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Clinical Pharmacology and Therapeutics

Ru Chen, Sarmistha Sanyal, Aliza Thompson, Joachim H Ix, Kylie Haskins, Laurie Muldowney, Shashi Amur
The Biomarker Qualification Program was established at the Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA) to expedite the integration of promising biomarkers across multiple drug development programs. The first set of biomarkers qualified in 2008 consisted of seven nonclinical safety biomarkers for the detection of acute drug-induced nephrotoxicity in rats, and included urinary kidney injury molecule-1 (KIM-1). This article discusses the use of KIM-1 in drug development and research before and after CDER's qualification of KIM-1...
May 15, 2018: Clinical Pharmacology and Therapeutics
Maciej J Zamek-Gliszczynski, Xiaoyan Chu, Jack A Cook, Joseph M Custodio, Aleksandra Galetin, Kathleen M Giacomini, Caroline A Lee, Mary F Paine, Adrian S Ray, Joseph A Ware, Matthias B Wittwer, Lei Zhang
Metformin drug-drug interaction (DDI) studies are conducted during development of drugs that inhibit organic cation transporters and/or multidrug and toxin extrusion proteins (OCTs/MATEs). Monitoring solely changes in systemic exposure, the typical DDI study endpoint appears inadequate for metformin, which is metabolically stable, has poor passive membrane permeability, and undergoes transporter-mediated tissue distribution and clearance. Evaluation of renal clearance, antihyperglycemic effects, and potentially lactate as an exploratory safety marker, can support rational metformin dose adjustment...
May 15, 2018: Clinical Pharmacology and Therapeutics
David Rhainds, Mathieu R Brodeur, Jean-Claude Tardif
Cardiovascular diseases (CVD) are the first cause of death in the world. CVD risk is influenced by multiple factors, some non-modifiable such as age, sex and genetic background, and others modifiable. Great progress has been made over the last decades in the identification of biomarkers of incident or recurrent CV risk and surrogate endpoints of CV outcomes. We present the current state of knowledge for CV biomarkers in plasma including lipids, apolipoproteins, inflammation-related, and emerging omics-based biomarkers...
May 15, 2018: Clinical Pharmacology and Therapeutics
Evan D Kharasch, Amanda Crafford
Bupropion hydroxylation is a bioactivation and metabolic pathway, and the standard clinical CYP2B6 probe. This investigation determined the influence of CYP2B6 allelic variants on clinical concentrations and metabolism of bupropion enantiomers. Secondary objectives evaluated the influence of CYP2C19 and P450 oxidoreductase variants. Healthy volunteers in specific cohorts (CYP2B6*1/*1, CYP2B6*1/*6, CYP2B6*6/*6, and also CYP2B6*4 carriers) received single-dose oral bupropion. Plasma and urine bupropion and hydroxybupropion was quantified...
May 14, 2018: Clinical Pharmacology and Therapeutics
Raymond Evers, Micheline Piquette-Miller, Joseph W Polli, Frans G M Russel, Jason A Sprowl, Kimio Tohyama, Joseph A Ware, Saskia N de Wildt, Wen Xie, Kim L R Brouwer
No abstract text is available yet for this article.
May 14, 2018: Clinical Pharmacology and Therapeutics
Cynthia V Rider, Nigel J Walker, Suramya Waidyanatha
The National Toxicology Program's (NTP) mission is "to evaluate agents of public health concern, by developing and applying the tools of modern toxicology and molecular biology." Botanical dietary supplements (BDS) represent agents of public health concern due to widespread exposure to high doses, a lack of safety data for most products, variable quality, and reports of adverse events. This commentary will address lessons learned in NTP testing activities with BDS and recommendations for moving forward...
May 10, 2018: Clinical Pharmacology and Therapeutics
Johann Bartko, Christian Schoergenhofer, Michael Schwameis, Christa Firbas, Martin Beliveau, Colin Chang, Jean-Francois Marier, Darrell Nix, James C Gilbert, Sandip Panicker, Bernd Jilma
Aberrant activation of the classical complement pathway is the common underlying pathophysiology of orphan diseases such as bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease and warm autoimmune haemolytic anaemia. Therapeutic options for these complement-mediated disorders are limited and BIVV009, a humanized monoclonal antibody directed against complement factor C1s, may be potentially useful for inhibition of the classical complement pathway. A phase-1, first-in-human, double-blind, randomized, placebo-controlled, dose-escalation trial of single and multiple doses of BIVV009 or placebo was conducted in 64 volunteers to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic profiles...
