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Clinical Pharmacology and Therapeutics

Charles E DiLiberti, Charles Bon, Pina D'Angelo, Keith Gallicano, Diane Potvin
No abstract text is available yet for this article.
November 14, 2018: Clinical Pharmacology and Therapeutics
Lenita Lindström-Gommers, Theresa Mullin
Eight years ago this journal published "The Value and Benefits of the International Conference on Harmonization to Drug Regulatory Authorities: Advancing Harmonization for Better Public Health"1 to mark the 20th anniversary of ICH. Much has happened since following the reform of ICH which culminated in 2015 with the establishment of ICH as an international non-profit association. This entailed a transformation of the collaboration between a limited number of parties in an informal setting into a formal international organization with its own legal entity...
November 14, 2018: Clinical Pharmacology and Therapeutics
Rodrigo Ruano, Elizabeth Ann L Enninga, Paola E Brana Rivera, Andre Terzic
Technology advances have raised the outlook for regenerative solutions aimed at restoring organ health. Fetal surgery, implemented to reinstate early organ growth and restitute function in select congenital conditions, is increasingly considered with the prospect of improved postnatal outcomes. Herein, we highlight clinical prenatal interventions for rescue of fetal lung development in congenital diaphragmatic hernia and fetal neurological regeneration for spina bifida. Regenerative therapeutic care in utero is poised to transform management algorithms...
November 11, 2018: Clinical Pharmacology and Therapeutics
Virginia D Schmith, Kellie Schoolar Reynolds, Kim L R Brouwer, Paolo Vicini
Many articles in clinical pharmacology may highly influence drug development and regulatory decision making, far beyond the measure conveyed by the Journal Impact Factor. Quantifying impact from the grey content (e.g., nonpublished information) remains an evolving dilemma. A collaboration is proposed with library scientists and bioinformaticians to develop methods to measure the impact of grey content on drug development and regulatory decision making. Mechanisms to reward this impact are discussed.
November 11, 2018: Clinical Pharmacology and Therapeutics
Bramasta Nugraha, Michele F Buono, Lisa von Boehmer, Simon P Hoerstrup, Maximilian Y Emmert
Human cardiac drug discovery and disease modeling face challenges in recapitulating cellular complexity and animal-to-human translation due to the limitations of conventional 2D cell culture and animal models. The development of human cardiac organoid technologies could help in stimulating and maintaining differentiated cell functions for extended periods of time. By closely mimicking in vivo organ functions in vitro they could thereby help in overcoming the obstacles mentioned above. By constructing human cardiac organoids from pluripotent stem cell-derived cells, derived from patients with specific known geno- and phenotypes, more complex and robust in vitro tools have recently become available for disease modeling...
November 11, 2018: Clinical Pharmacology and Therapeutics
Ameet Sarpatwari, Rachel Barenie, Gregory Curfman, Aaron S Kesselheim
In 2010, Congress created an abbreviated application pathway for biosimilars, versions of approved biologics made by different manufacturers. However, as of November 1, 2018, the Food and Drug Administration had approved only 13 biosimilars under this pathway, of which just 6 were available for patients to use. We review the history of US regulation of biologics and identify manufacturing, regulatory, and marketing issues that have limited biosimilar market entry and uptake, concluding with recommendations for reform...
November 11, 2018: Clinical Pharmacology and Therapeutics
Liang Zhao, Myong-Jin Kim, Lei Zhang, Robert Lionberger
Quantitative methods and modeling (QMM) covers a broad spectrum of toolsets of which physiologically-based models and quantitative clinical pharmacology are most critical for generic drugs. QMM has been increasingly applied by the U.S. Food and Drug Administration (FDA) to facilitating generic drug development and review, and has played a critical role in the modernization of bioequivalence (BE) assessment, especially for locally acting drug products, complex products of other types, and modified-release solid oral dosage forms...
