901 results match your criteria CTS: Clinical and Translational Science [Journal]


Cell Therapies for Parkinson's Disease.

Authors:
Stefan Irion

Clin Transl Sci 2019 Feb 16. Epub 2019 Feb 16.

BlueRock Therapeutics, New York, New York, USA.

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http://dx.doi.org/10.1111/cts.12612DOI Listing
February 2019

The DILI-sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation.

Authors:
Paul Watkins

Clin Transl Sci 2019 Feb 14. Epub 2019 Feb 14.

The University of North Carolina at Chapel Hill, Institute for Drug Safety Sciences, 6 Davis Drive, PO Box 12137, North Carolina, United States.

The DILI-sim Initiative is a public-private partnership involving scientists from industry, academia and the FDA. The Initiative uses Quantitative Systems Toxicology (QST) to build and refine a model (DILIsym ) capable of understanding and predicting liver safety liabilities in new drug candidates and to optimize interpretation of liver safety biomarkers used in clinical studies. Insights gained to date include the observation that most dose-dependent hepatoxicity can be accounted for by combinations of just three mechanisms (oxidative stress, interference with mitochondrial respiration, and alterations in bile acid homeostasis) and the importance of non-competitive inhibition of bile acid transporters. Read More

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http://dx.doi.org/10.1111/cts.12629DOI Listing
February 2019
1 Read

Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11β-HSD1 Inhibitor, in Healthy Young and Elderly Subjects.

Clin Transl Sci 2019 Feb 11. Epub 2019 Feb 11.

Astellas Pharma, Inc, One Astellas Way, N6-148, Northbrook, IL, 60062.

Inhibition of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) represents a potential mechanism for improving pain conditions. ASP3662 is a potent and selective inhibitor of 11β-HSD1. Two Phase I clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of single and multiple ascending doses of ASP3662 in healthy young and elderly non-Japanese and young Japanese subjects. Read More

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http://dx.doi.org/10.1111/cts.12618DOI Listing
February 2019

Emerging Role of Organ-on-a-Chip Technologies in Quantitative Clinical Pharmacology Evaluation.

Clin Transl Sci 2019 Feb 11. Epub 2019 Feb 11.

Office of Clinical Pharmacology (OCP), Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA), 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.

The recently enacted Prescription Drug User Fee Act (PDUFA) VI includes in its performance goals "enhancing regulatory science and expediting drug development". The key elements in "enhancing regulatory decision tools to support drug development and review" include "advancing model-informed drug development (MIDD)". This paper describes (1) the FDA's Office of Clinical Pharmacology's continuing efforts in developing quantitative clinical pharmacology models (disease-, drug- and clinical trial- models) to advance MIDD, (2) how emerging novel tools such as organ-on-a-chip technologies or microphysiological systems can provide new insights into physiology and disease mechanisms, biomarker identification and evaluation, and elucidation of mechanisms of adverse drug reactions, and (3) how the single organ or linked organ microphysiological systems can provide critical system parameters for improved physiologically-based pharmacokinetic and pharmacodynamic evaluations. Read More

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http://dx.doi.org/10.1111/cts.12627DOI Listing
February 2019
1 Read

Evaluation of the ability of immune humanized mice to demonstrate CD20-specific cytotoxicity induced by ofatumumab.

Clin Transl Sci 2019 Feb 9. Epub 2019 Feb 9.

Division of Applied Regulatory Sciences, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.

CD20 monoclonal antibodies are well-established therapeutics for the treatment of B-cell malignancies. Several mechanisms of target cell killing occur from anti-CD20 therapy including complement-dependent cell lysis (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Human Fc Receptors (FcR) are required to mediate these functions and are either not present or not cross-reactive in mice and most animal species. Read More

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http://dx.doi.org/10.1111/cts.12613DOI Listing
February 2019
1 Read

Targeting RNA: a transformative therapeutic strategy.

Authors:
Wei Yin Mark Rogge

Clin Transl Sci 2019 Feb 1. Epub 2019 Feb 1.

Quantitative Clinical Pharmacology, Takeda Pharmaceutical Company Ltd, 35 Landsdowne Street, Cambridge, MA, 02139, USA.

