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Po-Chang Chiang, Karthik Nagapudi, Peter W Fan, Jia Liu
With the rising cost of drug research, "do more with less" has become a new emphasis in the pharmaceutical industry. Consequently, the early analysis of PK/PD, efficacy, and safety parameters for a new drug target is critical for ensuring informed decision-making as soon as possible during the drug discovery process. When ADME properties of compounds are suboptimalwhich is especially true during the early stages of drug discovery, obtaining the desired exposure can be challenging via the most common routes (oral, IV)...
June 14, 2018: Journal of Pharmaceutical Sciences
Matthew Cardinal, Constantino Kantaridis, Tong Zhu, Pengling Sun, Debra D Pittman, John E Murphy, Steven Arkin
BACKGROUND: Tissue factor pathway inhibitor (TFPI) is a protease inhibitor of tissue factor-activated coagulation factor VII (TF-FVIIa) complex and activated factor X (FXa). PF-06741086 is a monoclonal antibody that targets TFPI to increase clotting activity. OBJECTIVES: This study was a randomized, double-blind, sponsor-open, placebo-controlled, single intravenous (IV) or subcutaneous (SC) dose escalation study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06741086...
June 16, 2018: Journal of Thrombosis and Haemostasis: JTH
Maiko Nomoto, Jim Ferry, Ziad Hussein
Avatrombopag, a c-Mpl agonist, has been developed to provide an alternative therapy to standard platelet transfusion care for the treatment of thrombocytopenia. The main objectives of this article were to describe the pharmacokinetics (PK) of avatrombopag, to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship between plasma avatrombopag concentrations and platelet count, and to identify potential intrinsic and extrinsic factors affecting PK or PK/PD in patients with chronic liver disease (CLD)...
June 15, 2018: Journal of Clinical Pharmacology
Wojciech Danysz, Yan Han, Fugang Li, Jim Nicoll, Philipp Buch, Thomas Hengl, Maarten Ruitenberg, Chris Parsons
Transformation of white adipose tissue (WAT) to a brown adipose tissue-like (BAT-like) phenotype has emerged as an attractive approach against e.g. using g ß3 adrenergic receptor agonists. These could however, produce side-effects following systemic exposure. The present study explored the possibility of local use of CL-316,243 - a selective ß3 agonist - to circumvent this problem. Rats treated s.c. for 2 weeks (0.3 and 1 mg/kg) showed decreased inguinal fat pad (IFP) weight/volume, increased UCP-1 staining and expressed BAT-like features in H&E stained micrographs...
June 11, 2018: Biochimica et Biophysica Acta
Edward Hammond, Nicole M Haynes, Carleen Cullinane, Todd V Brennan, Darryn Bampton, Paul Handley, Tomislav Karoli, Fleur Lanksheer, Liwen Lin, Yiping Yang, Keith Dredge
BACKGROUND: Pixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration of tumor-associated macrophages (TAMs) yet also stimulate dendritic cells (DCs), leading to activation of natural killer (NK) cells. Preclinically, pixatimod inhibits heparanase (HPSE) which may be associated with its inhibitory effect on TAMs whereas its immunostimulatory activity on DCs is through the MyD88-dependent TLR9 pathway. Pixatimod recently completed a Phase Ia monotherapy trial in advanced cancer patients...
June 14, 2018: Journal for Immunotherapy of Cancer
Taotao Wang, Tao Zhang, Ti Meng, Ying Li, Lu Chen, Qianting Yang, Haiyan Dong, Jin'e Lei, Limei Chen, Yalin Dong
BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a life-threatening disease in immunosuppressed patients. Voriconazole is commonly used to prevent and treat IPA in the clinic, but the optimal prophylactic antifungal regimen is unknown. The objective of this study was to clarify the mechanism underlying how voriconazole prevents IPA based on a target cellular pharmacokinetics/pharmacodynamics model, with the aim of identifying a way to design an optimal prophylactic antifungal regimen...
June 7, 2018: Journal of Translational Medicine
Elin Boger, Markus Fridén
BACKGROUND: Predicting local lung tissue pharmacodynamic (PD) responses of inhaled drugs is a longstanding challenge related to the lack of experimental techniques to determine local free drug concentrations. This has prompted the use of physiologically based pharmacokinetic (PBPK) modeling to potentially predict local concentration and response. A unique opportunity for PBPK model evaluation is provided by the clinical PD data for salbutamol, which in its inhaled dosage form (400 μg), produces a higher bronchodilatory effect than in its oral dosage form (2 mg) despite lower drug concentrations in blood...
June 7, 2018: Journal of Aerosol Medicine and Pulmonary Drug Delivery
Meric Ovacik, Kedan Lin
The tutorial introduces the readers to the fundamentals of antibody pharmacokinetics (PK) in the context of drug development. Topics covered include an overview of antibody development, PK characteristics and the application of antibody PK/Pharmacodynamics (PD) in research and development decision-making. We also discuss the general considerations for planning a nonclinical PK program and describe the types of PK studies that should be performed during early development of monoclonal antibodies (mAbs). This article is protected by copyright...
