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Clinical Pharmacology and Therapeutics

Cory V Gerlach, Mazin Derzi, Shashi K Ramaiah, Vishal S Vaidya
Pharmaceutical and biotechnology companies routinely use biomarkers to obtain quantitative metrics for drug exposure, efficacy, and safety and to inform clinical trial design with regard to patient selection, treatments, and outcomes. Biomarker science has the unique capability to catalyze precompetitive collaborations between academia, industry, regulatory agencies, and other stakeholders with the ultimate goal of accelerating the delivery of safe and effective medicines to patients, particularly in areas of high unmet need...
November 16, 2017: Clinical Pharmacology and Therapeutics
Hanna Kim, Kristina M Brooks, Cheng Cai Tang, Paul Wakim, Mary Blake, Stephen R Brooks, Gina A Montealegre Sanchez, Adriana A de Jesus, Yan Huang, Wanxia Li Tsai, Massimo Gadina, Apurva Prakash, Jonathan Marcus Janes, Xin Zhang, William L Macias, Parag Kumar, Raphaela Goldbach-Mansky
Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance respectively. The half-life of baricitinib in patients less than 40kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily...
November 14, 2017: Clinical Pharmacology and Therapeutics
Maulik Patel, Shumei M Kato, Razelle Kurzrock
Technological advances in high-throughput next-generation sequencing (NGS) along with advances in computational processes have brought about the dawn of the genomic medicine era. NGS has enabled molecular characterization of malignancies, and facilitated the development and approval of gene- and immune-targeted therapies, both of which impact the mutanome. Clinical implementation of this technology, approval of novel targeted agents, and establishment of molecular tumor boards has enabled precision oncology to become a reality...
November 14, 2017: Clinical Pharmacology and Therapeutics
Howard J Fingert
Numerous barriers have been identified which detract from successful applications of clinical trial data and platforms. Despite the challenges, opportunities are growing to advance compliance, quality, and practical applications through top-down establishment of guiding principles, coupled with bottom-up approaches to promote data science competencies among data producers. Recent examples of successful applications include modern treatments for hematologic malignancies, developed with support from public-private partnerships, guiding principles for data-sharing, standards for protocol designs and data management, digital technologies, and quality analytics...
November 14, 2017: Clinical Pharmacology and Therapeutics
Tanay S Samant, Shyeilla Dhuria, Yasong Lu, Marc Laisney, Shu Yang, Arnaud Grandeury, Martin Mueller-Zsigmondy, Kenichi Umehara, Felix Huth, Michelle Miller, Caroline Germa, Mohamed Elmeliegy
Ribociclib (KISQALI®), a cyclin-dependent kinase 4/6 inhibitor approved for the first-line treatment of HR+/HER2- advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH-elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using (1) biorelevant media solubility, (2) physiologically based pharmacokinetic (PBPK) modeling, (3) non-compartmental analysis (NCA) of clinical trial data, and (4) population PK (PopPK) analysis...
November 14, 2017: Clinical Pharmacology and Therapeutics
Malcolm Rowland, K Sandy Pang
Among pharmacokinetic concepts, clearance has been the most widely applied in clinical pharmacology and drug development. With so much written on the subject it might be thought that there is nothing more to say. So it is noteworthy that some basic aspects related to hepatic clearance, and specifically the most popular model, the well-stirred model, have been challenged by Benet et al. This commentary examines the challenge and provides our views.
November 14, 2017: Clinical Pharmacology and Therapeutics
Sam Jackson, Albert F Candia, Stephen Delaney, Simone Floettmann, Clifford Wong, John D Campbell, Sariah Kell, Jeremy Lum, Edith Hessel, Paula Traquina, Mark McHale, Ian Robinson, John Bell, Rainard Fuhr, David Keeling, Robert L Coffman
Current asthma treatments address symptoms rather than the underlying disease pathophysiology, a better understanding of which has led to the identification of the Th2 high endotype. The activation of Toll-like receptors to induce Type I interferons directly in the lungs represents a novel therapeutic approach to reset this underlying Th2 pathophysiology with the potential to provide long-term disease modification. We present the nonclinical data and phase 1 clinical profile of an inhaled TLR9 agonist, AZD1419, a C-type CpG designed to induce interferon in the lung...
