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Clinical and Translational Science

Rianne de Ligt, Esther van Duijn, Dimitri Grossouw, Sieto Bosgra, Jacobus Burggraaf, Albert Windhorst, Pierre A M Peeters, Gerrit A van der Luijt, Camilla Alexander-White, Wouter H J Vaes
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 (26 Al) chlorohydrate (ACH) was prepared to commercial specifications. A 26 Al radio-microtracer was used to distinguish dosed aluminum from natural background, using accelerated mass spectroscopy. The 26 Al citrate was administered intravenously (i...
July 27, 2018: Clinical and Translational Science
Jie Shen, Brandon Swift, Richard Mamelok, Samuel Pine, John Sinclair, Mayssa Attar
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. The aim of this publication is to serve as a tutorial for conducting FIH trials, for both small molecule and biological drug candidates, with topics covering regulatory requirements, preclinical safety testing, study design considerations, safety monitoring, biomarker assessment, and global considerations...
July 26, 2018: Clinical and Translational Science
Hwa-Ping Feng, Zifang Guo, Luzelena Caro, William L Marshall, Fang Liu, Deborah Panebianco, Pavan Vaddady, Christina Reitmann, Patricia Jumes, Dennis Wolford, Iain Fraser, Robert Valesky, Monika Martinho, Joan R Butterton, Marian Iwamoto, Lynn Webster, Wendy W Yeh
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 AUC0-24 were 1.03 (90% confidence interval (CI), 0.92-1.15) and 1.09 (90% CI, 0...
July 24, 2018: Clinical and Translational Science
Hwa-Ping Feng, Zifang Guo, Luzelena Caro, William L Marshall, Fang Liu, Deborah Panebianco, Pavan Vaddady, April Barbour, Christina Reitmann, Patricia Jumes, Jocelyn Gilmartin, Dennis Wolford, Robert Valesky, Monika Martinho, Joan R Butterton, Marian Iwamoto, Iain Fraser, Lynn Webster, Wendy W Yeh
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. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC0-∞ were 0.98 (0...
July 24, 2018: Clinical and Translational Science
Sarah Robertson
No abstract text is available yet for this article.
July 10, 2018: Clinical and Translational Science
Babar Bashir, Douglas F Stickle, Inna Chervoneva, Walter K Kraft
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. Co-administration with cyclosporine resulted in increase in apixaban maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC(0-tlast) ) with associated geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of 143% (112, 183) and 120% (97, 148), respectively...
July 3, 2018: Clinical and Translational Science
Jaime A Aponte Ortiz, Ewa Konik, Elizabeth C Eckert, Kay M Pepin, Alexandra Greenberg-Worisek
No abstract text is available yet for this article.
July 3, 2018: Clinical and Translational Science
Tohru Takebe, Ryoka Imai, Shunsuke Ono
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 US. The observed success rates of academic drug discovery and development were 75% at Phase 1, 50% at Phase 2, 59% at Phase 3, and 88% at the new drug application/biologics license application (NDA/BLA) phase. These results were similar to the corresponding success rates of the pharmaceutical industry...
June 25, 2018: Clinical and Translational Science
Nathan P Coussens, G Sitta Sittampalam, Rajarshi Guha, Kyle Brimacombe, Abigail Grossman, Thomas D Y Chung, Jeffrey R Weidner, Terry Riss, O Joseph Trask, Douglas Auld, Jayme L Dahlin, Viswanath Devanaryan, Timothy L Foley, James McGee, Steven D Kahl, Stephen C Kales, Michelle Arkin, Jonathan Baell, Bruce Bejcek, Neely Gal-Edd, Marcie Glicksman, Joseph V Haas, Philip W Iversen, Marilu Hoeppner, Stacy Lathrop, Eric Sayers, Hanguan Liu, Bart Trawick, Julie McVey, Vance P Lemmon, Zhuyin Li, Owen McManus, Lisa Minor, Andrew Napper, Mary Jo Wildey, Robert Pacifici, William W Chin, Menghang Xia, Xin Xu, Madhu Lal-Nag, Matthew D Hall, Sam Michael, James Inglese, Anton Simeonov, Christopher P Austin
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...
June 7, 2018: Clinical and Translational Science
Jeffrey L Woodhead, Franziska Paech, Martina Maurer, Marc Engelhardt, Anne H Schmitt-Hoffmann, Jochen Spickermann, Simon Messner, Mathias Wind, Anne-Therese Witschi, Stephan Krähenbühl, Scott Q Siler, Paul B Watkins, Brett A Howell
Elevations of liver enzymes have been observed in clinical trials with BAL30072, a novel antibiotic. In vitro assays have identified potential mechanisms for the observed hepatotoxicity, including electron transport chain (ETC) inhibition and reactive oxygen species (ROS) generation. DILIsym, a quantitative systems pharmacology (QSP) model of drug-induced liver injury, has been used to predict the likelihood that each mechanism explains the observed toxicity. DILIsym was also used to predict the safety margin for a novel BAL30072 dosing scheme; it was predicted to be low...
