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


Influence of rifampin-mediated OATP1B1/1B3 inhibition on the pharmacokinetics of clazosentan.

Clin Transl Sci 2019 Apr 20. Epub 2019 Apr 20.

Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.

Clazosentan is a selective endothelin A receptor antagonist in development for prevention and treatment of vasospasm post subarachnoid hemorrhage. It is a substrate of organic-anion-transporting polypeptide (OATP)1B1/1B3 based on preclinical data. This randomized, double-blind, two-period cross-over study investigated the pharmacokinetics, safety, and tolerability of an intravenous (i. Read More

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http://dx.doi.org/10.1111/cts.12639DOI Listing

Quantitative Systems Pharmacology Model of Chimeric Antigen Receptor T-Cell Therapy.

Clin Transl Sci 2019 Apr 16. Epub 2019 Apr 16.

College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA.

Chimeric antigen receptor T-cell (CART) therapy is a new and promising cancer therapy. However, severe toxicity due to cytokine release syndrome (CRS) in CART-treated patients highlighted the possible danger of this new therapy. Disease burden and CART doses are the potential factors associated with CRS but the detail relationships between these factors and the severity of the CRS remain largely unknown. Read More

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https://onlinelibrary.wiley.com/doi/abs/10.1111/cts.12636
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http://dx.doi.org/10.1111/cts.12636DOI Listing
April 2019
2 Reads
2.110 Impact Factor

Organic Anion Transporter Polypeptide 1B1 Polymorphism Modulates the Extent of Drug-Drug Interaction and Associated Biomarker Levels in Healthy Volunteers.

Clin Transl Sci 2019 Apr 13. Epub 2019 Apr 13.

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA.

Understanding transporter-mediated drug-drug interactions is an integral part of risk assessment in drug development. Recent studies support the use of hexadecanedioate (HDA), tetradecanedioate (TDA), coproporphyrin (CP)-I, and CP-III as clinical biomarkers for evaluating organic anion-transporting polypeptide (OATP)1B1 (SLCO1B1) inhibition. The current study investigated the effect of OATP1B1 genotype c. Read More

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https://onlinelibrary.wiley.com/doi/abs/10.1111/cts.12625
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http://dx.doi.org/10.1111/cts.12625DOI Listing
April 2019
4 Reads

Interaction Between Sex and Organic Anion-Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib-N-Oxide and Regorafenib-Glucuronide in Mice.

Clin Transl Sci 2019 Apr 6. Epub 2019 Apr 6.

Division of Pharmaceutics and Pharmaceutical Chemistry and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.

Regorafenib, a multikinase inhibitor used in the treatment of various solid tumors, undergoes extensive uridine 5'-diphosphate glucuronosyltransferase (Ugt)1a9-mediated glucuronidation to form regorafenib-N-β-glucuronide (M7; RG), but the contribution of hepatic uptake transporters, such as organic anion-transporting polypeptide (Oatp)1b2, to the pharmacokinetics of regorafenib remains poorly understood. Using NONMEM-based, population-based, parent-metabolite modeling, we found that Oatp1b2 and sex strongly impact the systemic exposure to RG in mice receiving oral regorafenib. Metabolic studies revealed that the liver microsomal expression of cytochrome P450 (Cyp)3a11 is twofold lower in female mice, whereas Ugt1a9 levels and function are not sex dependent. Read More

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https://onlinelibrary.wiley.com/doi/abs/10.1111/cts.12630
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http://dx.doi.org/10.1111/cts.12630DOI Listing
April 2019
4 Reads

Exposure-Response Modeling and Simulation of Progression-Free Survival and Adverse Events of Sorafenib Treatment in Patients With Advanced Thyroid Cancer.

Clin Transl Sci 2019 Mar 28. Epub 2019 Mar 28.

Bayer AG, Berlin, Germany.

Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In the phase III DECISION trial in patients with DTC, sorafenib exposure and the incidence of some adverse events (AEs) were higher than in previous trials; therefore, we analyzed exposure-response relationships, including progression-free survival (PFS) and selected AEs in patients with DTC. A novel, stratified prediction-corrected visual predictive check (pc-VPC) was developed to show robustness of the exposure-response relationships. Read More

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http://dx.doi.org/10.1111/cts.12634DOI Listing
March 2019
1 Read

Regulatory Affairs 101: Introduction to Investigational New Drug Applications and Clinical Trial Applications.

Clin Transl Sci 2019 Mar 18. Epub 2019 Mar 18.

Denali Therapeutics Inc., South San Francisco, CA, USA.

