treating moderate to severe plaque psoriasis. As part of the guselkumab psoriasis clinical trial program, using a confirmatory approach, a population pharmacokinetics (PopPK) model was established using 13 014 PK samples from 1454 guselkumab-treated patients across 3 phase 2/3 trials...
January 17, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29341179/better-characterization-of-vinflunine-pharmacokinetics-variability-and-exposure-toxicity-relationship-to-improve-its-use-analyses-from-18-trials
#7
A Schmitt, L Nguyen, G Zorza, P Ferré, A Pétain
AIMS: Vinflunine is a novel tubulin-targeted inhibitor indicated as a single agent for the treatment of bladder cancers after failure of prior platinum-based therapy. Its pharmacokinetics (PK) and pharmacodynamics (PD) have been independently characterized through several phase I and phase II studies. However, no global pharmacometric analysis had been conducted yet. METHODS: Vinflunine concentrations and safety data from 18 phase I and phase II studies were used to conduct population PK and PK/PD analysis, using Nonmem...
January 17, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29340623/pharmacokinetics-of-rituximab-and-clinical-outcomes-in-patients-with-anti-neutrophil-cytoplasmic-antibody-associated-vasculitis
#8
Divi Cornec, Brian F Kabat, John R Mills, Melissa Cheu, Amber M Hummel, Darrell R Schroeder, Matthew D Cascino, Paul Brunetta, David L Murray, Melissa R Snyder, Fernando Fervenza, Gary S Hoffman, Cees G M Kallenberg, Carol A Langford, Peter A Merkel, Paul A Monach, Philip Seo, Robert F Spiera, E William St Clair, John H Stone, David R Barnidge, Ulrich Specks
Objectives: To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes. Methods: This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m2). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission...
January 10, 2018: Rheumatology
https://www.readbyqxmd.com/read/29339723/fasoracetam-in-adolescents-with-adhd-and-glutamatergic-gene-network-variants-disrupting-mglur-neurotransmitter-signaling
#9
Josephine Elia, Grace Ungal, Charlly Kao, Alexander Ambrosini, Nilsa De Jesus-Rosario, Lene Larsen, Rosetta Chiavacci, Tiancheng Wang, Christine Kurian, Kanani Titchen, Brian Sykes, Sharon Hwang, Bhumi Kumar, Jacqueline Potts, Joshua Davis, Jeffrey Malatack, Emma Slattery, Ganesh Moorthy, Athena Zuppa, Andrew Weller, Enda Byrne, Yun R Li, Walter K Kraft, Hakon Hakonarson
The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12-17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50-800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks...
January 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29339550/relative-target-affinities-of-t-cell-dependent-bispecific-antibodies-determine-biodistribution-in-a-solid-tumor-mouse-model
#10
Danielle Mandikian, Nene Takahashi, Amy A Lo, Ji Li, Jeffrey Eastham-Anderson, Dionysos Slaga, Jason Ho, Maria Hristopoulos, Robyn Clark, Klara Totpal, Kedan Lin, Sean B Joseph, Mark S Dennis, Saileta Prabhu, Teemu T Junttila, C Andrew Boswell
Anti-HER2/CD3, a T cell-dependent bispecific antibody (TDB) construct, induces T cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. While therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy...
January 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29339394/population-pharmacokinetics-of-finafloxacin-in-healthy-volunteers-and-patients-with-complicated-urinary-tract-infections
#11
Max Taubert, Mark Lückermann, Andreas Vente, Axel Dalhoff, Uwe Fuhr
Background: Finafloxacin is a novel fluoroquinolone with increased antibacterial activity at acidic pH and reduced susceptibility to several resistance mechanisms. A phase II study revealed a good efficacy/safety profile in patients with complicated urinary tract infections (cUTI) while pharmacokinetics was characterized by highly variable concentration vs. time profiles, suggesting the need for an elaborated pharmacokinetic model.Methods: Data from three clinical trials were evaluated; 127 healthy volunteers were dosed orally (N=77) or intravenously (N=50) and 139 patients with cUTI received finafloxacin intravenously...
