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Clinical and Translational Science

A W Krug, P Vaddady, R A Railkar, B J Musser, J Cote, Agh Ederveen, D G Krefetz, E DeNoia, A L Free, L Morrow, M V Chakravarthy, E Kauh, D A Tatosian, P A Kothare
GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing...
July 20, 2017: Clinical and Translational Science
S Hu, A F Leblanc, A A Gibson, K W Hong, J Y Kim, L J Janke, L Li, A Vasilyeva, D B Finkelstein, J A Sprowl, D H Sweet, E Schlatter, G Ciarimboli, Jhm Schellens, S D Baker, N Pabla, A Sparreboom
Cisplatin is among the most widely used anticancer drugs and known to cause a dose-limiting nephrotoxicity, which is partially dependent on the renal uptake carrier OCT2. We here report a previously unrecognized, OCT2-independent pathway of cisplatin-induced renal injury that is mediated by the organic anion transporters OAT1 and OAT3. Using transporter-deficient mouse models, we found that this mechanism regulates renal uptake of a mercapturic acid metabolite of cisplatin that acts as a precursor of a potent nephrotoxin...
July 8, 2017: Clinical and Translational Science
T Burt, D MacLeod, K Lee, A Santoro, D K DeMasi, T Hawk, M Feinglos, M Rowland, R J Noveck
Intra-target microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits...
July 8, 2017: Clinical and Translational Science
M D Joshi, J N O'Donnell, N Venkatesan, J Chang, H Nguyen, N J Rhodes, G Pais, R L Chapman, B Griffin, M H Scheetz
A translational need exists to understand and predict vancomycin-induced kidney toxicity. We describe: (i) a vancomycin high-performance liquid chromatography (HPLC) method for rat plasma and kidney tissue homogenate; (ii) a rat pharmacokinetic (PK) study to demonstrate utility; and (iii) a catheter retention study to enable future preclinical studies. Rat plasma and pup kidney tissue homogenate were analyzed via HPLC for vancomycin concentrations ranging from 3-75 and 15.1-75.5 μg/mL, respectively, using a Kinetex Biphenyl column and gradient elution of water with 0...
July 4, 2017: Clinical and Translational Science
Koichi Miyazaki, Yasunori Sato, Hideki Hanaoka, Yoshiaki Uyama
When global clinical trials are carried out, it is important to consider the influence of racial and ethnic differences on the outcome. From this viewpoint, global clinical trials in East Asia, where racial differences are estimated to be small, are now attracting close attention. Under such circumstances, we conducted a survey using the data registered with to investigate the status of participation of East Asian countries in global clinical trials and differences in the regions selected for drug development between Japanese enterprises and non-Japanese enterprises...
July 4, 2017: Clinical and Translational Science
T Burt, K S Button, Hhz Thom, R J Noveck, M R Munafò
The "false-negatives" of clinical development are the effective treatments wrongly determined ineffective. Statistical errors leading to "false-negatives" are larger than those leading to "false-positives," especially in typically underpowered early-phase trials. In addition, "false-negatives" are usually eliminated from further testing, thereby limiting the information available on them. We simulated the impact of early-phase power on economic productivity in three developmental scenarios. Scenario 1, representing the current status quo, assumed 50% statistical power at phase II and 90% at phase III...
July 4, 2017: Clinical and Translational Science
K Erb-Zohar, D Kropeit, J Scheuenpflug, H-P Stobernack, Egj Hulskotte, A van Schanke, H Zimmermann, H Rübsamen-Schaeff
Letermovir is a novel antiviral in clinical development for prophylaxis against human cytomegalovirus in immunocompromised transplant recipients. This two-part, single-center, randomized, double-blind, placebo-controlled trial evaluated the safety and pharmacokinetics of a hydroxypropyl β-cyclodextrin (HPβCD)-based intravenous formulation of letermovir in healthy women. Subjects received single, escalating doses (120, 240, 480, 720, and 960 mg; 6 letermovir, 2 placebo per cohort) or multiple, once-daily doses (240 mg; 8 letermovir, 4 placebo) of HPβCD-formulated letermovir and the associated pharmacokinetic profiles and adverse events were investigated...
July 4, 2017: Clinical and Translational Science
A Chapron, D D Shen, B R Kestenbaum, C Robinson-Cohen, J Himmelfarb, C K Yeung
Drug-dose modification in chronic kidney disease (CKD) utilizes glomerular filtration rate (GFR) with the implicit assumption that multiple renal excretory processes decline in parallel as CKD progresses. We compiled published pharmacokinetic data to evaluate if GFR predicts renal clearance changes as a function of CKD severity. For each drug, we calculated ratio of renal clearance to filtration clearance (Rnf). Of 21 drugs with Rnf >0.74 in subjects with GFR >90 mL/min (implying filtration and secretion), 13 displayed significant change in Rnf vs...
July 4, 2017: Clinical and Translational Science
H-P Feng, P Vaddady, Z Guo, F Liu, D Panebianco, V Levine, L Caro, J R Butterton, M Iwamoto, W W Yeh
Use of agents to suppress gastric acid secretion is common among patients with hepatitis C virus (HCV) infection. The aims of this open-label, three-period, fixed-sequence study were to evaluate the effect of famotidine and pantoprazole on the pharmacokinetics and safety of elbasvir/grazoprevir fixed-dose combination (FDC) in 16 healthy subjects. Elbasvir and grazoprevir each exhibited similar pharmacokinetics following single-dose administration of elbasvir/grazoprevir with or without famotidine or pantoprazole...