June 7, 2018: Clinical and Translational Science
Toshinori Hirai, Toshimasa Itoh, Toshimi Kimura, Hirotoshi Echizen
AIM: Febuxostat is an active xanthine oxidase (XO) inhibitor that is widely used in the hyperuricemia treatment. We aimed to evaluate the predictive performance of a pharmacokinetic-pharmacodynamic (PK-PD) model for hypouricemic effects of febuxostat. METHODS: Previously, we have formulated a PK--PD model for predicting hypouricemic effects of febuxostat as a function of baseline serum urate levels, body weight, renal function, and drug dose using datasets reported in preapproval studies (Hirai T et al...
June 6, 2018: British Journal of Clinical Pharmacology
Sarandeep S S Boyanapalli, Ying Huang, Zhengyuan Su, David Cheng, Chengyue Zhang, Yue Guo, Rohit Rao, Ioannis P Androulakis, Ah-Ng Kong
Chronic inflammation is a key driver of cancer development. Nitrite levels, which are regulated by inducible nitric oxide synthase (iNOS), play a critical role in inflammation. While the anti-oxidant and anti-inflammatory effects of curcumin, a natural product present in the roots of Curcuma longa have been widely studied, the acute pharmacokinetics (PK) and pharmacodynamics (PD) of curcumin in suppressing pro-inflammatory markers and epigenetic modulators remain unclear. In this study, we evaluated the PK and PD of curcumin-induced suppression of lipopolysaccharide (LPS)-mediated inflammation in rat lymphocytes...
June 5, 2018: Biopharmaceutics & Drug Disposition
Wei Lv, Jianpei Xu, Xiaoqi Wang, Xinrui Li, Qunwei Xu, Hongliang Xin
Ischemic stroke is a leading cause of long-term disability and death worldwide. Current drug delivery vehicles for the treatment of ischemic stroke are less than satisfactory, in large part due to their short circulation lives, lack of specific targeting to the ischemic site, and poor controllability of drug release. In light of the upregulation of reactive oxygen species (ROS) in the ischemic neuron, we herein developed a bioengineered ROS-responsive nanocarrier for stroke-specific delivery of a neuroprotective agent, NR2B9C, against ischemic brain damage...
June 5, 2018: ACS Nano
Dongping Zeng, Meizhen Sun, Zhoumeng Lin, Miao Li, Ronette Gehring, Zhenling Zeng
Tildipirosin, a 16-membered-ring macrolide antimicrobial, has recently been approved for the treatment of swine respiratory disease and bovine respiratory disease. This macrolide is extensively distributed to the site of respiratory infection followed by slow elimination. Clinical efficacy has been demonstrated in cattle and swine clinical field trials. However, the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with the efficacy of tildipirosin remains undefined. The objective of this study was to develop a PK/PD model following subcutaneous injection of tildipirosin against Pasteurella multocida in a murine lung infection model...
2018: Frontiers in Microbiology
Paul A Moore, Kalpana Shah, Yinhua Yang, Ralph Alderson, Penny Roberts, Vatana Long, Daorong Liu, Jonathan C Li, Steve Burke, Valentina Ciccarone, Hua Li, Claudia B Fieger, Jeff Hooley, Ann Easton, Monica Licea, Sergey Gorlatov, Kathleen L King, Peter Young, Arash Adami, Deryk Loo, Gurunadh R Chichili, Liqin Liu, Douglas H Smith, Jennifer G Brown, Francine Z Chen, Scott Koenig, Jennie Mather, Ezio Bonvini, Syd Johnson
We have developed MGD007 (anti-glycoprotein A33 x anti-CD3), a DART® protein designed to redirect T-cells to target gpA33 expressing colon cancer. The gpA33 target was selected based on an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic CRC specimens, including putative cancer stem cell populations. MGD007 displays the anticipated bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T-cells...
June 4, 2018: Molecular Cancer Therapeutics
E S Buys, D P Zimmer, J Chickering, R Graul, Y T Chien, A Profy, J R Hadcock, J L Masferrer, G T Milne
Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC), an enzyme that catalyzes the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine-3',5'-monophophate (cGMP), transduces many of the physiological effects of the gasotransmitter NO. Upon binding of NO to the prosthetic heme group of sGC, a conformational change occurs, resulting in enzymatic activation and increased production of cGMP. cGMP modulates several downstream cellular and physiological responses, including but not limited to vasodilation...