January 16, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29339228/stability-and-plasmatic-protein-binding-of-novel-zidovudine-prodrugs-targeting-site-ii-of-human-serum-albumin
#12
Esteban M Schenfeld, Sergio R Ribone, Mario A Quevedo
Despite its vastly demonstrated clinical efficacy, zidovudine (AZT) exhibits several suboptimal pharmacokinetic properties. In particular, its short plasmatic half-life (t1/2 ~ 1 h) is related to its low bound fraction to whole plasmatic proteins and in particular to human serum albumin (HSA). The design of prodrugs constitutes a promising strategy to enhance AZT pharmacokinetic properties, including its affinity for HSA. Recently, we reported the synthesis and chemical stability evaluation of three novel prodrugs of AZT obtained by derivatization with dicarboxylic acids (1-3)...
January 12, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29339225/metabolism-and-pharmacokinetics-of-a-potent-n-acylindole-antagonist-of-the-oxe-receptor-for-the-eosinophil-chemoattractant-5-oxo-6-8-11-14-eicosatetraenoic-acid-5-oxo-ete-in-rats-and-monkeys
#13
Chintam Nagendra Reddy, Hussam Alhamza, Shishir Chourey, Qiuji Ye, Vivek Gore, Chantal Cossette, Sylvie Gravel, Irina Slobodchikova, Dajana Vuckovic, Joshua Rokach, William S Powell
We previously identified the indole 264 as a potent in vitro antagonist of the human OXE receptor that mediates the actions of the powerful eosinophil chemoattractant 5-oxo-ETE. No antagonists of this receptor are currently commercially available or are being tested in clinical studies. The lack of a rodent ortholog of the OXE receptor has hampered progress in this area because of the unavailability of commonly used mouse or rat animal models. In the present study, we examined the feasibility of using the cynomolgus monkey as an animal model to investigate the efficacy of orally administered 264 in future in vivo studies...
January 12, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29339169/the-timing-of-p2y12-inhibitor-initiation-in-the-treatment-of-acs-does-the-evidence-exist-in-this-era
#14
REVIEW
Harsh Golwala, Deepak L Bhatt
The majority of acute coronary syndromes (ACS) are well characterized as a consequence of plaque rupture and subsequent thrombosis. Antiplatelet agents targeting inhibition of P2Y12 receptors on the platelets have shown to reduce future risk of cardiovascular events in this patient population. However, the timing of initiation of these agents, in particular, in patients managed with invasive strategy with percutaneous coronary interventions (PCI) is debatable. The data supporting pretreatment with antiplatelet agents prior to PCI in ACS patients dates to trials performed >15 years ago, wherein the time to PCI was >5 days, and henceforth, the utility of pretreatment with these agents in the contemporary era remains uncertain...
January 12, 2018: Progress in Cardiovascular Diseases
https://www.readbyqxmd.com/read/29338536/p2y12-receptor-inhibitors-an-evolution-in-drug-design-to-prevent-arterial-thrombosis
#15
Danny Kupka, Dirk Sibbing
P2Y12 inhibitors are a critical component of dual antiplatelet therapy (DAPT) - a combination of a P2Y12 receptor inhibitor and aspirin - which is the superior strategy to prevent arterial thrombosis in patients with acute coronary syndromes (ACS) and undergoing stent implantation. Areas covered: Basic science articles, clinical studies, and reviews from 1992-2017 were searched using Pubmed library to collet impactful literature. After an introduction to the purinergic receptor biology, this review summarizes current knowledge on P2Y12 receptor inhibitors including their specific pharmacodynamic as well as pharmacokinetic and drug interaction features...