Testing novel drugs on fellow human beings is fraught with potential ethical concerns; however, developing drugs to treat the wide spectrum of human diseases and disorders is a moral imperative. How do we best navigate the balance between protecting the individual vs. the greater good? Global government regulatory bodies are accountable for ensuring that medical experiments on human subjects are appropriately justified and subject to close oversight. Read More

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http://dx.doi.org/10.1111/cts.12635DOI Listing
March 2019
1 Read

Pharmacokinetics of Anakinra in Subjects of Heavier vs. Lighter Body Weights.

Clin Transl Sci 2019 Mar 18. Epub 2019 Mar 18.

Amgen Inc., Thousand Oaks, California, USA.

This trial (20010168) studied how body weight (BW) and body mass index (BMI) influenced the pharmacokinetics (PK) of anakinra. Subjects (n = 32) were assigned to four groups (n = 8) according to BW and BMI. Randomization was according to a four-treatment, four-period, four-sequence crossover design. Read More

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http://dx.doi.org/10.1111/cts.12622DOI Listing

Exposure-Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status.

Clin Transl Sci 2019 Mar 18. Epub 2019 Mar 18.

MedImmune, Gaithersburg, Maryland, USA.

Tremelimumab, an anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody that enhances T-cell activation, was evaluated in a randomized, double-blind, placebo-controlled, phase IIb study (NCT01843374) in patients with unresectable malignant mesothelioma. The study demonstrated no clinically meaningful differences in overall survival (OS). The objective of this analysis was to evaluate the relationship of exposure with OS. Read More

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http://dx.doi.org/10.1111/cts.12633DOI Listing
March 2019
1 Read

Fecal Microbiota Transplantation: An Ambiguous Translational Pathway for a Promising Treatment.

Clin Transl Sci 2019 Mar 12. Epub 2019 Mar 12.

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

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http://dx.doi.org/10.1111/cts.12621DOI Listing

From Molecule to Patient: Building Bridges Not Walls with Clinical Pharmacology and Translational Medicine.

Authors:
Naoto Uemura

Clin Transl Sci 2019 Mar 18;12(2):84. Epub 2019 Mar 18.

Department of Clinical Pharmacology and Therapeutics, Oita University Faculty of Medicine, General Clinical Research Center, and Clinical Pharmacology Center, Oita University Hospital, Yufu-shi, Oita, Japan.

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http://dx.doi.org/10.1111/cts.12628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440562PMC

VKORC1 and Novel CYP2C9 Variation Predict Warfarin Response in Alaska Native and American Indian People.

Clin Transl Sci 2019 Mar 1. Epub 2019 Mar 1.

Department of Pharmacy, University of Washington, Seattle, Washington, USA.

Alaska Native and American Indian (AN/AI) people have unique pharmacogene variation that may affect warfarin disposition and therapeutic response. We performed targeted genotyping for cytochrome P450 (CYP)2C9, vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1), CYP4F2, CYP4F11, and gamma-glutamyl carboxylase (GGCX) variants in AN/AI people receiving warfarin. The primary outcome was stable warfarin dose, defined as one dose, and associated international normalized ratio within the target range, at least 6 months after starting therapy, with two matching doses at least 2 weeks apart. Read More

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http://dx.doi.org/10.1111/cts.12611DOI Listing
March 2019
2 Reads

Determinants of Cytochrome P450 2D6 mRNA Levels in Healthy Human Liver Tissue.

Clin Transl Sci 2019 Mar 1. Epub 2019 Mar 1.

Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.

Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme that exhibits large interindividual variability. Recent studies suggest that differential transcriptional regulation of CYP2D6 in part may be responsible for the variability. In this study, we characterized potential determinants of CYP 2D6  transcript levels in healthy human liver tissue samples (n = 115), including genetic polymorphisms in CYP2D6 and the genes encoding transcription regulators for CYP2D6 expression; mRNA expression of the transcription factors and their known target genes; and hepatic levels of bile acids and retinoids, agents that modulate the expression/activity of the transcription factors. Read More

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http://dx.doi.org/10.1111/cts.12632DOI Listing
March 2019
3 Reads

Use of Titration as a Therapeutic Individualization Strategy: An Analysis of Food and Drug Administration-Approved Drugs.

Clin Transl Sci 2019 Feb 21. Epub 2019 Feb 21.

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

Selecting a dose regimen that is both safe and effective for patients is one of the most critical elements of a successful drug development program. Titrating the dose regimen of a drug based on patient response may help to identify safe and effective dosages at the individual patient level. Therefore, we quantified and characterized the use of response-guided titration for drugs recently approved by the US Food and Drug Administration (FDA) to assess how frequently this dosing strategy is used and how titration regimens are evaluated during drug development. Read More

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http://dx.doi.org/10.1111/cts.12626DOI Listing
February 2019

Cell Therapies for Parkinson's Disease.

Authors:
Stefan Irion

Clin Transl Sci 2019 Mar 16;12(2):95-97. Epub 2019 Feb 16.