The therapeutic pathways that modulate transcription mechanisms currently include gene knockdown and splicing modulation. However, additional mechanisms may come into play as more understanding of molecular biology and disease etiology emerge. Building on advances in chemistry and delivery technology, oligonucleotide therapeutics are emerging as an established, validated class of drugs that can modulate a multitude of genetic targets. Read More

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http://dx.doi.org/10.1111/cts.12624DOI Listing
February 2019

Molecular Neuroimaging of the Dopamine Transporter (DAT) as a Patient Enrichment Biomarker for Clinical Trials for Early Parkinson Disease.

Clin Transl Sci 2019 Feb 1. Epub 2019 Feb 1.

Critical Path Institute, 1730 East River Road, Tucson, AZ, 85718.

The Critical Path for Parkinson's (CPP) Imaging Biomarker and Modeling and Simulation working groups aimed to achieve qualification opinion by the European Medicines Agency's (EMA) Committee for Medical Products for Human Use (CHMP) for the use of baseline dopamine transporter (DAT) neuroimaging for patient selection in early Parkinson disease (PD) clinical trials. This manuscript describes the regulatory science strategy to achieve this goal. CPP is an international consortium of 3 Parkinson's charities and 9 pharmaceutical partners, coordinated by Critical Path Institute). Read More

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http://dx.doi.org/10.1111/cts.12619DOI Listing
February 2019

Identification and Evaluation of Clinical Substrates of Organic Anion Transporting Polypeptides 1B1 and 1B3.

Clin Transl Sci 2019 Feb 1. Epub 2019 Feb 1.

School of Pharmacy, University of Washington, Seattle, WA, 98195.

Organic anion transporting polypeptides (OATP) 1B1 and 1B3 facilitate the uptake of drugs and endogenous compounds into the liver. In recent years, the impact of these transporters on drug-drug interactions (DDIs) has become a focus of research, and the evaluation of their role in drug disposition is recommended by regulatory agencies worldwide. While sensitive substrates of OATP1B1/1B3 have been identified in the literature and probe drugs have been proposed by regulatory agencies, there is no general consensus on the ideal in vivo substrate for clinical drug-drug interaction studies as analysis may be confounded by contribution from other metabolic and/or transport pathways. Read More

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http://dx.doi.org/10.1111/cts.12623DOI Listing
February 2019

Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor.

Clin Transl Sci 2019 Jan 29. Epub 2019 Jan 29.

Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.

Drug-drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P-gp) substrate. The effects of steady-state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P-gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated. Read More

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http://dx.doi.org/10.1111/cts.12610DOI Listing
January 2019
1 Read

Does in vitro CYP down-regulation translate to in vivo drug-drug interactions? Preclinical and clinical studies with 13-cis-retinoic acid.

Clin Transl Sci 2019 Jan 25. Epub 2019 Jan 25.

Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington.

All-trans-retinoic acid (atRA) down-regulates CYP2D6 in several model systems. The aim of this study was to determine whether all active retinoids downregulate CYP2D6 and whether in vitro downregulation translates to in vivo drug-drug interactions (DDI). atRA, 13cisRA, and 4-oxo-13cisRA all decreased CYP2D6 mRNA in human hepatocytes in a concentration-dependent manner. Read More

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http://dx.doi.org/10.1111/cts.12616DOI Listing
January 2019

Characteristics of single pivotal trials supporting regulatory approvals of novel non-orphan, non-oncology drugs in EU and US from 2012 to 2016.

Clin Transl Sci 2019 Jan 25. Epub 2019 Jan 25.

H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.

For regulatory approval of a new medicine, the gold standard for demonstration of efficacy has traditionally been a minimum of two positive, adequate, and well-controlled clinical trials. Nevertheless, drugs to treat cancer and rare diseases are usually approved based on a single and often uncontrolled pivotal trial. In contrast, little is known about single pivotal trial approvals for non-orphan, non-oncology drugs. Read More

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http://dx.doi.org/10.1111/cts.12617DOI Listing
January 2019

Predicting efavirenz concentrations in the brain tissue of HIV-infected individuals and exploring their relationship to neurocognitive impairment.

Clin Transl Sci 2019 Jan 24. Epub 2019 Jan 24.

Eshelman School of Pharmacy, Chapel Hill, North Carolina.

