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Clinical Pharmacology and Therapeutics

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https://www.readbyqxmd.com/read/28419467/refining-liver-safety-risk-assessment-application-of-mechanistic-modeling-and-serum-biomarkers-to-cimaglermin-alfa-ggf2-clinical-trials
#1
Diane M Longo, Grant T Generaux, Brett A Howell, Scott Q Siler, Daniel J Antoine, Donald Button, Anthony Caggiano, Andrew Eisen, Jennifer Iaci, Ric Stanulis, Tom Parry, Merrie Mosedale, Paul B Watkins
Cimaglermin alfa (GGF2) is a recombinant human protein growth factor in development for heart failure. Phase 1 trials were suspended when 2 cimaglermin alfa-treated subjects experienced concomitant elevations in serum aminotransferases and total bilirubin meeting current FDA criteria for a serious liver safety signal (i.e. "Hy's Law"). We assayed mechanistic biomarkers in archived clinical trial serum samples which confirmed the hepatic origin of the aminotransferase elevations in these two subjects and identified apoptosis as the major mode of hepatocyte death...
April 17, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28419437/a-new-paradigm-learn-learn-more-dose-exposure-response-at-the-centre-of-drug-development-and-regulatory-approval
#2
REVIEW
Alan Maloney
No abstract text is available yet for this article.
April 17, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28419431/moving-beyond-maximum-tolerated-dose-for-targeted-oncology-drugs-use-of-clinical-utility-index-to-optimize-venetoclax-dosage-in-multiple-myeloma-patients
#3
Kevin J Freise, Aksana K Jones, Maria E Verdugo, Rajeev M Menon, Paulo C Maciag, Ahmed Hamed Salem
Exposure-response analyses of venetoclax in combination with bortezomib and dexamethasone in previously treated patients with multiple myeloma (MM) were performed on a Phase 1b venetoclax dose-ranging study. Logistic regression models were utilized to determine relationships, identify sub-populations with different responses and optimize the venetoclax dosage that balanced both efficacy and safety. Bortezomib refractory status and number of prior treatments were identified to impact the efficacy response to venetoclax treatment...
April 17, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28411400/physiologically-based-pharmacokinetic-modeling-suggests-limited-drug-drug-interaction-between-clopidogrel-and-dasabuvir
#4
Mohamad Shebley, Wentao Fu, Prajakta Badri, Daniel A J Bow, Volker Fischer
Dasabuvir, a non-nucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug-drug interaction (DDI) with clopidogrel. A physiologically-based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl-β-D glucuronide metabolite of which has been reported as a strong mechanism-based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data...
April 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28398598/pharmacogenomics-based-point-of-care-clinical-decision-support-significantly-alters-drug-prescribing
#5
Peter H O'Donnell, Nisha Wadhwa, Keith Danahey, Brittany A Borden, Sang Mee Lee, Julianne P Hall, Catherine Klammer, Sheena Hussain, Mark Siegler, Matthew J Sorrentino, Andrew M Davis, Yasmin A Sacro, Rita Nanda, Tamar S Polonsky, Jay L Koyner, Deborah L Burnet, Kristen Lipstreuer, David T Rubin, Cathleen Mulcahy, Mary E Strek, William Harper, Adam S Cifu, Blase Polite, Linda Patrick-Miller, Kiang-Teck J Yeo, Edward K Y Leung, Samuel L Volchenboum, Russ B Altman, Olufunmilayo I Olopade, Walter M Stadler, David O Meltzer, Mark J Ratain
Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green/genomically favorable, yellow/genomic caution, red/high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint...
April 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28390139/effect-of-us-food-and-drug-administration-s-cardiovascular-safety-guidance-on-diabetes-drug-development
#6
Thomas J Hwang, Jessica M Franklin, Aaron S Kesselheim
In 2008, the Food and Drug Administration issued guidance on the need for cardiovascular outcomes trials to assess the safety of new diabetes medications. Using two large commercial databases, we evaluated the effect of the FDA's cardiovascular safety guidance on drug development for Type 2 diabetes as well as a comparison group of drugs intended to treat other alimentary and metabolic conditions. The FDA's guidance was associated with a 31% differential decrease in the rate of diabetes drugs entering Phase 2 trials, but the remaining drugs were significantly more likely to target novel biological pathways (72% of drugs had novel mechanisms after the guidance vs...
April 8, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28390138/electronic-medical-record-integrated-pharmacogenomics-and-related-clinical-decision-support-concepts
#7
REVIEW
Pedro J Caraballo, Suzette J Bielinski, Jennifer L St Sauver, Richard M Weinshilboum
No abstract text is available yet for this article.
