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Ruth Rosales, Loreto Rojas, Francisco Zamora, Giannina Izquierdo, Claudia Benavides, Claudio González
Polymyxins have been available since the 1960s, however, because of their adverse effects, their use has been reserved for the treatment of infections caused by multiresistant bacteria. The increase in the clinical experience acquired in recent years and the published medical literature have raised doubts about the information provided by the product, indicating the need to update dosage recommendations, pharmacokinetics and pharmacokinetic/pharmacodynamic information (PK/PD). In addition, differences in concentration and dose between the different products of colistin may lead to errors of indication/administration and pose a risk to patients...
April 2018: Revista Chilena de Infectología: órgano Oficial de la Sociedad Chilena de Infectología
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
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
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
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
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
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
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
Jason Child, Xinhui Chen, Rakesh D Mistry, Stig Somme, Christine MacBrayne, Peter L Anderson, Ronald N Jones, Sarah K Parker
Background: Metronidazole is traditionally dosed every 6-8 hours even though in adults it has a long half-life, concentration-dependent killing, and 3-hour postantibiotic effect. Based on this logic, some pediatric hospitals adopted once-daily dosing for appendicitis, despite limited pharmacokinetics-pharmacodynamics (PK/PD) in children. We studied pediatric patients with appendicitis given metronidazole once daily to determine whether this dosing would meet target area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio of ≥70 for Bacteroides fragilis...
May 16, 2018: Journal of the Pediatric Infectious Diseases Society
María-Gabriela Pérez-Guillé, Alejandra Toledo-López, Liliana Rivera-Espinosa, Radames Alemon-Medina, Chiharu Murata, Ismael Lares-Asseff, Juan Luis Chávez-Pacheco, Josefina Gómez-Garduño, Ana-Lilia Zamora Gutiérrez, Claudia Orozco-Galicia, Karina Ramírez-Morales, Gustavo Lugo-Goytia
BACKGROUND: Dexmedetomidine (DEX) is an α-2 adrenergic agonist with sedative and analgesic properties. Although not approved for pediatric use by the Food and Drug Administration, DEX is increasingly used in pediatric anesthesia and critical care. However, very limited information is available regarding the pharmacokinetics of DEX in children. The aim of this study was to investigate DEX pharmacokinetics and pharmacodynamics (PK-PD) in Mexican children 2-18 years of age who were undergoing outpatient surgical procedures...
May 17, 2018: Anesthesia and Analgesia
Longfei Zhang, Xun Wu, Zilong Huang, Nan Zhang, Yuzhi Wu, Qinren Cai, Xiangguang Shen, Huanzhong Ding
To evaluate the relationship between the pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect of cefquinome against Actinobacillus pleuropneumoniae, a tissue cage infection model was established in piglets. In this model, an initial count of A. pleuropneumoniae of approximately 106 CFU/mL was exposed to different concentrations of cefquinome after multiple administration at dosages of 0.2, 0.4, 0.8, 1, 2, 4 mg/kg body weight once a day for 3 days. Concentration of cefquinome and bacterial numbers of A...
June 2018: Veterinary Microbiology
Robert C Owens, Catharine C Bulik, David R Andes
The first guidelines for conducting antimicrobial stewardship in the hospitalized setting were published in 2007. These guidelines recommend that stewardship programs employ the science of pharmacokinetics-pharmacodynamics (PK-PD) as well as adopting computerized decision support technologies when possible. The United States Food and Drug Administration have adopted PK-PD as a cornerstone in the evaluation of antimicrobial agents during clinical development. The core principles of PK-PD center around describing the relationship between drug exposure indexed to the susceptibility of the infecting bacterial pathogen and patient response...
April 13, 2018: Diagnostic Microbiology and Infectious Disease
Cheryl Li, Satoshi Shoji, Jean Beebe
AIMS: The purpose of this study was to characterize pharmacokinetics (PK) of PF-04236921, a novel anti-IL-6 monoclonal antibody, and its pharmacokinetics/pharmacodynamics (PK/PD) relationship on serum C-Reactive Protein (CRP) in healthy volunteers and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Crohn's disease (CD) METHODS: Population modelling analyses were conducted using nonlinear mixed effects modelling. Data from 2 phase 1 healthy volunteer studies, a phase 1 RA study, a Phase 2 CD study, and a Phase 2 SLE study were included...
May 18, 2018: British Journal of Clinical Pharmacology
Vahid Farrokhi, Jeffrey R Chabot, Hendrik Neubert, Zhiyong Yang
Osteopontin is a secreted glycophosphoprotein that is highly implicated in many physiological and pathological processes such as biomineralization, cell-mediated immunity, inflammation, fibrosis, cell survival, tumorigenesis and metastasis. Antibodies against osteopontin have been actively pursued as potential therapeutics for various diseases by pharmaceutical companies and academic laboratories. Many studies have demonstrated the efficacy of osteopontin inhibition in a variety of preclinical models of diseases such as rheumatoid arthritis, cancer, nonalcoholic steatohepatitis, but clinical utility has not yet been demonstrated...
May 17, 2018: Scientific Reports
Yuan-Heng Ma, Si-Yuan Wang, Yu-Peng Ren, Jian Li, Ting-Jie Guo, Wei Lu, Tian-Yan Zhou
Rising evidence has shown the development of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors in the practices of cancer therapy. It is reported that the efficacy of axitinib (AX), a VEGFR inhibitor, is limited in the treatment of breast cancer as a single agent or in combination with other chemotherapeutic drugs due to the probability of rising population of cancer stem-like cells (CSCs) caused by AX. The present study evaluated the effect of dopamine (DA) improving AX's efficacy on MCF-7/ADR breast cancer in vitro and in vivo, and developed a pharmacokinetic-pharmacodynamic (PK-PD) model describing the in vivo experimental data and characterizing the interaction of effect between AX and DA...
May 17, 2018: Acta Pharmacologica Sinica
Youssef Hijazi, Matthias Klinger, Andrea Kratzer, Benjamin Wu, Patrick A Baeuerle, Peter Kufer, Andreas Wolf, Dirk Nagorsen, Min Zhu
OBJECTIVE: We describe the relationship between pharmacokinetics (PK) of blinatumomab and pharmacodynamic (PD) changes in peripheral lymphocytes, serum cytokines, and tumor size in patients with non-Hodgkin lymphoma (NHL). METHODS: In a phase 1 study, 76 patients with relapsed/refractory NHL received blinatumomab by continuous intravenous infusion at various doses (0.5 to 90 µg/m2/day). PD changes were analyzed with respect to dose, blinatumomab concentration at steady state (Css), and cumulative area under the concentration-versus-time curve (AUCcum)...
May 17, 2018: Current Clinical Pharmacology
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