June 7, 2018: Clinical and Translational Science
Valérie Cosson, Franziska Schaedeli-Stark, Mona Arab-Alameddine, Clarisse Chavanne, Elena Guerini, Michael Derks, Navita L Mallalieu
Dizziness, the most frequently observed adverse event in patients with major depressive disorder, was observed with basimglurant, a selective, orally active metabotropic glutamate receptor subtype 5 negative allosteric modulator. The potential relationship between dizziness and basimglurant exposure was explored. The pharmacokinetics of basimglurant was characterized with nonlinear mixed effects modeling using data from 288 trial participants enrolled in five clinical trials. The pharmacokinetics of basimglurant after daily oral administration of a modified release formulation was best described by a two-compartment disposition model with a transit compartment, lag time for the absorption, and first-order elimination...
June 7, 2018: Clinical and Translational Science
Meric Ovacik, Kedan Lin
The tutorial introduces the readers to the fundamentals of antibody pharmacokinetics (PK) in the context of drug development. Topics covered include an overview of antibody development, PK characteristics and the application of antibody PK/Pharmacodynamics (PD) in research and development decision-making. We also discuss the general considerations for planning a nonclinical PK program and describe the types of PK studies that should be performed during early development of monoclonal antibodies (mAbs). This article is protected by copyright...
June 7, 2018: Clinical and Translational Science
Abdul Basit, John K Amory, Bhagwat Prasad
Development of an oral testosterone therapy has proven extremely challenging because of extensive and variable first-pass metabolism. We investigated the in vivo metabolism of testosterone with increasing oral doses of testosterone, both alone and with the co-administration of dutasteride (5α-reductase inhibitor) by liquid-chromatography tandem mass spectrometry (LC-MS/MS). In eugonadal men prior to dosing, the circulating concentration of testosterone, androstenedione, etiocholanolone-glucuronide, and androsterone-glucuronide was 8...
June 7, 2018: Clinical and Translational Science
Jeremiah Hadwen, Faraz Farooq Luke Witherspoon, Sarah Schock, Kevin Mongeon, Alex MacKenzie
Duchenne muscular dystrophy is a recessive X-linked disease characterized by progressive muscle wasting; cardiac or respiratory failure causes death in most patients by the third decade.  The disease is caused by mutations in the dystrophin gene that lead to a loss of functional dystrophin protein. Although there are currently few treatments for Duchenne muscular dystrophy, previous reports have shown that upregulating the dystrophin paralog utrophin in Duchenne muscular dystrophy mouse models is a promising therapeutic strategy...
June 7, 2018: Clinical and Translational Science
Tao Liu, Vijay Ivaturi, Philip Sabato, Jogarao V S Gobburu, Jacqueline M Greer, John J Wright, B Douglas Smith, Keith W Pratz, Michelle A Rudek
Sorafenib administered at the approved dose continuously is not tolerated long-term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax ) model...
July 2018: Clinical and Translational Science
Yang He, Dong-Hui Ao, Xiao-Qing Li, Shan-Shan Zhong, Rong A, Yang-Yang Wang, Ya-Juan Xiang, Bao-Lei Xu, Ting-Ting Yang, Xu-Guang Gao, Guang-Zhi Liu
As a proinflammatory cytokine, CD137 (4-1BB, TNFRSF9) is present in membrane-bound and soluble forms. Increased expression of CD137 was recently found in T cells in human atherosclerotic plaques. However, the exact role of CD137 in ischemic stroke is not clear. In this study we analyzed the protein levels of soluble CD137 (sCD137) and the expression of CD137 on CD4+ T cells in the peripheral blood of patients with acute atherothrombotic stroke by using the cytometry beads array (CBA) and flow cytometry. Within 24 hours of onset, the stroke patients showed elevated levels of sCD137 (2...
July 2018: Clinical and Translational Science
Lynn D Hudson, Rebecca D Kush, Eileen Navarro Almario, Nathalie Seigneuret, Tammy Jackson, Barbara Jauregui, David Jordan, Ronald Fitzmartin, F Liz Zhou, James K Malone, Jose Galvez, Lauren B Becnel
No abstract text is available yet for this article.
July 2018: Clinical and Translational Science
Jessica K Juarez, Joseph C Wenke, Jessica C Rivera
No abstract text is available yet for this article.
July 2018: Clinical and Translational Science
Michael J Jelinek, Sang Mee Lee, Alicia Wyche Okpareke, Claudia Wing, Jay L Koyner, Patrick T Murray, Walter M Stadler, Peter H O' Donnell
Acute kidney injury (AKI) limits cisplatin use. We tested whether urine cystatin C (uCyC) and neutrophil gelatinase-associated lipocalin (uNGAL) can preidentify patients at risk for AKI. Patients initiating cisplatin-based chemotherapy were prospectively enrolled. uNGAL/uCyC were measured pre/post-cisplatin administration and compared with serum creatinine (sCr). AKI was defined as sCr increase ≥50% or ≥0.3 mg/dL above baseline. In all, 102 patients were enrolled; 95 provided evaluable data. Twenty-five patients developed AKI...
July 2018: Clinical and Translational Science
Pascale Fisel, Elke Schaeffeler, Matthias Schwab
The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge...
July 2018: Clinical and Translational Science
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