April 8, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28380682/the-association-of-the-skin-microbiota-with-health-immunity-and-disease
#8
Markus Egert, Rainer Simmering, Christian U Riedel
The human skin is densely colonized by a highly diverse microbiota comprising all three domains of life. Long believed to represent mainly a source of infection, the human skin microbiota is nowadays well accepted as an important driver of human (skin) health and well-being. This microbiota is influenced by many host and environmental factors and interacts closely with the skin immune system. Although cause and effect are usually difficult to discriminate, changes in the skin microbiota clearly play a role in the pathobiology of many types of skin disease and cosmetic disorders...
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28380664/chronic-administration-of-anacetrapib-is-associated-with-accumulation-in-adipose-and-slow-elimination
#9
Rajesh Krishna, Ferdous Gheyas, Yang Liu, David Hagen, Brittany Walker, Akshita Chawla, Josee Cote, Robert O Blaustein, David E Gutstein
Anacetrapib is a novel CETP inhibitor in late stage clinical development, shown in preceding clinical trials to have residual pharmacological activity after prolonged washout following chronic dosing. Preclinical findings suggests that white adipose tissue is a potential depot and that accumulation into adipose tissue governs the long-term kinetics of anacetrapib in mice. A Phase 1 study performed to test this hypothesis in humans revealed that plasma exposure was correlated with fat content in food administered with the drug...
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28380657/genetic-polymorphisms-in-organic-cation-transporter-1-attenuates-hepatic-metformin-exposure-in-humans
#10
Elias Immanuel Ordell Sundelin, Lars Christian Gormsen, Jonas Brorson Jensen, Mikkel Holm Vendelbo, Steen Jakobsen, Ole Lajord Munk, Mette Marie Hougaard Christensen, Kim Brøsen, Jørgen Frøkiaer, Niels Jessen
Metformin has been used successfully to treat type 2 diabetes for decades. However, the efficacy of the drug varies considerably from patient to patient and this may in part be due to its pharmacokinetic properties. The aim of this study was to examine if common polymorphisms in SLC22A1, encoding the transporter protein OCT1, affect the hepatic distribution of metformin in humans. We performed non-invasive (11) C-metformin PET/CT to determine hepatic exposure in 12 subjects genotyped for variants in SLC22A1...
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28379623/on-pump-cardiac-surgery-enhances-platelet-renewal-and-impairs-aspirin-pharmacodynamics-effects-of-improved-dosing-regimens
#11
V Cavalca, B Rocca, F Veglia, G Petrucci, B Porro, V Myasoedova, R De Cristofaro, L Turnu, A Bonomi, P Songia, L Cavallotti, M Zanobini, M Camera, F Alamanni, A Parolari, C Patrono, E Tremoli
On-pump cardiac surgery may trigger inflammation and accelerate platelet cyclooxygenase-1 renewal, thereby modifying low-dose aspirin pharmacodynamics. Thirty-seven patients on standard aspirin 100mg once-daily were studied before surgery and randomized within 36 hours post-surgery to 100mg once-daily, 100mg twice-daily or 200mg once-daily for 90 days. On day 7 post-surgery, immature and mature platelets, platelet mass, thrombopoieitin, glycocalicin, leukocytes, C-reactive protein, and interleukin-6 significantly increased...
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28378927/worldwide-distribution-of-cytochrome-p450-alleles-a-meta-analysis-of-population-scale-sequencing-projects
#12
Yitian Zhou, Magnus Ingelman-Sundberg, Volker M Lauschke
Genetic polymorphisms in cytochrome P450 (CYP) genes can result in altered metabolic activity towards a plethora of clinically important medications. Thus, single nucleotide variants and copy number variations in CYP genes are major determinants of drug pharmacokinetics and toxicity and constitute pharmacogenetic biomarkers for drug dosing, efficacy and safety. Strikingly, the distribution of CYP alleles differs considerably between populations with important implications for personalized drug therapy and healthcare programs...
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28378919/ethnic-difference-in-the-pharmacodynamics-efficacy-relationship-of-dipeptidyl-peptidase-4-inhibitors-between-japanese-and-non-japanese-patients-a-systematic-review
#13
Yuka Ito, Kaori Ambe, Mayu Kobayashi, Masahiro Tohkin
A systematic review of the differences in the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors between Japanese and non-Japanese subjects was conducted. We searched for randomized controlled trials in patients with type 2 diabetes mellitus which studied the intervention of a DPP-4 inhibitor once-daily versus placebo, as monotherapy or as add-on therapy. Data regarding placebo-corrected HbA1c reduction and trough DPP-4 inhibition rate after >=12 weeks' treatment were extracted. In the 12 eligible studies, linear regression analysis revealed that the HbA1c reduction at each DPP-4 inhibition level was larger in studies involving Japanese patients than in studies involving non-Japanese patients, with statistical significance between the two groups (p<0...