Sparse data exist on the penetration of antiretrovirals into brain tissue. In this work we present a framework to use efavirenz pharmacokinetic (PK) data in plasma, cerebrospinal fluid (CSF) and brain tissue of eight rhesus macaques to predict brain tissue concentrations in HIV-infected individuals. We then perform exposure-response analysis with the model-predicted efavirenz area under the concentration-time curve (AUC) and neurocognitive scores collected from a group of 24 HIV-infected participants. Read More

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http://dx.doi.org/10.1111/cts.12620DOI Listing
January 2019
2.110 Impact Factor

How to conduct clinical trials in children: a tutorial.

Clin Transl Sci 2019 Jan 18. Epub 2019 Jan 18.

Children's Mercy Kansas City, Kansas City, MO.

Despite a growing interest in, and commitment to, implementing pediatric clinical trials, approximately one in every five trials in children fails due to inappropriate study design, suboptimal experiment planning, or inadequate participant enrollment. This tutorial, presented from the perspectives of seasoned pediatric investigators, an experienced research coordinator, and an established pediatric clinical trials network, is designed to provide practical guidance for successfully implementing pediatric clinical trials at an academic center, or another comparable institution. This article is protected by copyright. Read More

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http://dx.doi.org/10.1111/cts.12615DOI Listing
January 2019
1 Read

Access to Routinely Collected Clinical Data for Research: A Process Implemented at an Academic Medical Center.

Clin Transl Sci 2019 Jan 18. Epub 2019 Jan 18.

School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

Electronic health records are valuable for clinical and translational research. Institutions must protect patient privacy and comply with applicable regulations while allowing appropriate access to clinical data for research. The processes that investigators must follow to access clinical data can be substantially different at different institutions. Read More

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http://dx.doi.org/10.1111/cts.12614DOI Listing
January 2019
1 Read

Evaluation of Wearable Digital Devices in a Phase I Clinical Trial.

Clin Transl Sci 2019 Jan 11. Epub 2019 Jan 11.

Takeda Pharmaceuticals International, Inc., Cambridge, Massachusetts, USA.

We assessed the performance of two US Food and Drug Administration (FDA) 510(k)-cleared wearable digital devices and the operational feasibility of deploying them to augment data collection in a 10-day residential phase I clinical trial. The Phillips Actiwatch Spectrum Pro (Actiwatch) was used to assess mobility and sleep, and the Vitalconnect HealthPatch MD (HealthPatch) was used for monitoring heart rate (HR), respiratory rate (RR), and surface skin temperature (ST). We measured data collection rates, compared device readouts with anticipated readings and conventional in-clinic measures, investigated data limitations, and assessed user acceptability. Read More

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http://dx.doi.org/10.1111/cts.12602DOI Listing
January 2019
2 Reads

PF-04447943, a Phosphodiesterase 9A Inhibitor, in Stable Sickle Cell Disease Patients: A Phase Ib Randomized, Placebo-Controlled Study.

Clin Transl Sci 2018 Dec 31. Epub 2018 Dec 31.

Pfizer, Inc., Cambridge, Massachusetts, USA.

This phase Ib study randomized patients with stable sickle cell disease (SCD) aged 18-65 years to twice-daily PF-04447943 (a phosphodiesterase 9A inhibitor; 5 or 25 mg) or placebo, with/without hydroxyurea coadministration, for up to 29 days. Blood samples were collected at baseline and various posttreatment time points for assessments of PF-04447943 pharmacokinetics (PKs)/pharmacodynamics (PDs). Change from baseline in potential SCD-related biomarkers was evaluated. Read More

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http://dx.doi.org/10.1111/cts.12604DOI Listing
December 2018
2 Reads

Impact of Insulin Tregopil and Its Permeation Enhancer on Pharmacokinetics of Metformin in Healthy Volunteers: Randomized, Open-Label, Placebo-Controlled, Crossover Study.

Clin Transl Sci 2018 Dec 28. Epub 2018 Dec 28.

Biocon Research Ltd.,, Bengaluru, Karnataka, India.

Oral insulin tregopil (IN-105; a new drug under development) may be coadministered with oral antidiabetic drugs, such as metformin in patients with type 2 diabetes mellitus for optimal glycemic control. IN-105 has sodium caprate excipient, a permeation enhancer, for enhancing absorption in the stomach and increasing bioavailability via an oral route. Sodium caprate may increase bioavailability of metformin by a similar mechanism. Read More

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http://dx.doi.org/10.1111/cts.12609DOI Listing
December 2018
1 Read

The ACCOuNT Consortium: A Model for the Discovery, Translation, and Implementation of Precision Medicine in African Americans.

