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Clinical Pharmacology and Therapeutics

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https://www.readbyqxmd.com/read/28090657/toward-greater-insights-on-pharmacokinetics-and-exposure-response-relationships-for-therapeutic-biologics-in-oncology-drug-development
#1
Yaning Wang, Brian Booth, Atiqur Rahman, Geoffrey Kim, Shiew Mei Huang, Issam Zineh
There has been increased interest in optimizing dosing regimens for oncology products over the past decade. Investigations to refine dosing regimens often occur after new drug approval.(1) There is growing focus on the use of exposure-response (ER) approaches to identify optimal dosing regimens for therapeutic biologics. Herein, we describe several recent observations that have informed our thinking on the use of ER analyses in the dose regimen optimization of therapeutic biologics developed to treat cancer...
January 16, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28090653/genome-wide-study-links-pnpla3-variant-with-elevated-hepatic-transaminase-after-acute-lymphoblastic-leukemia-therapy
#2
Yiwei Liu, Christian A Fernandez, Colton Smith, Wenjian Yang, Cheng Cheng, John C Panetta, Nancy Kornegay, Chengcheng Liu, Laura B Ramsey, Seth E Karol, Laura J Janke, Eric C Larsen, Naomi Winick, William L Carroll, Mignon L Loh, Elizabeth A Raetz, Stephen P Hunger, Meenakshi Devidas, Jun J Yang, Charles G Mullighan, Jinghui Zhang, William E Evans, Sima Jeha, Ching-Hon Pui, Mary V Relling
Remission induction therapy for acute lymphoblastic leukemia (ALL) includes medications that may cause hepatotoxicity, including asparaginase. We used a genome-wide association study (GWAS) to identify loci associated with elevated alanine transaminase (ALT) levels after induction therapy in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols. Germline DNA was genotyped using arrays and exome sequencing. Adjusting for age, body mass index, ancestry, asparaginase preparation and dosage, the PNPLA3 rs738409 (C>G) I148M variant, previously associated with fatty liver disease risk, had the strongest genetic association with ALT (P = 2...
January 16, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28090649/-the-pharmacogenomics-research-network-translational-pharmacogenetics-program-outcomes-and-metrics-of-pharmacogenetic-implementations-across-diverse-healthcare-systems
#3
Jasmine A Luzum, Ruth E Pakyz, Amanda R Elsey, Cyrine E Haidar, Josh F Peterson, Michelle Whirl-Carrillo, Samuel K Handelman, Kathleen Palmer, Jill M Pulley, Marc Beller, Jonathan S Schildcrout, Julie R Field, Kristin W Weitzel, Rhonda M Cooper-DeHoff, Larisa H Cavallari, Peter H O'Donnell, Russ B Altman, Naveen Pereira, Mark J Ratain, Dan M Roden, Peter J Embi, Wolfgang Sadee, Teri E Klein, Julie A Johnson, Mary V Relling, Liewei Wang, Richard M Weinshilboum, Alan R Shuldiner, Robert R Freimuth
Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the NIH Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams...
January 16, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28074611/impact-of-pbpk-on-regulatory-reviews-and-product-labels-frequent-utilization-in-the-field-of-oncology
#4
Kenta Yoshida, Nageshwar Budha, Jin Yan Jin
No abstract text is available yet for this article.
January 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28074556/qt-interval-shortening-with-isavuconazole-in-vitro-and-in-vivo-effects-on-cardiac-repolarization
#5
J Keirns, A Desai, D Kowalski, C Lademacher, S Mujais, B Parker, M J Schneidkraut, R Townsend, T Wojtkowski, T Yamazaki, M Yen, P R Kowey
Effects of isavuconazole (active moiety of isavuconazonium sulfate) on cardiac ion channels in vitro and cardiac repolarization clinically were assessed in a Phase 1, randomized, double-blind study in healthy individuals who received isavuconazole (after 2-day loading dose), at therapeutic or supratherapeutic doses daily for 11 days, moxifloxacin (400 mg QD), or placebo. A post-hoc analysis of the Phase 3 SECURE trial assessed effects on cardiac safety. L-type Ca(2+) channels were most sensitive to inhibition by isavuconazole...