June 17, 2017: Clinical and Translational Science
E Dubcenco, P M Beers-Block, L P Kim, P Schotland, J G Levine, C A McCloskey, E D Bashaw
Proton pump inhibitors (PPIs) have become known for both their therapeutic effect and good safety profile. An application was submitted to the US Food and Drug Administration for approval of a reformulated PPI product that failed bioequivalence testing, but was submitted on the basis of the long history of PPI use as a "surrogate" for equivalence. This review evaluates the safety data for PPIs, discuss variability of pharmacokinetic parameters of PPIs in the reformulation setting, and potential implications of those changes for long-term safety...
June 15, 2017: Clinical and Translational Science
I H Bartelink, N Zhang, R J Keizer, N Strydom, P J Converse, K E Dooley, E L Nuermberger, R M Savic
Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse-to-human translational pharmacokinetics (PKs) - pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species-specific protein binding, drug-drug interactions, and patient-specific pathology...
May 31, 2017: Clinical and Translational Science
D J Bowen, T Hyams, M Goodman, K M West, J Harris-Wai, J-H Yu
No abstract text is available yet for this article.
May 29, 2017: Clinical and Translational Science
B T Gufford, G R Ainslie, J R White, M E Layton, J M Padowski, G M Pollack, M F Paine
Easy-to-use naloxone formulations are needed to help address the opioid overdose epidemic. The pharmacokinetics of i.v., i.m., and a new i.n. naloxone formulation (2 mg) were compared in six healthy volunteers. Relative to i.m. naloxone, geometric mean (90% confidence interval [CI]) absolute bioavailability of i.n. naloxone was modestly lower (55%; 90% CI, 43-70% vs. 41%; 90% CI, 27-62%), whereas average (±SE) mean absorption time was substantially shorter (74 ± 8.8 vs. 6.7 ± 4.9 min). The opioid-attenuating effects of i...
May 15, 2017: Clinical and Translational Science
K M Morrissey, L Z Benet, J A Ware
No abstract text is available yet for this article.
July 2017: Clinical and Translational Science
S-D Li, Y-B Chen, L-G Qiu, M-Q Qin
The objective of this study was to explore the mechanism underlying osteoblast suppression in the process of hematopoietic stem cells mobilization induced by granulocyte colony-stimulating factor (G-CSF). The apoptosis of human and mouse osteoblasts was examined by detecting caspase 3. The levels of serum DKK1 and osteocalcin in the supernatant of co-culture of mouse osteoblasts and mouse bone marrow nucleated cells were measured. The number of mouse osteoblasts co-cultured with mouse bone marrow nucleated cells was measured and the osteocalcin mRNA level was also measured...
July 2017: Clinical and Translational Science
S Xinqiang, Z Mu, C Lei, L Y Mun
Epigallocatechin-3-gallate (EGCG) is the most abundant and biologically active catechin in green tea, and it exerts multiple effects in humans through mechanisms that remain to be clarified. The present study used bioinformatics to identify possible mechanisms by which EGCG reduces the risk of ovarian cancer. Possible human protein targets of EGCG were identified in the PubChem database, possible human gene targets were identified in the National Center for Biotechnology Information database, and then both sets of targets were analyzed using Ingenuity Pathway Analysis (IPA)...
July 2017: Clinical and Translational Science
R A Boyd, L DiCarlo, J W Mandema
We carried out a dose-response model-based meta-analysis to assess venous thromboembolism (VTE) and bleeding with factor Xa (FXa) inhibitors (apixaban, edoxaban, rivaroxaban) and a thrombin inhibitor (dabigatran) compared with European (EU) (40 mg q.d.) and North American (NA) (30 mg Q12H) dose regimens of a low molecular weight heparin (enoxaparin) following orthopedic surgery. Statistically significant differences in both VTE and bleeding outcomes were found between the NA and EU doses of enoxaparin, with odds ratios (95% confidence interval) for the NA vs...
July 2017: Clinical and Translational Science
V Slowik, U Apte
No abstract text is available yet for this article.
July 2017: Clinical and Translational Science
A Roda, R Aldini, C Camborata, S Spinozzi, P Franco, M Cont, A D'Errico, F Vasuri, A Degiovanni, L Maroni, L Adorini
Obeticholic acid (OCA) is a semisynthetic bile acid (BA) analog and potent farnesoid X receptor agonist approved to treat cholestasis. We evaluated the biodistribution and metabolism of OCA administered to carbon tetrachloride-induced cirrhotic rats. This was to ascertain if plasma and hepatic concentrations of OCA are potentially more harmful than those of endogenous BAs. After administration of OCA (30 mg/kg), we used liquid chromatography-mass spectrometry to measure OCA, its metabolites, and BAs at different timepoints in various organs and fluids...
July 2017: Clinical and Translational Science
A M Keeler, M K ElMallah, T R Flotte
No abstract text is available yet for this article.
July 2017: Clinical and Translational Science
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