Clin Transl Sci 2018 Dec 28. Epub 2018 Dec 28.

Department of Pharmacology, Center for Pharmacogenomics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

The majority of pharmacogenomic (PGx) studies have been conducted on European ancestry populations, thereby excluding minority populations and impeding the discovery and translation of African American-specific genetic variation into precision medicine. Without accounting for variants found in African Americans, clinical recommendations based solely on genetic biomarkers found in European populations could result in misclassification of drug response in African American patients. To address these challenges, we formed the Transdisciplinary Collaborative Center (TCC), African American Cardiovascular Pharmacogenetic Consortium (ACCOuNT), to discover novel genetic variants in African Americans related to clinically actionable cardiovascular phenotypes and to incorporate African American-specific sequence variations into clinical recommendations at the point of care. Read More

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http://doi.wiley.com/10.1111/cts.12608
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http://dx.doi.org/10.1111/cts.12608DOI Listing
December 2018
7 Reads

Development of a Modified Score System as Prediction Model for Successful Vaginal Birth After Cesarean Delivery.

Clin Transl Sci 2019 Jan 18;12(1):53-57. Epub 2018 Dec 18.

The Second Department of Obstetrics, Cangzhou Central Hospital, Cangzhou, Yunhe District, Hebei Province, China.

This study was designed to establish a modified prediction score system to improve the safety and success rate of vaginal birth after cesarean delivery (VBAC). We recruited 406 patients (between January 2012 and December 2016) and generated a modified score system in predicting the success rate of VBAC. All patients were required to sign informed consent forms. Read More

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http://dx.doi.org/10.1111/cts.12603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342239PMC
January 2019
1 Read

Tranilast Treatment Attenuates Cerebral Ischemia-Reperfusion Injury in Rats Through the Inhibition of Inflammatory Responses Mediated by NF-κB and PPARs.

Authors:
Yue Zhuo Jun Zhuo

Clin Transl Sci 2018 Dec 10. Epub 2018 Dec 10.

Department of Interventional Radiology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China.

Ischemia-reperfusion injury (IRI) occurs when blood supply returns to tissue after interruption, which is associated with life-threatening inflammatory response. Tranilast is a widely used antiallergic agent in the treatment against bronchial asthma and keloid. To study the function of tranilast, we used IRI in rat models. Read More

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https://onlinelibrary.wiley.com/doi/abs/10.1111/cts.12606
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http://dx.doi.org/10.1111/cts.12606DOI Listing
December 2018
10 Reads

Relative Bioavailability of Orally Dispersible Tablet Formulations of Levo- and Racemic Praziquantel: Two Phase I Studies.

Clin Transl Sci 2019 Jan 21;12(1):66-76. Epub 2018 Dec 21.

Quantitative Pharmacology, Merck KGaA, Darmstadt, Germany.

Orally dispersible tablet (ODT) formulations of levo praziquantel (L-PZQ) and racemic PZQ (rac-PZQ) are being developed to treat schistosomiasis in preschool-aged children. Two crossover studies (N = 32 and 36, respectively) assessed the relative bioavailability of these ODTs vs. Cysticide in adults. Read More

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https://onlinelibrary.wiley.com/doi/abs/10.1111/cts.12601
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http://dx.doi.org/10.1111/cts.12601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342245PMC
January 2019
3 Reads

Considerations for Implementing Precision Therapeutics for Children.

Clin Transl Sci 2018 Dec 5. Epub 2018 Dec 5.

Children's Mercy Hospital, Kansas City, Missouri, USA.

Improving the utilization of pharmacologic agents in the pediatric population yields significant, perhaps life-long, benefits. Genetic factors related to the disposition of a medication or an alteration at the target receptor site contributes to the observed variability of exposure and response between individuals. An additional source of this variability specific to the pediatric population is ontogeny, where age-specific changes during development may require dose adjustments to obtain the same levels of drug exposure and response. Read More

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http://dx.doi.org/10.1111/cts.12607DOI Listing
December 2018
1 Read

Unveiling the Genetic Architecture of Human Disease for Precision Medicine.

Clin Transl Sci 2019 Jan 26;12(1):3-5. Epub 2018 Nov 26.

Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, Arizona, USA.

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http://doi.wiley.com/10.1111/cts.12593
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http://dx.doi.org/10.1111/cts.12593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342243PMC
January 2019
11 Reads

Psychological and Genetic Predictors of Pain Tolerance.