BlueRock Therapeutics, New York, New York, USA.

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http://dx.doi.org/10.1111/cts.12612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440559PMC

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

Authors:
Paul B Watkins

Clin Transl Sci 2019 Mar;12(2):122-129

Institute for Drug Safety Sciences, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

The drug-induced liver injury (DILI)-sim Initiative is a public-private partnership involving scientists from industry, academia, and the US Food and Drug Administration (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 hepatotoxicity 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 noncompetitive inhibition of bile acid transporters. Read More

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http://dx.doi.org/10.1111/cts.12629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440570PMC
March 2019
1 Read

Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Healthy Young and Elderly Subjects.

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

Astellas Pharma, Inc., Northbrook, Illinois, USA.

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 (PKs), and pharmacodynamics (PDs) 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://doi.wiley.com/10.1111/cts.12618
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http://dx.doi.org/10.1111/cts.12618DOI Listing
February 2019
2 Reads

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

Clin Transl Sci 2019 Mar;12(2):113-121

Office of Clinical Pharmacology (OCP), Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA), Silver Spring, Maryland, 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 (i) the US Food and Drug Administration (FDA) Office of Clinical Pharmacology's continuing efforts in developing quantitative clinical pharmacology models (disease, drug, and clinical trial models) to advance MIDD, (ii) 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 (iii) 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440571PMC
March 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, US Food and Drug Administration, Silver Spring, Maryland, 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 cytotoxicity (CDC) cell lysis and antibody-dependent cell-mediated cytotoxicity. Human Fc receptors (FcRs) 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 Mar 27;12(2):98-112. Epub 2019 Feb 27.

Quantitative Clinical Pharmacology, Takeda Pharmaceutical Company Ltd, Cambridge, Massachusetts, 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 is emerging as an established, validated class of drugs that can modulate a multitude of genetic targets. Read More

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http://doi.wiley.com/10.1111/cts.12624
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http://dx.doi.org/10.1111/cts.12624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440575PMC
March 2019
3 Reads

Molecular Neuroimaging of the Dopamine Transporter as a Patient Enrichment Biomarker for Clinical Trials for Early Parkinson's Disease.

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

Critical Path Institute, Tucson, Arizona, USA.

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 (EMA) Committee for Medical Products for Human Use (CHMP) for the use of baseline dopamine transporter neuroimaging for patient selection in early Parkinson's disease clinical trials. This paper describes the regulatory science strategy to achieve this goal. CPP is an international consortium of three Parkinson's charities and nine pharmaceutical partners, coordinated by the 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, Washington, USA.

Organic anion transporting polypeptides (OATPs) 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. Although 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 DDI 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
7 Reads

Does In Vitro Cytochrome P450 Downregulation 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, USA.

All-trans-retinoic acid (atRA) downregulates cytochrome P450 (CYP)2D6 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 (DDIs). The retinoids 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 the European Union and United States from 2012-2016.

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

H. Lundbeck A/S, 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
2 Reads

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, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Sparse data exist on the penetration of antiretrovirals into brain tissue. In this work, we present a framework to use efavirenz (EFV) 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 EFV 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
1 Read
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, Missouri, USA.

Despite a growing interest in, and commitment to, implementing pediatric clinical trials, approximately one in every five trials in children fails because of 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. Read More

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http://dx.doi.org/10.1111/cts.12615DOI Listing
January 2019
2 Reads

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 2019 Mar 31;12(2):180-188. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440678PMC
March 2019
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
3 Reads

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
12 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 2019 Mar 31;12(2):196-202. Epub 2018 Dec 31.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440572PMC
March 2019
14 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 2019 Mar 25;12(2):140-150. Epub 2019 Jan 25.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440566PMC
March 2019
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
15 Reads

Psychological and Genetic Predictors of Pain Tolerance.

Clin Transl Sci 2019 Mar 31;12(2):189-195. Epub 2018 Dec 31.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440569PMC
March 2019
13 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
29 Reads

Pharmacokinetic and Pharmacodynamic Considerations in the Design of Therapeutic Antibodies.

Clin Transl Sci 2019 Mar 27;12(2):130-139. Epub 2018 Dec 27.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440574PMC
March 2019
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 2019 Mar 9;12(2):85. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440561PMC
March 2019
15 Reads

Toward A Universal Biomedical Data Translator.

Authors:

Clin Transl Sci 2019 Mar 9;12(2):86-90. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440568PMC
March 2019
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
19 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
4 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
3 Reads

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

Clin Transl Sci 2019 Mar 20;12(2):172-179. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440564PMC
March 2019
6 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
9 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 2019 Mar 29;12(2):164-171. Epub 2018 Sep 29.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440576PMC
March 2019
14 Reads