November 10, 2018: Clinical Pharmacology and Therapeutics
Kasper Meidahl Petersen, Søren Bøgevig, Tonny Studsgaard Petersen, Thomas Bo Jensen, Kim Peder Dalhoff, Trine Henriksen, Henrik Enghusen Poulsen, Mikkel Bring Christensen
In a double-blinded, randomized, cross-over trial, we investigated hemodynamic effects of high-dose intravenous lipid emulsion (ILE) with/without metoprolol. Ten healthy volunteers each completed four trial days (placebo+ILE; metoprolol+placebo; metoprolol+ILE; placebo+placebo) in random order. Metoprolol was administered as an initial bolus (10 mg), followed by an infusion (50 mg) from 5 to 30 min. ILE was administered as a bolus at 12.5 min (2.5 ml/kg), followed by a 15-min infusion (0.25 ml/kg/min). On metoprolol+ILE days (compared to metoprolol+placebo) after 120-minutes, mean heart rates were significantly higher (difference: 5...
November 9, 2018: Clinical Pharmacology and Therapeutics
Charles Flexner
Safe and effective lifelong treatment to control HIV infection is one of the greatest scientific and public health achievements of the past century. The majority of infected individuals able to maintain a daily oral regimen now have a normal or near-normal life expectancy. More than 30 approved drugs and dozens of formulations have produced thousands of possible drug combinations used clinically in the past, but today most patients receive only a handful of high priority and rigorously tested regimens. Unique features of antiretroviral therapy include the need for lifelong treatment to control virus replication, and the possibility of rapid emergence of permanent drug resistance if these agents are not properly used...
November 9, 2018: Clinical Pharmacology and Therapeutics
Trevor R Baybutt, John C Flickinger, Ellen M Caparosa, Adam E Snook
In 2017, the United States Food and Drug Administration (FDA) approved the first two novel cellular immunotherapies using synthetic, engineered receptors known as chimeric antigen receptors (CAR), tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), expressed by patient-derived T cells for the treatment of hematological malignancies expressing the B-cell surface antigen CD19 in both pediatric and adult patients. This approval marked a major milestone in the use of antigen-directed 'living drugs' for the treatment of relapsed or refractory blood cancers, and with these two approvals, there is increased impetus to expand not only the target antigens but also the tumor types that can be targeted...
November 8, 2018: Clinical Pharmacology and Therapeutics
Caroline F Thorn, Michelle Whirl-Carrillo, Houda Hachad, Julie A Johnson, Ellen M McDonagh, Mark J Ratain, Mary V Relling, Stuart A Scott, Russ B Altman, Teri E Klein
Pharmacogenomics (PGx) can be seen as a model for biomedical studies: it includes all disease areas of interest, spans in vitro studies to clinical trials, while focusing on the relationships between genes and drugs and the resulting phenotypes. This review will examine different characteristics of PGx study publications and provide examples of excellence in framing PGx questions and reporting their resulting data in a way that maximizes the knowledge that can be built upon them. This article is protected by copyright...
November 8, 2018: Clinical Pharmacology and Therapeutics
Leona Ling, Jan L Hillson, Renger G Tiessen, Tjerk Bosje, Mattheus Paulus van Iersel, Darrell J Nix, Lynn Markowitz, Nicholas A Cilfone, Jay Duffner, Jim Streisand, Anthony M Manning, Santiago Arroyo
M281 is a fully human, anti-neonatal Fc receptor (FcRn) antibody that inhibits FcRn-mediated immunoglobulin G (IgG) recycling to decrease pathogenic IgG while preserving IgG production. A randomized, double-blind, placebo-controlled first-in-human study with 50 normal healthy volunteers was designed to probe safety and the physiological maximum for reduction of IgG. Intravenous infusion of single ascending doses up to 60 mg/kg induced dose-dependent serum IgG reductions, which were similar across all IgG subclasses...
November 6, 2018: Clinical Pharmacology and Therapeutics
Gigi Hirsch
Successfully delivering on the promise of emerging science in a world of value-driven healthcare requires that we fundamentally reengineer biomedical innovation processes to be both patient centered and sustainable. Massachusetts Institute of Technology's New Drug Development Paradigms (NEWDIGS), a "think and do" tank launched in 2010, provides a safe haven, precompetitive environment for multistakeholder collaboration to innovate how we innovate. Its newest project, Learning Ecosystems Accelerator for Patient-centered, Sustainable innovation (LEAPS), will pilot an innovation system designed to enhance decision making, outcomes, and trust among key stakeholders...
November 2, 2018: Clinical Pharmacology and Therapeutics
Ram R Miller, Ronenn Roubenoff
The impressive increase in lifespan that occurred in the 20th century has driven a boom in age-associated degeneration resulting from senescence. Geriatric syndromes such as sarcopenia and frailty do not fall neatly into classical medical definitions of disease because they result from subtle declines in physiological function that occur over many years instead of specific organ-related pathology. These conditions have become more clinically prominent with the aging population, and are the focus of research in regenerative medicine...