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28378909/in-silico-modeling-of-the-antiplatelet-pharmacodynamics-of-low-dose-aspirin-in-health-and-disease
#14
Alberto Giaretta, Bianca Rocca, Barbara Di Camillo, Gianna Maria Toffolo, Carlo Patrono
The influence of platelet turnover on cyclooxygenase (COX-1) inhibition by low-dose aspirin remains largely uncharacterized due to limited feasibility of studying aspirin pharmacodynamics in bone marrow precursors. We developed an in silico compartmental model describing aspirin effects on COX-1 activity in a population of megakaryocytes (MK) and in peripheral platelets. Model parameters were inferred from the literature and calibrated using measurements of serum thromboxane B2 (sTXB2 ), as proxy of COX-1 activity in peripheral platelets, in 17 healthy subjects and 24 patients with essential thrombocythemia (ET)...
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28378903/building-capability-for-clinical-pharmacology-research-in-sub-saharan-africa
#15
REVIEW
Marcelo M Gutierrez, Goonaseelan Colin Pillai, Sandra Felix, Fernando Romero, Kevin Omondi Onyango, Seth Owusu-Agyei, Kwaku Poku Asante, Karen I Barnes, Phumla Sinxadi, Elizabeth Allen, Salim Abdulla, Collen Masimirembwa, Michelle Munyoro, Getnet Yimer, Tsige Gebre-Mariam, Jonathan Spector, Bernhards Ogutu
No abstract text is available yet for this article.
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28378901/pharmacokinetics-and-pharmacodynamics-of-intravenous-immunoglobulin-g-maintenance-therapy-in-chronic-immune-mediated-neuropathies
#16
Wjr Fokkink, Bcp Koch, Crb Ramakers, P A van Doorn, T van Gelder, B C Jacobs
The regimen for intravenous immunoglobulin (IVIg) maintenance treatment varies considerably between patients with chronic immune-mediated neuropathies. Although it is widely recognized that treatment regimens should be improved, detailed pharmacokinetics of IVIg have not been established. We aimed to determine the pharmacokinetics of IVIg maintenance treatment in patients with clinically stable, treatment-dependent chronic immune-mediated neuropathy. Patients received a median IVIg dose of 30 (15 - 70) grams every 14 (7 - 28) days resulting in high IgG peak levels (median 25...
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28378879/coxibs-traditional-nsaids-and-cardiovascular-safety-post-precision-what-we-thought-we-knew-then-and-what-we-think-we-know-now
#17
Carlo Patrono, Colin Baigent
The aim of the present review is to analyze how thinking about the cardiovascular safety of NSAIDs has evolved during the past two decades, and discuss to what extent the additional information from PRECISION may alter our current mechanistic understanding and/or clinical practice. This article is protected by copyright. All rights reserved.
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28378877/occlusion-in-the-flow-of-new-drugs-for-cardiovascular-disease
#18
Michael S Ringel, Najaf Shah, Mathias Baedeker, Christopher T Lim, Aayam Lamichhane, Ulrik Schulze
There is a large misalignment between unmet need and both private and public investment activity in cardiovascular disease. In this paper we quantify the magnitude of the gap, analyze a range of potential root causes in two main categories (issues of feasibility or valuation), and propose steps toward solutions to close the gap. This article is protected by copyright. All rights reserved.
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28369788/model-based-approach-for-optimizing-study-design-and-clinical-drug-performances-of-extended-release-formulations-of-methylphenidate-for-the-treatment-of-adhd
#19
R Gomeni, Fmm Bressolle-Gomeni, T J Spencer, S V Faraone, L Fang, A Babiskin
Methylphenidate (MPH) is currently used to treat children with attention deficit hyperactivity disorder (ADHD). Several extended-release (ER) formulations characterized by a dual release process were developed to improve efficacy over an extended duration. In this study, a model-based approach using literature data was developed to: a) evaluate the most efficient pharmacokinetic (PK) model to characterize the complex PK profile of MPH ER formulations; b) provide PK endpoint metrics for comparing ER formulations; c) define criteria for optimizing development of ER formulations using a convolution-based model linking in-vitro release, in-vivo release and hour-by-hour behavioral ratings of ADHD symptoms; and d) define an optimized trial design for assessing the activity of MPH in pediatric populations...
March 29, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28317101/recent-advances-in-small-molecule-and-biological-therapeutic-approaches-in-the-treatment-of-psoriasis
#20
Jackson G Turbeville, Nupur U Patel, Leah A Cardwell, Elias Oussedik, Steven R Feldman
New treatments continue to be developed for psoriasis. In this review, we aim to summarize the results of the major published studies on biologic and small molecule drugs for the treatment of psoriasis. We emphasize the safety, efficacy, and tolerability of these treatment options. A review of the MEDLINE database was conducted for each class of medication. Randomized controlled trials were identified for each medication; data on efficacy, safety, and tolerability was reviewed. Biologic and small molecule treatment options are more effective than placebo, although there were few head-to-head trials to assess relative efficacy between biologics and small molecule treatments...
March 20, 2017: Clinical Pharmacology and Therapeutics
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