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Clinical Pharmacology and Therapeutics

S A Waldman, A Terzic
Success in pharmaceutical development led to a record 51 drugs approved in the past year, surpassing every previous year since 1950. Technology innovation enabled identification and exploitation of increasingly precise disease targets ensuring next generation diagnostic and therapeutic products for patient management. The expanding biopharmaceutical portfolio stands, however, in contradistinction to the unsustainable costs that reflect remarkable challenges of clinical development programs. This annual Therapeutic Innovations issue juxtaposes advances in translating molecular breakthroughs into transformative therapies with essential considerations for lowering attrition and improving the cost-effectiveness of the drug-development paradigm...
November 21, 2016: Clinical Pharmacology and Therapeutics
Peter Matzneller, Sabine Strommer, Christa Drucker, Karin Petroczi, Christian Schörgenhofer, Edith Lackner, Bernd Jilma, Markus Zeitlinger
OBJECTIVES: The previously described anti-endotoxin effect of colistin was not investigated in humans yet. We performed a randomized, double-blind, placebo-controlled crossover trial to determine the degree of colistin-driven modulation of inflammatory response in blood of lipopolysaccharide (LPS) - challenged healthy volunteers in a human endotoxemia model. METHODS: After a single intravenous dose of 2.5 million IU colistin methanesulfonate, IL-6, IL-8, TNF-α and IL-1β concentrations as well as other biomarkers of inflammation such as C-reactive protein, differential leukocyte counts and body temperature were measured up to 24 hours post-dose...
November 19, 2016: Clinical Pharmacology and Therapeutics
K R Vogel, G R Ainslie, P L Pearl, K M Gibson
Vigabatrin (VGB; γ-vinylGABA) is a unique antiepileptic directly elevating CNS GABA via inactivation of the GABA metabolic enzyme GABA-transaminase. VGB is effective in treating infantile spasms, a rare seizure disorder associated with significant morbidity. The potential for unexplained bilateral constriction of the visual field associated with VGB intervention can severely limit its temporal utility. Removal of this potential adverse effect with adjuvant intervention(s) would represent a significant advance in epilepsy therapeutics...
November 19, 2016: Clinical Pharmacology and Therapeutics
Manisha Lamba, Matthew M Hutmacher, Daniel E Furst, Ara Dikranian, Martin E Dowty, Daniela Conrado, Thomas Stock, Chudy Nduaka, Jack Cook, Sriram Krishnaswami
Extended-release (XR) formulations enable less frequent dosing versus conventional (e.g., immediate release [IR]) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model-informed, exposure-response (E-R) approach to translate controlled trial data from one formulation to another without a Phase III trial, using a tofacitinib case study. Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA)...
November 17, 2016: Clinical Pharmacology and Therapeutics
Xu Steven Xu, Xiaoyu Yan, Thomas Puchalski, Sagar Lonial, Henk M Lokhorst, Peter M Voorhees, Torben Plesner, Kevin Liu, Imran Khan, Richard Jansson, Tahamtan Ahmadi, Juan Jose Perez Ruixo, Honghui Zhou, Pamela L Clemens
New therapeutic strategies are urgently needed to improve clinical outcomes in patients with multiple myeloma (MM). Daratumumab is a first-in-class, CD38 human immunoglobulin G1κ monoclonal antibody approved for treatment of relapsed or refractory MM. Identification of an appropriate dose regimen for daratumumab is challenging due to its target-mediated drug disposition, leading to time- and concentration-dependent pharmacokinetics. We describe a thorough evaluation of the recommended dose regimen for daratumumab in patients with relapsed or refractory MM...
November 17, 2016: Clinical Pharmacology and Therapeutics
Rhiannon N Hardwick, Chad Viergever, Alice E Chen, Deborah G Nguyen
No abstract text is available yet for this article.
November 16, 2016: Clinical Pharmacology and Therapeutics
D Katz, I Katz, B S Porat-Katz, Y Shoenfeld
Legalization of cannabis' medicinal use is rapidly increasing worldwide, raising the need to evaluate medical implications of cannabis. Currently evidence supports cannabis and its active ingredients as an immune-modulating agents, affecting T-cells, B-cells, Monocytes and Microglia-cells, causing an overall reduction in pro-inflammatory cytokine expression and an increase in anti-inflammatory cytokines. Due to the supporting evidence of cannabinoids as an immune-modulating agent, research focusing on cannabinoids and autoimmunity has emerged...
November 10, 2016: Clinical Pharmacology and Therapeutics
Tanja Dujic, Kaixin Zhou, Sook Wah Yee, Nienke van Leeuwen, Catherine E de Keyser, Martin Javorský, Srijib Goswami, Linda Zaharenko, Mette Marie, H Christensen, Mattijs Out, Roger Tavendale, Michiaki Kubo, Monique M Hedderson, Amber A van der Heijden, Lucia Klimčáková, Valdis Pirags, Adriaan Kooy, Kim Brøsen, Janis Klovins, Sabina Semiz, Ivan Tkáč, Bruno H Stricker, Colin N A Palmer, Leen M 't Hart, Kathleen M Giacomini, Ewan R Pearson
Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporters genes, with inconsistent results. To clarify the significance of these variants in glycaemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (OCT1, OCT2, MATE1, MATE2-K and OCTN1) were analysed in up to 7,968 individuals...
November 10, 2016: Clinical Pharmacology and Therapeutics
Merrie Mosedale, Paul B Watkins
Drug-induced liver injury (DILI) is a major public health problem. Intrinsic (dose-dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie the hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis...