Clin Transl Sci 2018 Nov 23. Epub 2018 Nov 23.

Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, Arizona, USA.

Previous studies have shown associations between genetic polymorphisms and pain tolerance, but psychological evaluations are seldom measured. The objective of this study was to determine the independent effects of demographic, psychological, and genetic predictors of cold noxious pain tolerance. Healthy subjects (n = 89) completed the Pain Catastrophizing Scale (PCS) and Fear of Pain Questionnaire (FPQ-III), underwent genotyping for candidate single nucleotide polymorphisms (SNPs), and completed a cold-pressor test in a 1-2°C water bath for a maximum of 3 minutes. Read More

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http://dx.doi.org/10.1111/cts.12605DOI Listing
November 2018
4 Reads

Evaluation of Drug-Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P-gp Substrates in Patients With an Advanced Solid Tumor.

Clin Transl Sci 2019 Jan 20;12(1):58-65. Epub 2018 Dec 20.

Clinical Science, Clovis Oncology, Inc., Boulder, Colorado, USA.

This phase I study (CO-338-044; NCT02740712), conducted in patients with advanced solid tumors, evaluated the effect of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib on the pharmacokinetics (PK) of caffeine 200 mg, warfarin 10 mg, omeprazole 40 mg, and midazolam 2 mg (cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, and CYP3A substrates; dosed as a cocktail) and digoxin 0.25 mg (P-glycoprotein (P-gp) substrate; dosed separately) without rucaparib and following oral rucaparib 600 mg b.i. Read More

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http://doi.wiley.com/10.1111/cts.12600
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http://dx.doi.org/10.1111/cts.12600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342242PMC
January 2019
20 Reads

Pharmacokinetic and Pharmacodynamic Considerations in the Design of Therapeutic Antibodies.

Clin Transl Sci 2018 Nov 10. Epub 2018 Nov 10.

Preclinical and Translational Pharmacokinetics/Pharmacodynamics, Genentech, South San Francisco, California, USA.

The design and development of therapeutic monoclonal antibodies (mAbs) through optimizing their pharmacokinetic (PK) and pharmacodynamic (PD) properties is crucial to improve efficacy while minimizing adverse events. Many of these properties are interdependent, which highlights the inherent challenges in therapeutic antibody design, where improving one antibody property can sometimes lead to changes in others. Here, we discuss optimization approaches for PK/PD properties of therapeutic mAbs. Read More

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http://dx.doi.org/10.1111/cts.12597DOI Listing
November 2018
1 Read

Comparison of Electrocardiographic Biomarkers for Differentiating Drug-Induced Single vs. Multiple Cardiac Ion Channel Block.

Clin Transl Sci 2018 Nov 10. Epub 2018 Nov 10.

VivaQuant, St. Paul, Minnesota, USA.

Since introduction of the International Conference on Harmonization proarrhythmia guidelines in 2005, no new marketed drugs have been associated with unacceptable risk of Torsade de Pointes. Although cardiac safety improved, these guidelines had the unintended consequence of eliminating potentially beneficial drugs from pipelines early in development. More recently, it has been shown that a corrected QT (QTc) prolonging drug may be safe if it impacts multiple ion channels vs. Read More

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http://dx.doi.org/10.1111/cts.12596DOI Listing
November 2018
2 Reads

Deconstructing the Translational Tower of Babel.

Clin Transl Sci 2018 Nov 9. Epub 2018 Nov 9.

National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.

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http://doi.wiley.com/10.1111/cts.12595
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http://dx.doi.org/10.1111/cts.12595DOI Listing
November 2018
12 Reads

The Biomedical Data Translator Program: Conception, Culture, and Community.

Authors:

Clin Transl Sci 2018 Nov 9. Epub 2018 Nov 9.

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http://doi.wiley.com/10.1111/cts.12592
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http://dx.doi.org/10.1111/cts.12592DOI Listing
November 2018
8 Reads

Toward A Universal Biomedical Data Translator.

Authors:

Clin Transl Sci 2018 Nov 9. Epub 2018 Nov 9.

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http://doi.wiley.com/10.1111/cts.12591
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http://dx.doi.org/10.1111/cts.12591DOI Listing
November 2018
6 Reads

Effects of Common CYP1A2 Genotypes and Other Key Factors on Intraindividual Variation in the Caffeine Metabolic Ratio: An Exploratory Analysis.