November 14, 2017: Clinical Pharmacology and Therapeutics
Bruce A Chabner
The rapid evolution of our understanding of cancer biology has affected every phase of patient management, from early detection to drug development and clinical management. Central to this issue is the challenge of using biomarkers to identify the driving mutations present and identifiable by current assays in many tumors. These biomarkers are integral to the process of selecting patients for the testing of new drugs, many of which are specifically designed to inhibit oncogenic pathways.
November 14, 2017: Clinical Pharmacology and Therapeutics
Andrea Gaedigk, Magnus Ingelman-Sundberg, Neil A Miller, J Steven Leeder, Michelle Whirl-Carrillo, Teri E Klein
The Human Cytochrome P450 (CYP) Allele Nomenclature Database, a critical resource for the pharmacogenetics and genomics communities, has transitioned to the Pharmacogene Variation (PharmVar) Consortium. In this report we provide a summary of the current database, provide an overview of the PharmVar consortium, and highlight the PharmVar database which will serve as the new home for pharmacogene nomenclature.
November 14, 2017: Clinical Pharmacology and Therapeutics
Russ B Altman
Our ability to collect data at every stage of the translational pipeline creates great opportunities for formulating hypotheses both "upstream" (towards clinical implementation) and "downstream" (back to basic discovery). Translational researchers therefore must integrate information at multiple scales to both generate and test hypotheses-to some extent they must all be comfortable with the basics of "big data" analyses. This increased focus on data-driven science requires an understanding of basic experimental and clinical data collection-understanding that likely cannot efficiently be gathered through traditional apprenticeship models...
November 14, 2017: Clinical Pharmacology and Therapeutics
M Brockway, A A Fossa, J W Mason
FDA investigators recently demonstrated in a crossover study that early (J-Tpeak c) and late (Tpeak -Tend ) repolarization duration can differentiate selective potassium block with a high arrhythmia risk from multichannel block with lower risk in subjects receiving dofetilide, verapamil, quinidine or ranolazine. The purpose of this study was to determine if findings by FDA using their published software algorithm could be corroborated using an alternative software algorithm for the same metrics and to determine if methodological differences resulted in clinically meaningful differences in interpretation...
November 11, 2017: Clinical Pharmacology and Therapeutics
Julie T Watters, Jason H Pitzen, Linda J Sanders, Virginia Nickie M Bruce, Alissa R Cornell, Gary C Cseko, Janice S Grace, Pamela S Kwon, Andrea K Kukla, Michael S Lee, Michelle D Monosmith, John D Myren, Rebecca S Kottschade, Marc N Shaft, Jennifer Jenny A Weis, Jane C Welter, Adil E Bharucha
The Institute of Medicine and US Food and Drug Administration (FDA) recognize that activating clinical trials in the United States is lengthy and inefficient. Downstream consequences include increased expense, suboptimal accrual, move of clinical trials overseas, and delayed availability of treatments for patients. An in-tandem processing initiative is here highlighted that transformed the activation of clinical trials (TACT), reduced the activation time by 70%, and offers a paradigm for enhanced translational readiness...
November 6, 2017: Clinical Pharmacology and Therapeutics
Walter K Kraft
No abstract text is available yet for this article.