November 9, 2016: Clinical Pharmacology and Therapeutics
R Le Boisselier, J Alexandre, V Lelong-Boulouard, D Debruyne
The recent emergence of a multitude of synthetic cannabinoids (SCs) has generated a wealth of new information, suggesting the usefulness of state-of-the-art on lato sensu cannabinoids. By modulating a plurality of neurotransmission pathways, the endocannabinoid system is involved in many physiological processes increasingly explored. SCs desired and adverse effects are considered to be more intense than those observed with cannabis smoking, which is partly explained by the full agonist activity and higher affinity for cannabinoid receptors...
November 9, 2016: Clinical Pharmacology and Therapeutics
Berra B Yazar-Klosinski, Michael C Mithoefer
Phase 2 trials of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have demonstrated initial safety and efficacy for treatment of PTSD, with potential for expansion to depression and anxiety disorders. In these trials, single doses of MDMA are administered in a model of medication-assisted psychotherapy, differing from trials involving daily drug administration without psychotherapy. This model presents an opportunity to utilize accelerated regulatory pathways, such as FDA Breakthrough Therapy Designation, to most effectively and expeditiously test such novel approaches...
November 9, 2016: Clinical Pharmacology and Therapeutics
Ryo Ohara, Keiko Imamura, Fukiko Morii, Naohiro Egawa, Kayoko Tsukita, Takako Enami, Ran Shibukawa, Toshiki Mizuno, Masanori Nakagawa, Haruhisa Inoue
Drugs under development can cause unpredicted toxicity in humans due to differential drug responsiveness between humans and other disease models, resulting in clinical trial failures. Human induced pluripotent stem cells (iPSCs) are expected to represent a useful tool for toxicity testing. However, among many assays, appropriate cellular assays for predicting neurotoxicity in an iPSC-based model are still uncertain. Here, we generated neurons from iPSCs of Charcot-Marie-Tooth disease (CMT) patients, who are sensitive to anti-cancer drugs and present with the adverse reaction of neuropathy, and analyzed cellular phenotypes...
November 9, 2016: Clinical Pharmacology and Therapeutics
Sherry-Ann Brown, Lara Nhola, Joerg Herrmann
Once universally considered a rapidly fatal condition, cancer has increasingly become a chronic medical condition and co-morbidities and adverse effects of cancer therapies have become increasingly significant. One of the leading advancements, which has gained traction for the treatment of a variety of malignancies, is the class of small molecule tyrosine kinase inhibitors (TKIs). While in many aspects revolutionary, TKIs have their own profile of side effects, including cardiovascular side effects, the most common being hypertension, congestive heart failure, QTc prolongation, and instances of premature coronary heart disease...
November 2, 2016: Clinical Pharmacology and Therapeutics
Andrew W Roberts, David C S Huang
The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed...
November 2, 2016: Clinical Pharmacology and Therapeutics
Jacob P Laubach, Claudia E Paba Prada, Paul G Richardson, Dan L Longo
There has been substantial progress in clinical outcomes for patients with multiple myeloma. This encouraging trend derives in large part from the increasing number of effective therapeutic options and the ability as a result of this to achieve higher quality responses to treatment. The approval of both daratumumab and of elotuzumab in combination with lenalidomide and dexamethasone in late 2015 was a notable achievement in the field, as daratumumab and elotuzumab represent the first monoclonal antibodies available for use in multiple myeloma...
November 2, 2016: Clinical Pharmacology and Therapeutics
J G Allickson
No abstract text is available yet for this article.
November 2, 2016: Clinical Pharmacology and Therapeutics
Emanuele Cocucci, Ji Young Kim, Yuntao Bai, Navjotsingh Pabla
Intracellular drug accumulation is thought to be dictated by two major processes, passive diffusion through the lipid membrane or membrane transporters. The relative role played by these distinct processes remains actively debated. Moreover, the role of membrane-trafficking in drug transport remains underappreciated and unexplored. Here we discuss the distinct processes involved in cellular drug distribution and propose that better experimental models are required to elucidate the differential contributions of various processes in intracellular drug accumulation...
November 2, 2016: Clinical Pharmacology and Therapeutics
Jennifer L Orthmann-Murphy, Peter A Calabresi
Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disorder of the central nervous system (CNS). People with MS typically have a relapsing remitting disease course, with episodic neurological dysfunction corresponding to inflammation in the brain or spinal cord. Some relapsing patients develop a progressive disease course, with accumulation of disability over time, yet other people with MS only experience a progressive course. Over the past 20 years, 14 immunomodulatory therapies have been approved in MS in order to reduce the frequency of inflammatory relapses and prevent CNS damage...
November 2, 2016: Clinical Pharmacology and Therapeutics
Elena K Schneider, Felisa Reyes-Ortega, Jian Li, Tony Velkov
Cystic fibrosis is a life limiting disease caused by defective or deficient cystic fibrosis trans-membrane conductance regulator (CFTR) activity. The recent FDA approval of lumacaftor combined with ivacaftor (Orkambi) targets patients with the F508del-CFTR. The question remains, is this breakthrough combination therapy the 'magic-bullet' cure the vast majority of patients with CF? This review covers the contemporary clinical and scientific knowledge-base for Orkambi and highlights the emerging issues from recent conflicting literature reports...
November 2, 2016: Clinical Pharmacology and Therapeutics
Karthik Venkatakrishnan, Jeffrey A Ecsedy
Clinical pharmacodynamic evaluation is a key component of the "pharmacologic audit trail" in oncology drug development. We posit that its value can and should be greatly enhanced via application of a robust quantitative pharmacology framework informed by biologically mechanistic considerations. Herein, we illustrate examples of intersectional blindspots across the disciplines of quantitative pharmacology and translational science and offer a roadmap aimed at enhancing the caliber of clinical pharmacodynamic research in the development of oncology therapeutics...
November 2, 2016: Clinical Pharmacology and Therapeutics
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