Clin Transl Sci 2019 Jan 26;12(1):39-46. Epub 2018 Nov 26.

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA.

The caffeine metabolic ratio is an established marker for cytochrome P450 (CYP) 1A2 activity. Optimal sample size calculation for clinical pharmacokinetic xenobiotic-caffeine interaction studies requires robust estimates of interindividual and intraindividual variation in this ratio. Compared with interindividual variation, factors contributing to intraindividual variation are less defined. Read More

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http://dx.doi.org/10.1111/cts.12598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342244PMC
January 2019
12 Reads

Electrocardiographic Effects of a Supratherapeutic Dose of WCK 2349, a Benzoquinolizine Fluoroquinolone.

Clin Transl Sci 2019 Jan 27;12(1):47-52. Epub 2018 Nov 27.

Wockhardt, Mumbai,, India.

The purpose of this study was to measure the electrocardiographic (ECG) effects of WCK 2349 (the L-alanine ester prodrug of levonadifloxacin) at a supratherapeutic oral dose of 2,600 mg. A total of 48 healthy volunteers were randomized to treatment with placebo, WCK 2349, or oral moxifloxacin, 400 mg, in a crossover-designed thorough QT study. A supratherapeutic mean maximum levonadifloxacin concentration (C ) of 43. Read More

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http://dx.doi.org/10.1111/cts.12594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342240PMC
January 2019
3 Reads

Newborn Metabolic Profile Associated with Hyperbilirubinemia With and Without Kernicterus.

Clin Transl Sci 2019 Jan 28;12(1):28-38. Epub 2018 Oct 28.

Department of Epidemiology and Biostatistics and the California Preterm Birth Initiative, University of California San Francisco, San Francisco, California, USA.

Our objective was to assess the relationship between hyperbilirubinemia with and without kernicterus and metabolic profile at newborn screening. Included were 1,693,658 infants divided into a training or testing subset in a ratio of 3:1. Forty-two metabolites were analyzed using logistic regression (odds ratios (ORs), area under the receiver operating characteristic curve (AUC), 95% confidence intervals (CIs)). Read More

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http://dx.doi.org/10.1111/cts.12590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342241PMC
January 2019
2 Reads

Novel Implementation of Genotype-Guided Proton Pump Inhibitor Medication Therapy in Children: A Pilot, Randomized, Multisite Pragmatic Trial.

Clin Transl Sci 2018 Oct 20. Epub 2018 Oct 20.

Nemours Children's Hospital, Orlando, Florida, USA.

The efficacy of proton pump inhibitor (PPI) medications is highly dependent on plasma concentrations, which varies considerably due to cytochrome P450 (CYP2C19) genetic variation. We conducted a pragmatic, pilot study of CYP2C19 genotype-guided pediatric dosing of PPI medications. Children aged 5-17 years old with gastric-acid-related conditions were randomized to receive either conventional dosing of a PPI or genotype-guided dosing for a total of 12 weeks. Read More

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http://dx.doi.org/10.1111/cts.12589DOI Listing
October 2018
2 Reads

Chimeric Antigen Receptor T-Cells: Successful Translation of the First Cell and Gene Therapy From Bench to Bedside.

Clin Transl Sci 2018 Nov 22;11(6):537-539. Epub 2018 Sep 22.

Center for Clinical and Translational Science, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1111/cts.12586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226113PMC
November 2018
5 Reads
2.110 Impact Factor

NYX-2925, A Novel N-methyl-D-aspartate Receptor Modulator: A First-in-Human, Randomized, Double-blind Study of Safety and Pharmacokinetics in Adults.

Clin Transl Sci 2018 Sep 22. Epub 2018 Sep 22.

Aptinyx Inc., Evanston, Illinois, USA.

NYX-2925, a new chemical entity, acts as a co-agonist to glutamate at the N-methyl-D-aspartate receptor (NMDAR). At low concentrations of endogenous agonists (glycine/D-serine), NYX-2925 partially activates NMDARs, modulating neural pathways relevant for chronic pain. NYX-2925 is being developed for the treatment of chronic pain conditions, including painful diabetic peripheral neuropathy and fibromyalgia. Read More

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http://dx.doi.org/10.1111/cts.12584DOI Listing
September 2018
8 Reads

Assessment of CYP-Mediated Drug Interactions for Evocalcet, a New Calcimimetic Agent, Based on In Vitro Investigations and a Cocktail Study in Humans.