May 8, 2018: Clinical Pharmacology and Therapeutics
Deepak Kumar Bhatt, Aanchal Mehrotra, Andrea Gaedigk, Revathi Chapa, Abdul Basit, Haeyoung Zhang, Prachi Choudhari, Mikael Boberg, Robin E Pearce, Roger Gaedigk, Ulrich Broeckel, J Steven Leeder, Bhagwat Prasad
The ontogeny of hepatic uridine diphosphate-glucuronosyltransferases (UGTs) was investigated by LC-MS/MS proteomics to determine UGT protein abundance in human liver microsomes isolated from 136 pediatric (0-18 years) and 35 adult (age 18-67 years) donors. Microsomal protein abundances of UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 increased by ∼8, 55, 35, 33, 8 and 3-fold from neonates to adults, respectively. The estimated age at which 50% of the adult protein abundance is observed for UGT isoforms was between 2...
May 8, 2018: Clinical Pharmacology and Therapeutics
Benoit J Arsenault, Nicolas Perrot, Rishi Puri
Targeting atherogenic lipoprotein levels with statins remains the current cornerstone of atherosclerotic cardiovascular disease (ACVD) management. In patients at high ACVD risk who cannot achieve the desired low-density lipoprotein (LDL) cholesterol target, the addition of compounds such as ezetimibe and proprotein subtilisin/kexin type-9 (PCSK9) inhibitors incrementally lowers cardiovascular risk. New glucose-lowering drugs such as glucacon-like peptide-1 receptor (GLP1R) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors were also shown to improve cardiometabolic risk factors and provide cardiovascular benefits in patients with type 2 diabetes...
May 8, 2018: Clinical Pharmacology and Therapeutics
Hongbo Yuan, M Sanni Ali, Emily S Brouwer, Cynthia J Girman, Jeff J Guo, Jennifer L Lund, Elisabetta Patorno, Jonathan L Slaughter, Xuerong Wen, Dimitri Bennett
On December 8, 2016, the New England Journal of Medicine published a sounding board on Real World Evidence (RWE)1 by the US Food and Drug Administration (FDA) leadership. While the value of RWE based on nonrandomized observational studies was appreciated, such as for hypothesis generating, safety, and measuring quality in healthcare delivery, the authors expressed concerns on the quality of data sources and the ability of methodologies to control for confounding. In response, we offer a few considerations regarding these concerns...
May 7, 2018: Clinical Pharmacology and Therapeutics
Kelvin Kf Tsoi, Joyce Yc Chan, Felix Ch Chan, Hoyee W Hirai, Timothy Cy Kwok, Samuel Ys Wong
Memantine and the Acetylcholinesterase inhibitors (AChEIs) are two classes of drugs that are used to treat patients with Alzheimer's disease. We conducted a network meta-analysis of randomized controlled trials to compare the treatment effectiveness of monotherapy or combination therapy A total of 23,707 AD patients in 76 randomized trials were identified. In patients with mild-to-moderate AD, monotherapy with donepezil, galantamine or rivastigmine were superior to placebo in enhancing cognitive functions and activities of daily living (ADL), whereas monotherapy with donepezil or memantine were superior to placebo in improving behavioral symptoms...
May 1, 2018: Clinical Pharmacology and Therapeutics
Hatice Ceylan Koydemir, Aydogan Ozcan
From microscopy to diagnostics and monitoring of vital parameters, scientists, engineers, and educators have been making use of smartphones and smartphone components in various innovative ways, helping to democratize advanced measurement instruments used in research and education.
May 1, 2018: Clinical Pharmacology and Therapeutics
Venkatesh Pilla Reddy, Khanh Bui, Graeme Scarfe, Diansong Zhou, Maria Learoyd
We report physiologically based pharmacokinetic-modeling analyses to determine olaparib (tablet or capsule) drug-drug interactions (DDIs). Verified DDI simulations provided dose recommendations for olaparib co-administration with clinically relevant CYP3A4 modulators to eliminate potential risk to patient safety or olaparib efficacy. When olaparib is given with strong/moderate CYP3A inhibitors, the dose should be reduced to 100/150 mg bid (tablet), and 150/200 mg bid (capsule). Olaparib administration is not recommended with strong/moderate CYP3A inducers...