January 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28074547/a-pharmacokinetic-and-safety-study-of-trebananib-a-fc-fusion-peptibody-in-patients-with-advanced-solid-tumors-and-varying-degrees-of-renal-dysfunction
#6
Benjamin Wu, Lionel D Lewis, R Donald Harvey, Erik Rasmussen, Erick Gamelin, Yu-Nien Sun, Gregory Friberg, Jay L Koyner, Afshin Dowlati, Michael L Maitland
Clearance of trebananib (AMG 386), a 64 kD anti-angiogenic peptibody, has been associated with estimated glomerular filtration rate (eGFR). We prospectively evaluated trebananib pharmacokinetics and safety/tolerability in advanced solid tumor patients with varying degrees of renal function. Patients were assigned to normal renal function, mild, moderate, or severe renal dysfunction cohorts based on eGFR, received trebananib 15 mg/kg IV weekly, and underwent week 1 and week 5 pharmacokinetic and weekly safety assessments...
January 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28074488/molecular-sameness-is-key-guiding-principle-for-extrapolation-to-multiple-indications
#7
M McCamish, G R Woollett
No abstract text is available yet for this article.
January 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28074476/drug-development-trial-design-and-endpoints-in-oncology-adapting-to-rapidly-changing-science
#8
Gideon M Blumenthal, Kirsten B Goldberg, Richard Pazdur
No abstract text is available yet for this article.
January 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28074475/what-makes-you-feel-sick-after-inflammation-predictors-of-acute-and-persisting-physical-sickness-symptoms-induced-by-experimental-endotoxemia
#9
Sven Benson, Harald Engler, Alexander Wegner, Laura Rebernik, Ingo Spreitzer, Manfred Schedlowski, Sigrid Elsenbruch
We aimed to identify statistical predictor variables of LPS-induced physical sickness symptoms during the acute and late inflammatory phases using multivariate regression analyses. Data from N=128 healthy volunteers who received i.v. LPS injection (0.4 or 0.8 ng/kg) or placebo were pooled for analyses. Physical sickness symptoms experienced during the acute (0-6h post-injection) and late (6-24h post-injection) phases were assessed with the validated General-Assessment-of-Side-Effects (GASE) questionnaire. LPS-treated subjects reported significantly more physical sickness symptoms...
January 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28074473/predicting-cd4-t-cell-reconstitution-following-paediatric-haematopoietic-stem-cell-transplantation
#10
Rollo L Hoare, Paul Veys, Nigel Klein, Robin Callard, Joseph F Standing
Haematopoietic stem cell transplantation is an increasingly common treatment for children with a range of haematological disorders. Conditioning with cytotoxic chemotherapy and total body irradiation leaves patients severely immunocompromised. T-cell reconstitution can take several years due to delayed restoration of thymic output. Understanding T-cell reconstitution in children is complicated by normal immune system maturation, heterogeneous diagnoses, and sparse uneven sampling due to the long time spans involved...
January 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28074472/cost-evaluation-of-irinotecan-related-toxicities-associated-with-the-ugt1a1-28-patient-genotype
#11
R Roncato, E Cecchin, M Montico, E De Mattia, L Giodini, A Buonadonna, V Solfrini, F Innocenti, G Toffoli
The adoption of a pre-emptive UGT1A1*28 genotyping to increase irinotecan safety in clinical practice is still limited. This is the first actual study of costs associated to the management of irinotecan-related toxicity, and their association with UGT1A1*28 genotype. A retrospective analysis of the cost of toxicity management was conducted on 243 metastatic colorectal cancer patients enrolled in a clinical trial and treated with standard of care FOLFIRI. The mean predicted cost per patient was higher for *28/*28 (4,886€), versus *1/*1 (812€), (regression coefficient 1...
January 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28074467/systems-pharmacology-modeling-of-drug-induced-hyperbilirubinemia-differentiating-hepatotoxicity-and-inhibition-of-enzymes-transporters
#12
Kyunghee Yang, Christina Battista, Jeffrey L Woodhead, Simone H Stahl, Jerome T Mettetal, Paul B Watkins, Scott Q Siler, Brett A Howell
Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically-based pharmacokinetic model-predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir-mediated hyperbilirubinemia in humans and rats...
January 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28073152/characterizing-pharmacogenomic-guided-medication-use-with-a-clinical-data-repository
#13
Patrick C Mathias, Nathaniel Hendrix, Wei-Jhih Wang, Katelyn Keyloun, Maher Khelifi, Peter Tarczy-Hornoch, Beth Devine
The extent to which pharmacogenomic-guided medication use has been adopted in various health systems is unclear. To assess the uptake of pharmacogenomic-guided medication use, we determined its frequency across our health system, which does not have a structured testing program. Using a multi-site clinical data repository, we identified adult patients' first prescribed medications between January 2011 and December 2013 and investigated the frequency of germline and somatic pharmacogenomic testing, by PharmGKB level of FDA label information...
