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https://www.readbyqxmd.com/read/28640596/drug-target-kinetics-in-drug-discovery
#1
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/28637099/aggregation-and-phosphorylation-of-%C3%AE-synuclein-with-proteinase-k-resistance-in-focal-%C3%AE-synucleinopathy-predominantly-localized-to-the-cardiac-sympathetic-nervous-system
#2
Nei Fukasawa, Takahiro Fukuda, Masato Nagaoka, Tohru Harada, Hiroyuki Takahashi, Masahiro Ikegami
Aggregates of α-synuclein, a major component of Lewy bodies (LBs) and Lewy neurites (LNs), are distributed throughout the nervous system, including the central nervous system (CNS), sympathetic ganglia, enteric nervous system (ENS), cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin, in incidental Lewy body disease (ILBD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and pure autonomic failure (PAF) [1-3]. Here we report focal α-synucleinopathy predominantly localized to the cardiac sympathetic nervous system (SNS)...
June 21, 2017: Neuropathology and Applied Neurobiology
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
#3
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/28636184/pharmacokinetics-pharmacodynamics-of-bococizumab-a-monoclonal-antibody-to-pcsk9-after-single-subcutaneous-injection-at-3-sites-nct-02043301
#4
Ellen Q Wang, Anna Plotka, Joanne Salageanu, Catherine Sattler, Carla Yunis
AIM: To characterize the single-dose pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a monoclonal antibody inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), administered subcutaneously (s.c.) to the abdomen, thigh, or upper arm (NCT02043301). METHODS: Seventy-five adults with low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL and not on background lipid-lowering therapy were randomized (1:1:1) to a single 150-mg s.c. dose of bococizumab administered to the abdomen, thigh, or upper arm...
June 21, 2017: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/28630197/pharmacodynamics-of-cefepime-combined-with-tazobactam-against-clinically-relevant-enterobactereaceae-in-a-neutropenic-mouse-thigh-model
#5
Maria J Melchers, Anita C van Mil, Claudia Lagarde, Jan den Hartigh, Johan W Mouton
The lack of new antibiotics prompted the investigation of the combination of two existing agents cefepime, a broad-spectrum cephalosporin and tazobactam to broaden its efficacy against extended-spectrum beta-lactamase producing Enterobacteriaceae. We determined the pharmacokinetic and pharmacodynamic properties of the combination in a murine neutropenic thigh model in order to establishing its exposure- response relationships (ERR). The PK of cefepime was determined for five doses; that of tazobactam was determined in earlier studies (Melchers et al Antimicrob...
June 19, 2017: Antimicrobial Agents and Chemotherapy
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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/28613871/discovery-of-n-4-5-4-fluoro-phenyl-3-methyl-2-methylsulfanyl-3h-imidazol-4-yl-pyridin-2-yl-acetamide-cbs-3595-a-dual-p38%C3%AE-mapk-pde-4-inhibitor-with-activity-against-tnf%C3%AE-related-diseases
#12
Wolfgang Albrecht, Anke Unger, Silke M Bauer, Stefan A Laufer
The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38α MAPK and phosphodiesterase 4 (PDE4) and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha (TNFα) release...
June 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28611739/the-pk-pd-relationship-and-resistance-development-of-danofloxacin-against-mycoplasma-gallisepticum-in-an-in-vivo-infection-model
#13
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
#14
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/28605468/attenuation-of-insulin-action-by-an-allosteric-insulin-receptor-antibody-in-healthy-volunteers
#15
Kirk W Johnson, Ann Neale, Allan Gordon, Julie Roessig, Padma Bezwada, Sabine Vukelich, Ira Goldfine, Paul Rubin
Background: X358 (X358) is a fully human monoclonal antibody to the insulin receptor (InsR) that acts as a negative allosteric modulator of insulin signaling. It is being developed as a novel treatment for hyperinsulinemic hypoglycemia. This report describes pharmacokinetic (PK), and pharmacodynamic (PD) data from a first-in-human clinical trial. Methods: A double-blind, placebo-controlled, single ascending dose study was performed with 29 healthy adult males randomized to intravenous infusion of placebo or X358 at 0...
June 9, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28600397/semi-mechanistic-bone-marrow-exhaustion-pharmacokinetic-pharmacodynamic-model-for-chemotherapy-induced-cumulative-neutropenia
#16
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/28591833/a-new-fully-human-recombinant-fsh-follitropin-epsilon-two-phase-i-randomized-placebo-and-comparator-controlled-pharmacokinetic-and-pharmacodynamic-trials
#17
Khalid Abd-Elaziz, Ingrid Duijkers, Lars Stöckl, Bruno Dietrich, Christine Klipping, Kelvin Eckert, Steffen Goletz
STUDY QUESTION: What are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product? SUMMARY ANSWER: Overall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters...
June 7, 2017: Human Reproduction
https://www.readbyqxmd.com/read/28589492/a-phase-1-study-of-ly2874455-an-oral-selective-pan-fgfr-inhibitor-in-patients-with-advanced-cancer
#18
Michael Michael, Yung-Jue Bang, Young Suk Park, Yoon-Koo Kang, Tae Min Kim, Oday Hamid, Donald Thornton, Sonya C Tate, Eyas Raddad, Jeanne Tie
BACKGROUND: We report here a phase 1 study of LY2874455, a potent oral selective pan-fibroblast growth factor receptor (FGFR) inhibitor. OBJECTIVE: The primary objective was to determine the recommended phase 2 dosing (RP2D). Secondary objectives included determining toxicity, antitumor activity, pharmacokinetics (PK), and pharmacodynamic (PD) properties of LY2874455. PATIENTS AND METHODS: This study comprised two parts: (a) dose escalation with 3 + 3 cohorts in patients with solid tumors and (b) dose-expansion cohorts in patients with gastric cancer (GC) and non-small cell lung cancer (NSCLC)...
June 6, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28571972/discovery-of-novel-and-potent-stearoyl-coenzyme-a-desaturase-1-scd1-inhibitors-as-anticancer-agents
#19
Keisuke Imamura, Naoki Tomita, Youichi Kawakita, Yoshiteru Ito, Kouji Ono, Noriyuki Nii, Tohru Miyazaki, Kazuko Yonemori, Michiko Tawada, Hiroyuki Sumi, Yoshihiko Satoh, Yukiko Yamamoto, Ikuo Miyahisa, Masako Sasaki, Yoshinori Satomi, Megumi Hirayama, Ryuichi Nishigaki, Hironobu Maezaki
A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of 'non-spiro' 4, 4-disubstituted piperidine derivatives based on molecular modeling studies...
May 11, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28571114/population-modelling-integrating-pharmacokinetics-pharmacodynamics-pharmacogenetics-and-clinical-outcome-in-sunitinib-treated-cancer-patients
#20
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
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