May 1, 2018: Clinical Pharmacology and Therapeutics
Sebastian G Wicha, Oskar Clewe, Robin J Svensson, Stephen H Gillespie, Yanmin Hu, Anthony R M Coates, Ulrika S H Simonsson
A crucial step for accelerating tuberculosis drug development is bridging the gap between pre-clinical and clinical trials. In this study, we developed a pre-clinical model-informed translational approach to predict drug effects across pre-clinical systems and early clinical trials using the in vitro-based Multistate Tuberculosis Pharmacometric (MTP) model using rifampicin as an example. The MTP model predicted rifampicin biomarker response observed in (i) a hollow-fiber infection model, (ii) a murine study to determine PK/PD indices, and (iii) several clinical phase IIa early bactericidal activity (EBA) studies...
April 26, 2018: Clinical Pharmacology and Therapeutics
Matti K Itkonen, Aleksi Tornio, Outi Lapatto-Reiniluoto, Mikko Neuvonen, Pertti J Neuvonen, Mikko Niemi, Janne T Backman
Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, cross-over study in twelve healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC0-∞ of dasabuvir 4...
April 26, 2018: Clinical Pharmacology and Therapeutics
Prajakti A Kothare, Pravin Jadhav, Pankaj Gupta, Jane Croft Harrelson, Leslie Dickmann
No abstract text is available yet for this article.
April 26, 2018: Clinical Pharmacology and Therapeutics
Sook Wah Yee, Deanna J Brackman, Elizabeth A Ennis, Yuichi Sugiyama, Landry K Kamdem, Rebecca Blanchard, Aleksandra Galetin, Lei Zhang, Kathleen M Giacomini
Advances in genomic technologies have led to a wealth of information identifying genetic polymorphisms in membrane transporters, specifically how these polymorphisms affect drug disposition and response. This review describes the current perspective of the International Transporter Consortium (ITC) on clinically important polymorphisms in membrane transporters. ITC suggests that in addition to previously recommended polymorphisms in ABCG2 (BCRP) and SLCO1B1 (OATP1B1), polymorphisms in the emerging transporter, SLC22A1 (OCT1), be considered during drug development...
April 21, 2018: Clinical Pharmacology and Therapeutics
Sheng-Nan Zhou, Jun-Xiu Lu, Xue-Qing Wang, Mei-Rong Shan, Zhang Miao, Guo-Pin Pan, Xu Jian, Peng Li, Song Ping, Xin-Yan Pang, Yong-Ping Bai, Chao Liu, Shuang-Xi Wang
Development of nitrate tolerance is a major drawback to nitrate therapy. Prostacyclin (PGI2) is a powerful vasodilator produced from prostaglandin (PGH2) by prostacyclin synthase (PGIS) in endothelial cells. This study was to determine the role of PGIS S-nitrosylation in nitrate tolerance induced by nitroglycerin (GTN). In endothelial cells, GTN increased PGIS S-nitrosylation and disturbed PGH2 metabolism, which were normalized by mutants of PGIS cysteine 231/441 to alanine (C231/441A). Clearance of NO by carboxy-PTIO or inhibition of S-nitrosylation by N-acetyl-cysteine decreased GTN-induced PGIS S-nitrosylation...
April 19, 2018: Clinical Pharmacology and Therapeutics
Maria O Kovalchuk, Jules Aac Heuberger, Boudewijn Thm Sleutjes, Dimitrios Ziagkos, Leonard H van de Berg, Toby A Ferguson, Hessel Franssen, Geert Jan Groeneveld
Increased excitability of motor neurons in patients with amyotrophic lateral sclerosis may be a relevant factor leading to motor neuron damage. This randomized, double-blind, 3-way cross-over, placebo-controlled study evaluated peripheral motor nerve excitability-testing as biomarker of hyperexcitability and assessed effects of riluzole and retigabine in 18 patients with amyotrophic lateral sclerosis. We performed excitability-testing at baseline, and twice after participants had received a single dose of either 100mg riluzole, 300mg retigabine or placebo...
April 19, 2018: Clinical Pharmacology and Therapeutics
Mathijs C Bodde, Paul Welsh, Sandrin C Bergheanu, Willem M Lijfering, Bart Mertens, An-Ho Liem, Arnoud van der Laarse, Naveed Sattar, J Wouter Jukema
Serum troponin within the normal range is an emerging predictor of cardiovascular mortality. We aimed to determine how rapidly high-sensitivity troponin -I (hs-cTnI) levels are lowered by statin therapy in patients with stable cardiovascular disease. In the RADAR substudy, patients were randomized, to atorvastatin 20 mg/day (n = 39) or rosuvastatin 10 mg/day (n = 39) and up-titrated in 6 week intervals to 80 mg of atorvastatin or 40 mg of rosuvastatin. Hs-cTnI concentrations were measured at baseline and at 6 and 18 weeks of follow-up...
April 19, 2018: Clinical Pharmacology and Therapeutics
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