May 31, 2018: Nitric Oxide: Biology and Chemistry
Renli Teng, Sharen Muldowney, Yonggang Zhao, Jolene Kay Berg, Jonathan Lu, Naeem D Khan
PURPOSE: This single-dose, randomized, open-label, parallel-group, and crossover study assessed pharmacokinetics (PK), pharmacodynamics (PD), and safety of ticagrelor in subjects on hemodialysis versus healthy subjects. METHODS: Hemodialysis subjects were randomized, receiving a single ticagrelor 90-mg dose 1 day post-hemodialysis or just before hemodialysis, with an intervening washout of ≥ 7 days. Healthy subjects (creatinine clearance ≥ 90 mL/min) received a single ticagrelor 90-mg dose...
May 30, 2018: European Journal of Clinical Pharmacology
Zhen-Ping Chen, Pei-Jing Li, Gang Li, Ling Tang, Ying-Zi Zhen, Xin-Yi Wu, Xiao-Ling Cheng, Koon Hung Luke, Victor S Blanchette, Man-Chiu Poon, Qiu-Lan Ding, Run-Hui Wu
Background: Although much attention has been paid to the pharmacokinetics (PKs) of different factor VIII (FVIII) concentrates in persons with hemophilia A (HA), limited information is available in young boys with severe HA. In this study, we aimed to assess the PK parameters of FVIII products in boys with severe HA in China. Methods: A total of 36 boys (plasma-derived [pd]-FVIII, n = 15; recombinant [r] FVIII, n = 21) were enrolled between January 2015 and May 2016 in Beijing Children's Hospital...
May 30, 2018: Chinese Medical Journal
Raghunandan Reddy Kura, Eswar Kumar Kilari, Mastan Shaik
Background: Concomitant drug administration is a general phenomenon in patients with chronic diseases such as diabetes mellitus. Among the currently available oral antidiabetic drugs, gliclazide is a commonly prescribed drug considering its multiple benefits in diabetic patients. Aprepitant is a commonly prescribed antiemetic drug which is mainly metabolized by CYP3A4, reported to have modest inductive and inhibitory effects on CYP2C9 and CYP3A4, respectively. Since gliclazide is metabolized by CYP2C9 (major) and CYP3A4 (minor), it is very difficult to predict the influence of aprepitant and its metabolic interaction with gliclazide...
2018: PeerJ
John K Diep, Jenna Covelli, Rajnikant Sharma, Donna M Ruszaj, Keith S Kaye, Jian Li, Robert M Straubinger, Gauri G Rao
A number of companies manufacture polymyxin B using United States Pharmacopeia (USP) metrics, rather than chemical composition, to report biological activity. Given that polymyxin B contains several different components, it is unknown whether pharmacokinetic (PK) and pharmacodynamic (PD) variability exist between the different brands and whether USP metrics capture this variability. Here we investigated the composition of polymyxin B obtained from four manufacturers (Sigma-Aldrich, AK Scientific, USP, and MP Biomedicals) and evaluated their rate and extent of killing against multidrug resistant Acinetobacter baumannii and Klebsiella pneumoniae using in vitro static time-kill experiments...
May 25, 2018: International Journal of Antimicrobial Agents
Axel Facius, Eleonora Marostica, Philip Gardiner, Henrik Watz, Gezim Lahu
BACKGROUND: In the OPTIMIZE study, 4 weeks of roflumilast 250 µg once daily before escalation to the approved 500 µg once daily maintenance dose reduced treatment discontinuations and improved tolerability to roflumilast among patients with chronic obstructive pulmonary disease (COPD). In this study, we present the pharmacokinetic (PK) results and PK/pharmacodynamic (PD) modelling data from OPTIMIZE. METHODS: OPTIMIZE was a multicentre, double-blind, phase III study in which patients with severe COPD were randomized 1:1:1 to receive oral roflumilast 250 μg once daily, 500 μg every other day, or 500 μg once daily for 4 weeks, followed by 500 μg once daily for 8 weeks...
May 25, 2018: Clinical Pharmacokinetics
Tomoya Yokota, Johanna Bendell, Patricia LoRusso, Takahiro Tsushima, Ved Desai, Hirotsugu Kenmotsu, Junichiro Watanabe, Akira Ono, Bhavani Murugesan, Joseph Silva, Tateaki Naito, Jonathan Greenberg, Prasanna Kumar, Yibin Wang, Takahiro Jikoh, Ryota Shiga, David M Hyman, Alan Loh Ho, David R Spriggs, Gary K Schwartz, Mrinal M Gounder
BACKGROUND: We examined the impact of race on the maximum tolerated doses (MTD) and final approved doses (FAD) of single-agent molecular-targeted agents (MTA) in North America/Europe (NA/EU) and Asia. METHODS: We searched PubMed and regulatory databases to identify targeted drugs approved globally and compared their FAD and MTD in corresponding phase I/II studies conducted separately in NA/EU and Asia. To evaluate this further, we conducted parallel, prospective, first-in-human studies of DS-7423, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumours in the US and Japan...
May 24, 2018: British Journal of Cancer
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