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Clinical and Translational Science

Stefan Irion
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February 16, 2019: Clinical and Translational Science
Paul Watkins
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...
February 14, 2019: Clinical and Translational Science
Susan Bellaire, Mark Walzer, Tianli Wang, Walter Krauwinkel, Nancy Yuan, Gerard J Marek
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. Nonlinear, more than dose proportional PK were observed for ASP3662 after single-dose administration, particularly at lower doses (≤6 mg); the PK at steady-state were dose proportional, although the time to ASP3662 steady-state was dose dependent at lower doses (≤2 mg)...
February 11, 2019: Clinical and Translational Science
Nina Isoherranen, Rajnikanth Madabushi, Shiew-Mei Huang
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...
February 11, 2019: Clinical and Translational Science
Kenrick M Semple, Carlos M Gonzaléz, Melissa Zarr, Jose' Austin, Vikram Patel, Kristina E Howard
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. In contrast, some non-human primates have cross-reactive FcR however, their cellular expression and function may differ from humans...
February 9, 2019: Clinical and Translational Science
Wei Yin, Mark Rogge
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. These targets include over 10,000 proteins in the human genome that have hitherto been considered undruggable by small molecules and protein therapeutics...
February 1, 2019: Clinical and Translational Science
Klaus Romero, Daniela Conrado, Jackson Burton, Timothy Nicholas, Vikram Sinha, Sreeraj Macha, Malidi Ahamadi, Jesse Cedarbaum, John Seibyl, Kenneth Marek, Peter Basseches, Derek Hill, Ed Somer, Jill Gallagher, David T Dexter, Arthur Roach, Diane Stephenson
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)...
February 1, 2019: Clinical and Translational Science
Savannah J McFeely, Tasha K Ritchie, Jingjing Yu, Anna Nordmark, René H Levy, Isabelle Ragueneau-Majlessi
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.1-3 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...
February 1, 2019: Clinical and Translational Science
Varun Garg, Jinshan Shen, Chonghua Li, Sagar Agarwal, Asfiha Gebre, Sarah Robertson, Jiayin Huang, Linda Han, Licong Jiang, Kristin Stephan, Linda T Wang, Julie Lekstrom-Himes
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...
January 29, 2019: Clinical and Translational Science
Faith Stevison, Mika Kosaka, Jane R Kenny, Susan Wong, Cathryn Hogarth, John K Amory, Nina Isoherranen
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. The in vitro data predicted ~50% decrease in CYP2D6 activity in humans after dosing with 13cisRA. However, the geometric mean AUC ratio for dextromethorphan between treatment and control was 0...
January 25, 2019: Clinical and Translational Science
Anne Vinther Morant, Vivien Jagalski, Henrik Tang Vestergaard
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. Between 2012 and 2016, 23 novel therapeutic drugs were approved by the FDA and/or the EMA for 27 non-orphan, non-oncology indications each based on a single pivotal trial...
January 25, 2019: Clinical and Translational Science
Nithya Srinivas, Sarah Beth Joseph, Kevin Robertson, Laura P Kincer, Prema Menezes, Lourdes Adamson, Amanda P Schauer, Kimberly H Blake, Nicole White, Craig Sykes, Paul Luciw, Joseph J Eron, Alan Forrest, Richard Price, Serena Spudich, Ronald Swanstrom, Angela Dm Kashuba
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. Adult rhesus macaques were dosed daily with 200 mg efavirenz (as part of a four-drug regimen) for ten days...
January 24, 2019: Clinical and Translational Science
Valentina Shakhnovich, Christoph P Hornik, Gregory L Kearns, Jaylene Weigel, Susan M Abdel-Rahman
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...
January 18, 2019: Clinical and Translational Science
Susan C Guerrero, Sujatha Sridhar, Cynthia Edmonds, Christina F Solis, Jiajie Zhang, David D McPherson, Elmer V Bernstam
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. In this paper, we describe the process developed at our institution that has been active for five years and was used to satisfy over 200 requests for access to identified clinical data, usually within one day for internal requests and three days for visiting researchers...
January 18, 2019: Clinical and Translational Science
Elena S Izmailova, Ian L McLean, Gaurav Bhatia, Greg Hather, Matthew Cantor, David Merberg, Eric D Perakslis, Christopher Benko, John A Wagner
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...
January 11, 2019: Clinical and Translational Science
Robert J Charnigo, David Beidler, Denis Rybin, Debra D Pittman, Beesan Tan, Jo Howard, Alan D Michelson, Andrew L Frelinger, Nicholas Clarke
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. Of 30 patients, 15 received hydroxyurea and 28 completed the study...
December 31, 2018: Clinical and Translational Science
Anand Khedkar, Harold Lebovitz, Alexander Fleming, Alan Cherrington, Vinu Jose, Sandeep N Athalye, Ashwini Vishweswaramurthy
Oral insulin tregopil (IN-105; new drug under development) may be co-administered with oral anti-diabetic drugs such as metformin in type 2 diabetes mellitus patients for optimal glycemic control. IN-105 has sodium caprate excipient, a permeation enhancer, for enhancing absorption in stomach and increasing bioavailability via oral route. Sodium caprate may increase bioavailability of metformin by a similar mechanism. Therefore, it was necessary to study effect of IN-105 on pharmacokinetics of metformin. In this randomized, open-label, cross-over study, metformin was administered to healthy volunteers receiving IN-105/placebo under fed/fasting conditions...
December 28, 2018: Clinical and Translational Science
Paula N Friedman, Mohammed Shaazuddin, Li Gong, Robert L Grossman, Arthur F Harralson, Teri E Klein, Norman H Lee, Doriane C Miller, Edith A Nutescu, Travis J O'Brien, Peter H O'Donnell, Kevin J O'Leary, Matthew Tuck, David O Meltzer, Minoli A Perera
The majority of pharmacogenomic 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 Americans patients. To address these challenges, we formed the Transdisciplinary Collaborative Center (TCC), ACCOuNT (African American Cardiovascular Pharmacogenetic Consortium), 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...
December 28, 2018: Clinical and Translational Science
Yan-Ping Xing, Xin-Ying Qi, Xue-Zhen Wang, Feng-Zhen Yang
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. 87.2% of patients had successful VBAC and 12.8% patients had repeated cesarean section. We conducted multivariable logistic regression, and found seven variables that were associated with VBAC success, including previous primary indication of cesarean delivery [odds ratio (OR) 2...
December 10, 2018: Clinical and Translational Science
Yue Zhuo, Jun Zhuo
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 anti-allergic agent in the treatment against bronchial asthma and keloid. To study the function of tranilast, we used IRI rat model. The brain tissues of IRI rats with or without tranilast treatment were collected. Neuronal apoptosis in the brain was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and pro-inflammatory cytokine levels were measured by qRT-PCR and enzyme-linked immunosorbent assay...
December 10, 2018: Clinical and Translational Science
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