November 1, 2018: Clinical Pharmacology and Therapeutics
Corinne Seng Yue, Deniz Ozdin, Susannah Selber-Hnatiw, Murray Ducharme
The science of bioequivalence and biosimilarity has greatly evolved over the past three decades. Current methods for assessing bioequivalence mostly rely on noncompartmental pharmacokinetic analyses, which have proven to be reliable and robust for most products. However, the development of more complex products is forcing scientists and regulators to consider alternative approaches, including those derived from model-based, population pharmacokinetic analyses. This manuscript will examine the strengths and weaknesses of standard noncompartmental methods and compare them to model-based approaches, including a comparison of metrics associated with each method...
October 30, 2018: Clinical Pharmacology and Therapeutics
Yupeng Ren, Liang Li, Susan Kirshner, Yaning Wang, Chandrahas Sahajwalla, Ping Ji
A mathematical anti-drug antibody (ADA) model was developed to quantitatively assess immunogenicity for therapeutic proteins. The ADA model was built with antibody titer data in subjects from 10 clinical trials. The time-course of the antibody titers was quantitatively characterized with a two-component semi-mechanistic model describing the double peaks of ADA titers. The relationship between antibody titer and incidence was also explored. The ADA incidences in subjects from 12 clinical trials were used for internal and external validations...
October 29, 2018: Clinical Pharmacology and Therapeutics
Sara N Salerno, Gilbert J Burckart, Shiew-Mei Huang, Daniel Gonzalez
Pediatric drug-drug interactions (DDIs) can be life threatening, and a plan for assessing the interaction potential should be part of every pediatric drug development program. However, DDI studies are rarely performed in the pediatric population for ethical and practical reasons. Consequently, there is a paucity of information available regarding pediatric DDIs. This article will propose strategies for evaluating pharmacokinetic/pharmacodynamic DDIs throughout pediatric drug development and clinical use.
October 25, 2018: Clinical Pharmacology and Therapeutics
Manoj Khurana, Immo Zadezensky, Naomi Lowy, Dragos Roman, Jean-Marc Guettier, Liang Li, Jeffry Florian, Chandrahas G Sahajwalla, Vikram Sinha, Nitin Mehrotra
We present an application of a quantitative systems pharmacology (QSP) model to support a regulatory decision, specifically in assessing the adequacy of the proposed dosing regimen. On January 23, 2015, the US Food and Drug Administration (FDA) approved Natpara (human parathyroid hormone (PTH)) to control hypocalcemia in patients with hypoparathyroidism. Clinical trial results indicated that although once-daily PTH reduced calcium and vitamin D dose requirement while maintaining the normocalcemia, the regimen was not adequate to control hypercalciuria...
October 22, 2018: Clinical Pharmacology and Therapeutics
K Chris Min, Marissa F Dockendorf, John Palcza, Jack Tseng, Lei Ma, Julie A Stone, Huub J Kleijn, Peter Hodsman, Kazuko Masuo, Michael Tanen, Matthew D Troyer, Marianne van Vugt, Mark S Forman
BACE1 is required for the production of β-amyloid peptides and considered a potential treatment target for Alzheimer's disease (AD). To support Japan's participation in the global clinical development program, we characterized the safety, pharmacokinetics, and pharmacodynamics of the BACE1 inhibitor verubecestat (MK-8931) in 24 healthy Japanese adults in a 2-part, single-center, randomized, placebo-controlled phase I trial and compared the results with historic data from non-Japanese subjects. Both single (20, 100, and 450 mg) and multiple (80 and 150 mg once daily for 14 days) doses of verubecestat were well-tolerated...
October 22, 2018: Clinical Pharmacology and Therapeutics
Peter K Honig
The fourth hurdle in drug development and patient access to new therapeutics is reimbursement. The evidentiary requirements that are sufficient to regulators may not be sufficient to allow health technology assessment (HTA) bodies to make informed cost-effectiveness and formulary decisions. The accompanying paper by Vreman et al confirms that facilitated regulatory pathways may result in regulatory approvals but may not result in patient access to new and important medicines. This article is protected by copyright...
October 22, 2018: Clinical Pharmacology and Therapeutics
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