January 17, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29338293/betrixaban-a-new-oral-factor-xa-inhibitor-for-extended-venous-thromboembolism-prophylaxis-in-high-risk-hospitalized-patients
#16
Scott G Garland, Christina E DeRemer, Steven M Smith, John G Gums
OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of the factor Xa (FXa) inhibitor betrixaban for extended-duration prophylaxis of acute medically ill patients with venous thromboembolism (VTE) risk factors. DATA SOURCES: A MEDLINE/PubMed (January 1990 to October 2017) search was conducted using the following keywords: betrixaban, PRT054021, FXa inhibitor, novel oral anticoagulant, NOAC, direct oral anticoagulant, DOAC, and target specific oral anticoagulant, TSOAC...
January 1, 2018: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/29338251/delivery-of-oxytocin-to-the-brain-for-the-treatment-of-autism-spectrum-disorder-by-nasal-application
#17
Akiko Tanaka, Tomoyuki Furubayashi, Mari Arai, Daisuke Inoue, Shunsuke Kimura, Akiko Kiriyama, Kosuke Kusamori, Hidemasa Katsumi, Reiko Yutani, Toshiyasu Sakane, Akira Yamamoto
Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the blood stream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application...
January 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29336875/systems-pharmacology-dissection-of-the-anti-stroke-mechanism-for-the-chinese-traditional-medicine-xing-nao-jing
#18
Yuhua Chen, Yue Sun, Wende Li, Hong Wei, Tianlin Long, Hua Li, Quanhua Xu, Wei Liu
Xing-Nao-Jing (XNJ) is a well-known injection that has been extensively applied in clinical treatment of stroke in China. However, the underlying mechanism of clinical administration of XNJ in stroke remains unclear. In this study, a systems pharmacology strategy based on pharmacokinetic and pharmacodynamics data was applied to analyze the pharmacological effect of XNJ on stroke. Sixteen active compounds were filtered from XNJ through Drug-likeness (DL) and Brain-blood-barrier (BBB) evaluations. Ninety-four potential targets of these active components were identified by SysDT and SEA...
December 20, 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/29336615/pharmacokinetic-bioequivalence-safety-and-acceptability-of-ornibel%C3%A2-a-new-polymer-composition-contraceptive-vaginal-ring-etonogestrel-ethinylestradiol-11-00-3-474%C3%A2-mg-compared-with-nuvaring%C3%A2-etonogestrel-ethinylestradiol-11-7-2-7%C3%A2-mg
#19
Jaime Algorta, Maria Diaz, Raquel de Benito, Marc Lefebvre, Eric Sicard, Milton Furtado, Pedro Antonio Regidor, Celestino Ronchi
OBJECTIVE: To show the clinical development of Ornibel® (ExeltisHealthcare, Spain) a contraceptive vaginal ring manufactured with a new polymer composition and containing etonogestrel/ethinylestradiol, compared to Nuvaring® (MSD, Spain). SUBJECTS AND METHODS: Randomised, single dose, 2-period, 2-sequence, 2-stage crossover, comparative bioavailability study conducted in 40 healthy female subjects. All subjects received both treatments for 28 days in each of two periods, separated by a 28 days washout...
January 16, 2018: European Journal of Contraception & Reproductive Health Care
https://www.readbyqxmd.com/read/29335861/alterations-of-gefitinib-pharmacokinetics-by-co-administration-of-herbal-medications-in-rats
#20
Kwon-Yeon Weon, Min Gi Kim, Soyoung Shin, Tae Hwan Kim, Sang Hoon Joo, Eunsook Ma, Seok Won Jeong, Sun Dong Yoo, Yu Seok Youn, Beom Soo Shin
OBJECTIVE: To evaluate the potential pharmacokinetic interactions of the anticancer agent gefifitinib (Iressa®) and the oriental medications Guipi Decoction (, GPD, Guibi-tang in Korean) and Bawu Decoction (, BWD, Palmul-tang in Korean). METHODS: Methylcellulose (MC, control), GPD (1,200 mg/kg), or BWD (6,000 mg/kg) was orally administered to rats either as a single dose or multiple doses prior to gefitinib administration. To examine the effects of a single dose of the herbal medicines, gefifitinib (10 mg/kg) was orally administered after 5 min or 1 h of MC or the herbal medicine pretreatments...
January 15, 2018: Chinese Journal of Integrative Medicine
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