November 6, 2017: Clinical Pharmacology and Therapeutics
Milos Brankovic, K Martijn Akkerhuis, Nick van Boven, Olivier Manintveld, Tjeerd Germans, Jasper Brugts, Kadir Caliskan, Victor Umans, Alina Constantinescu, Isabella Kardys
We determined the temporal effects of neurohormonal antagonists and loop diuretics on serially assessed (3-monthly) cardio-renal biomarkers, functional status, and clinical outcomes in 250 patients with chronic heart failure (CHF) with reduced ejection fraction. In blood, we measured NT-proBNP, troponin T, C-reactive protein, creatinine, cystatin C; in urine, N-acetyl-beta-d-glucosaminidase and kidney-injury-molecule-1. ACE-inhibitors/ARB were inversely associated with cardiac impairment, inflammation and renal tubular damage, but not with glomerular dysfunction...
November 6, 2017: Clinical Pharmacology and Therapeutics
John P Gibbs, Rajeev Menon, Sreeneeranj Kasichayanula
With so much emphasis on reducing attrition and becoming more efficient in the delivery of healthcare, there are many opportunities to leverage existing clinical data in drug development and to foster the practice of reverse translation. The application of quantitative approaches to convert clinical trial and real-world data to knowledge will continue to drive innovation. Herein we discuss recent examples of reverse translation and consider future opportunities to capture critical clinical knowledge to inform decision-making in drug development...
November 6, 2017: Clinical Pharmacology and Therapeutics
Stefano Ponzano, Kevin Blake, Milton Bonelli, Harald Enzmann
The European Medicines Agency (EMA) revises its guideline on minimizing risk in first-in-human trials to reflect changing practice and in light of a recent tragic incident.
November 6, 2017: Clinical Pharmacology and Therapeutics
Rajesh Krishna
Pharmaceutical development is witnessing an increase in the use of digital technologies in the delivery of pharmaceutical substances, data generation, and data interpretation. These digital technologies offer the valuable benefits of speed, enhanced integration with various other components, visualization of a continuum, and improving precision of delivery or measurement. The adoption of these opportunities in early clinical development has been slow and sparse. This commentary analyzes these benefits, including the socialization and adoption of such practices...
November 6, 2017: Clinical Pharmacology and Therapeutics
Teri A Manolio, Carolyn M Hutter, Mark Avigan, Ricardo Cibotti, Robert L Davis, Joshua C Denny, Lois La Grenade, Lisa M Wheatley, Mary N Carrington, Wasun Chantratita, Wen-Hung Chung, Andrea D Dalton, Shuen-Iu Hung, Ming Ta Michael Lee, J Steven Leeder, Juan J L Lertora, Surakameth Mahasirimongkol, Howard L McLeod, Maja Mockenhaupt, Michael Pacanowski, Elizabeth J Phillips, Simone Pinheiro, Munir Pirmohamed, Cynthia Sung, Wimon Suwankesawong, Lauren Trepanier, Santa J Tumminia, David Veenstra, Rika Yuliwulandari, Neil H Shear
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is one of the most devastating of adverse drug reactions (ADRs) and was, until recently, essentially unpredictable. With the discovery of several risk alleles for drug-induced SJS/TEN and the demonstration of effectiveness of screening in reducing incidence, the stage is set for implementation of preventive strategies in populations at risk. Yet much remains to be learned about this potentially fatal complication of commonly used drugs.
November 6, 2017: Clinical Pharmacology and Therapeutics
Deepaneeta Sarmah, Vishal Agrawal, Pallavi Rane, Shashikala Bhute, Mitsuyoshi Watanabe, Kiran Kalia, Zhumur Ghosh, Kunjan R Dave, Dileep R Yavagal, Pallab Bhattacharya
No abstract text is available yet for this article.
November 1, 2017: Clinical Pharmacology and Therapeutics
Christopher L Shaffer
The probability of achieving marketing approval of a novel therapeutic for psychiatric indications is extremely low due largely to the inability to demonstrate durable and reproducible efficacy in phase II trials and beyond. These failures are often attributed to the lack of translation of the underlying neuropharmacology from animal model(s) to the disease population. However, how assured is such a conclusion considering the clinical efficacy path rarely meticulously parallels the preclinical experiment(s) that underwrote it?...
October 27, 2017: Clinical Pharmacology and Therapeutics
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