Clin Transl Sci 2019 Jan 24;12(1):20-27. Epub 2018 Oct 24.

Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Evocalcet is a novel calcimimetic agent for the treatment of secondary hyperparathyroidism (SHPT). This study evaluated the effects of evocalcet on inhibition and induction of cytochrome P450 (CYP) isozymes. Although drug interactions arising from reversible inhibition of CYP isozymes by evocalcet were considered unlikely based on the results of in vitro studies and static model analyses, the potential for evocalcet to cause time-dependent inhibition of CYP3A or induction of several CYP isozymes could not be ruled out. Read More

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http://dx.doi.org/10.1111/cts.12588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342237PMC
January 2019
2 Reads

Ceftazidime-Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups.

Clin Transl Sci 2018 Sep 17. Epub 2018 Sep 17.

AstraZeneca, Alderley Park, Macclesfield, UK.

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator-associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well-described by two-compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Read More

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http://doi.wiley.com/10.1111/cts.12585
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http://dx.doi.org/10.1111/cts.12585DOI Listing
September 2018
23 Reads

Evaluation of Pharmacokinetics and Pharmacodynamics of BI 425809, a Novel GlyT1 Inhibitor: Translational Studies.

Clin Transl Sci 2018 Nov 23;11(6):616-623. Epub 2018 Aug 23.

Boehringer Ingelheim International GmbH, Biberach an der Riss, Germany.

BI 425809 is a potent and selective glycine transporter 1 (GlyT1) inhibitor being developed for the treatment of cognitive impairment in Alzheimer disease and schizophrenia. Translational studies evaluated the effects of BI 425809 on glycine levels in rat and human cerebrospinal fluid (CSF). Oral administration of BI 425809 in rats induced a dose-dependent increase of glycine CSF levels from 30% (0. Read More

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http://dx.doi.org/10.1111/cts.12578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226115PMC
November 2018
5 Reads

Evaluation of the Cardiac Safety of Long-Acting Endectocide Moxidectin in a Randomized Concentration-QT Study.

Clin Transl Sci 2018 Nov 19;11(6):582-589. Epub 2018 Sep 19.

Medicines Development for Global Health, Melbourne, Australia.

Potential effects on cardiac repolarization of single doses of moxidectin, a potent long-acting macrocyclic lactone endectocide, were assessed in a concentration-QT (c-QT; exposure-response) study. This double-blind, placebo-controlled, parallel-group study in healthy male volunteers (n = 60) randomized subjects to a single oral dose of moxidectin (4 mg, 8 mg, 16 mg, 24 mg, or 36 mg) or matching placebo. Serial plasma samples for pharmacokinetic (PK) analysis and concurrent triplicate electrocardiogram measurements were taken at baseline and 14 prespecified time points over 72 hours, yielding 900 QT interval-plasma concentration time-matched pairs. Read More

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http://dx.doi.org/10.1111/cts.12583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226119PMC
November 2018
7 Reads

Assessment of Dermal Absorption of Aluminum from a Representative Antiperspirant Formulation Using a Al Microtracer Approach.

Clin Transl Sci 2018 Nov 27;11(6):573-581. Epub 2018 Jul 27.

TNO, Zeist, The Netherlands.

A clinical pharmacokinetic study was performed in 12 healthy women to evaluate systemic exposure to aluminum following topical application of a representative antiperspirant formulation under real-life use conditions. A simple roll-on formulation containing an extremely rare isotope of aluminum ( Al) chlorohydrate (ACH) was prepared to commercial specifications. A Al radio-microtracer was used to distinguish dosed aluminum from natural background, using accelerated mass spectroscopy. Read More

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http://dx.doi.org/10.1111/cts.12579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226111PMC
November 2018
4 Reads

Design and Conduct Considerations for First-in-Human Trials.

Clin Transl Sci 2019 Jan 24;12(1):6-19. Epub 2018 Aug 24.

Non-Clinical and Translational Sciences, Allergan, California, USA.