January 10, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28073148/ema-perspective-on-oncology-study-design-for-marketing-authorization-and-beyond
#14
B Jonsson, J Martinalbo, F Pignatti
No abstract text is available yet for this article.
January 10, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28073144/food-effect-studies-for-oncology-drug-products
#15
Sandeep Parsad, Mark J Ratain
Oral antineoplastic agents provide convenience to the patient, but are accompanied by challenges distinct from parenteral cancer treatment. Challenges include a more complex pharmacokinetic profile with food influencing the absorption of many agents. Standards for evaluating and labeling prandial implications on oral chemotherapy are inconsistent; studies to determine food effects should be conduced early, and potentially often, during drug development with standardization on how rationale fasting or fed recommendations are presented in the package insert...
January 10, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28073142/cardio-oncology-progress-in-diagnosis-and-treatment-of-cardiac-dysfunction
#16
REVIEW
Jasper Tromp, Lars C Steggink, Dirk J Van Veldhuisen, Jourik A Gietema, Peter van der Meer
No abstract text is available yet for this article.
January 10, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28032900/cancer-prevention-in-the-era-of-precision-oncology
#17
N N Brahme, E Szabo
Cancer is a highly heterogeneous disease, both between and within different target organs. Precision cancer prevention requires understanding the molecular pathways leading to cancer on a "per-person" level, identification of individuals most at risk for developing cancer, and tailoring interventions to accommodate pathogenesis, risk, and individual responses to interventions. This commentary will discuss how an investment in precision prevention research can accelerate cancer prevention agent development-the key to reducing cancer incidence and mortality...
December 29, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28027596/implementing-pharmacogenomics-in-europe-design-and-implementation-strategy-of-the-ubiquitous-pharmacogenomics-consortium
#18
Cathelijne H van der Wouden, Anne Cambon-Thomsen, Erika Cecchin, Ka-Chun Cheung, Cristina Lucía Dávila-Fajardo, Vera H Deneer, Vita Dolžan, Magnus Ingelman-Sundberg, Siv Jönsson, Mats O Karlsson, Marjolein Kriek, Christina Mitropoulou, George P Patrinos, Munir Pirmohamed, Matthias Samwald, Elke Schaeffeler, Matthias Schwab, Daniela Steinberger, Julia Stingl, Gere Sunder-Plassmann, Giuseppe Toffoli, Richard M Turner, Mandy H van Rhenen, Jesse J Swen, Henk-Jan Guchelaar
Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programmes have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs...
December 27, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28002639/clinical-pharmacogenetics-implementation-consortium-cpic-guideline-for-cyp2d6-genotype-and-use-of-ondansetron-and-tropisetron
#19
Gillian C Bell, Kelly E Caudle, Michelle Whirl-Carrillo, Ronald J Gordon, Keiko Hikino, Cynthia A Prows, Andrea Gaedigk, Jose A G Agundez, Senthilkumar Sadhasivam, Teri E Klein, Matthias Schwab
5-hydroxytryptamine type 3 (5-HT3 ) receptor antagonists are used in the prevention of chemotherapy- induced, radiation-induced and postoperative nausea and vomiting. CYP2D6 polymorphisms can influence the metabolism of some of these drugs (i.e. ondansetron and tropisetron) thereby affecting drug efficacy. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for ondansetron and tropisetron based on CYP2D6 genotype (updates at www.pharmgkb...
December 21, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28002638/drug-induced-ototoxicity-mechanisms-pharmacogenetics-and-protective-strategies
#20
REVIEW
Claudia Lanvers-Kaminsky, Antoinette G Am Zehnhoff-Dinnesen, Ross Parfitt, Giuliano Ciarimboli
Drug ototoxicity limits quality of life of patients after treatment, having serious consequences especially for psychosocial development of children. While the ototoxicity of many drugs resolves after treatment discontinuation, the use of platinum derivatives and aminoglycosides is associated with permanent hearing loss. In this review, we have listed ototoxic drugs and the mechanisms by which they damage the ears. Moreover, possible protective strategies and important methods for early detection of ototoxic effects are discussed...
December 21, 2016: Clinical Pharmacology and Therapeutics
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