A milestone step in translational science to transform basic scientific discoveries into therapeutic applications is the advancement of a drug candidate from preclinical studies to initial human testing. First-in-human (FIH) trials serve as the link to advance new promising drug candidates and are conducted primarily to determine the safe dose range for further clinical development. Cross-functional collaboration is essential to ensure efficient and successful FIH trials. Read More

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http://doi.wiley.com/10.1111/cts.12582
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http://dx.doi.org/10.1111/cts.12582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342261PMC
January 2019
10 Reads

No Pharmacokinetic Interactions Between Elbasvir or Grazoprevir and Methadone in Participants Receiving Maintenance Opioid Agonist Therapy.

Clin Transl Sci 2018 Nov 24;11(6):553-561. Epub 2018 Jul 24.

Merck & Co., Inc., Kenilworth, New Jersey, USA.

We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK-8742-P010 and MK-5172-P030) in non-hepatitis C virus (HCV)-infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R- and S-methadone AUC were 1. Read More

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http://dx.doi.org/10.1111/cts.12564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226122PMC
November 2018
13 Reads
2.110 Impact Factor

No Pharmacokinetic Interactions Between Elbasvir or Grazoprevir and Buprenorphine/Naloxone in Healthy Participants and Participants Receiving Stable Opioid Agonist Therapy.

Clin Transl Sci 2018 Nov 24;11(6):562-572. Epub 2018 Jul 24.

Merck & Co., Inc., Kenilworth, New Jersey, USA.

The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single-dose trial in healthy participants. Trial 2 was a multiple-dose trial in participants on BUP/NAL maintenance therapy. Read More

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http://dx.doi.org/10.1111/cts.12565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226112PMC
November 2018
29 Reads
2.110 Impact Factor

Clinical Studies for the Sake of Negative Data: The Proof Is in the Pudding.

Authors:
Sarah Robertson

Clin Transl Sci 2018 Nov 10;11(6):535-536. Epub 2018 Jul 10.

Vertex Pharmaceuticals, Department of Clinical Pharmacology.

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http://dx.doi.org/10.1111/cts.12568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226110PMC
November 2018
2 Reads

Drug-Drug Interaction Study of Apixaban with Cyclosporine and Tacrolimus in Healthy Volunteers.

Clin Transl Sci 2018 Nov 27;11(6):590-596. Epub 2018 Jul 27.

Department of Pharmacologyand Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Apixaban is metabolized by cytochrome P450 (CYP) 3A4 in the liver and intestine, undergoes direct intestinal excretion, and is a substrate to permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. We examined the drug interactions between cyclosporine and tacrolimus (combined inhibitors of CYP3A4, P-gp, and BCRP) with apixaban in 12 healthy adult male volunteers. Apixaban 10 mg was administered orally alone, in combination with 100 mg cyclosporine or 5 mg tacrolimus. Read More

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http://dx.doi.org/10.1111/cts.12580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226116PMC
November 2018
22 Reads

Premarket Approval Through the 510(k) Process: Lessons from the Translation Process of Magnetic Resonance Elastography.

Clin Transl Sci 2018 Sep 27;11(5):447-449. Epub 2018 Jul 27.

Center for Clinical and Translational Research, Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1111/cts.12581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132361PMC
September 2018
2 Reads

The Current Status of Drug Discovery and Development as Originated in United States Academia: The Influence of Industrial and Academic Collaboration on Drug Discovery and Development.

Clin Transl Sci 2018 Nov 30;11(6):597-606. Epub 2018 Jul 30.

Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Academic drug discovery is a vital component to current drug discovery and development environments. In this study, we investigated 798 drug discovery projects that took place between 1991 and 2015 at 36 academic institutions in the United States. The observed success rates of academic drug discovery and development were 75% at phase I, 50% at phase II, 59% at phase III, and 88% at the new drug application/biologics license application (NDA/BLA) phase. Read More

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http://dx.doi.org/10.1111/cts.12577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226120PMC
November 2018
19 Reads

Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery.

Clin Transl Sci 2018 Sep 24;11(5):461-470. Epub 2018 Jul 24.

National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States.

The Assay Guidance Manual (AGM) is an eBook of best practices for the design, development, and implementation of robust assays for early drug discovery. Initiated by pharmaceutical company scientists, the manual provides guidance for designing a "testing funnel" of assays to identify genuine hits using high-throughput screening (HTS) and advancing them through preclinical development. Combined with a workshop/tutorial component, the overall goal of the AGM is to provide a valuable resource for training translational scientists. Read More

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http://doi.wiley.com/10.1111/cts.12570
Publisher Site
http://dx.doi.org/10.1111/cts.12570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132369PMC
September 2018
13 Reads