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Journal of Clinical Pharmacology

David J Greenblatt, Maulik Patel, Jerold S Harmatz, Wayne T Nicholson, Christopher M Rubino, Christina R Chow
Pharmacokinetics and antithrombotic effects of the Factor Xa inhibitor rivaroxaban were studied in subjects with mild renal insufficiency concurrently taking the P-glycoprotein and moderate CYP3A inhibitor verapamil, a drug commonly administered to patients with hypertension, ischemic heart disease, or atrial fibrillation. Age-matched controls with normal renal function were studied concurrently. Subjects' overall mean age was 59 years. Mean creatinine clearance values in the 2 groups were 105 and 71 mL/min...
November 30, 2017: Journal of Clinical Pharmacology
Hyeong-Seok Lim, Seung Min Kim, Dong-Wha Kang
Although stroke is a leading cause of disability, the quantitative relationship between baseline clinical and imaging characteristics and long-term disability outcomes has rarely been studied. Prospectively collected clinical data from 405 patients with acute ischemic stroke including brain magnetic resonance images (MRIs) and disability outcomes assessed using the modified Rankin Scale (mRS) 3 month after the onset of disease were analyzed using a proportional odds cumulative logit model implemented in NONMEM...
November 30, 2017: Journal of Clinical Pharmacology
John M Weiler, Christine A Sorkness, Leslie Hendeles, Sara Nichols, Yaping Zhu
This was a randomized, double-blind, crossover, clinical-end-point pilot study examining the hypothesis that inhaled fluticasone propionate decreases exhaled nitric oxide (eNO) concentrations within a week of beginning treatment and shows evidence of dose separation across the marketed dose range. Subjects had a ≥6-month history of asthma and screening eNO ≥60 parts per billion. At the start of each treatment period, eNO was ≥55 parts per billion, and forced expiratory volume in 1 second was ≥50% predicted...
November 28, 2017: Journal of Clinical Pharmacology
Ryoko Toda, Masanari Shiramoto, Emi Komai, Kazuyoshi Yoshii, Masamichi Hirayama, Yoshihiro Kawabata
The pharmacokinetics (PK) and pharmacodynamics (PD) of proton pump inhibitors differ among cytochrome P450 (CYP) 2C19 genotypes. Therefore, we developed azeloprazole sodium (Z-215), a novel proton pump inhibitor, whose metabolism is not affected by CYP2C19 activity in vitro. However, the PK and PD of azeloprazole sodium have not been evaluated in Japanese subjects. We conducted an open-label, crossover study in healthy Japanese male volunteers to evaluate the plasma concentration and intragastric pH with respect to CYP2C19 genotype after repeated administration of 10, 20, and 40 mg azeloprazole sodium and 10 and 20 mg rabeprazole sodium (rabeprazole)...
November 28, 2017: Journal of Clinical Pharmacology
Yingxue Chen, Diansong Zhou, Weifeng Tang, Wangda Zhou, Nidal Al-Huniti, Eric Masson
Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase and is used for the treatment of non-small-cell lung cancer (NSCLC) with activating EGFR mutations. Gefitinib is metabolized by CYP2D6 and CYP3A4. This analysis compared the systemic exposure of gefitinib after oral administration in CYP2D6 ultrarapid metabolizers (UM) vs extensive metabolizers (EM). Physiologically based pharmacokinetic (PBPK) modeling was conducted using a population-based simulator. The model was calibrated using itraconazole-gefitinib clinical drug-drug interaction data and validated with gefitinib data in CYP2D6 EM vs poor metabolizers (PM)...
November 28, 2017: Journal of Clinical Pharmacology
Jennifer K Leohr, Debra Luffer-Atlas, M Jane Luo, David J DeBrota, Colin Green, Thomas E Mabry, Jeffrey G Suico
The safety, pharmacokinetic, and pharmacodynamic effects of LY2584702, a selective inhibitor for p70 S6 serine/threonine protein kinase-1, were evaluated in healthy dyslipidemic volunteers. LY2584702 was tolerated well as a monotherapy and dose-dependently reduced low-density lipoprotein cholesterol and triglycerides by up to 60% and 50%, respectively, without significantly changing high-density lipoprotein cholesterol levels in plasma. LY2584702 also dose-dependently decreased factor V activity. Alanine aminotransferase elevations were noted in 2 subjects when LY2584702 was given with atorvastatin...
November 26, 2017: Journal of Clinical Pharmacology
Xiaohui Wei, Leonid Gibiansky, Yehong Wang, Franklin Fuh, Rich Erickson, Sharon O'Byrne, Meina T Tang
Etrolizumab, a humanized monoclonal antibody, specifically binds to the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. Pharmacokinetic (PK) and pharmacodynamic (PD) data were collected from an etrolizumab phase 1 trial in patients with moderate to severe ulcerative colitis (UC). We developed a mechanism-based model to simultaneously describe the kinetics of serum etrolizumab concentration and free β7 receptors on circulating intestinal-homing CD4+ T lymphocytes. Included in the analysis were 38 phase 1 UC patients who received single or 3 monthly doses of etrolizumab intravenously or subcutaneously across a dose range of 0...
November 26, 2017: Journal of Clinical Pharmacology
Karthick Vishwanathan, Paul A Dickinson, Khanh Bui, Philippe A Cassier, Alastair Greystoke, Eleanor Lisbon, Victor Moreno, Karen So, Karen Thomas, Doris Weilert, Timothy A Yap, Ruth Plummer
Two phase 1, open-label studies assessed the impact of food or gastric pH modification (omeprazole) on the exposure and safety/tolerability of osimertinib and its metabolites. The food effect study was an open-label, 2-period crossover study in patients with advanced non-small-cell lung cancer, randomized into 2 treatment sequences: single-dose osimertinib 80 mg in a fed then fasted state or fasted then fed. The gastric pH study was an open-label, 2-period fixed sequence study assessing the effect of omeprazole on osimertinib exposure in healthy male volunteers...
November 26, 2017: Journal of Clinical Pharmacology
Jessica A Brady, K Melissa Hallow
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce glucose levels in diabetes by inhibiting renal glucose reabsorption in the proximal tubule (PT), resulting in urinary glucose excretion. A recent large cardiovascular outcomes trial suggested that the SGLT2i empagliflozin may also decrease risk of renal dysfunction. Because sodium (Na) and glucose reabsorption are coupled through SGLT2, it is hypothesized that the renal benefits may be derived from lowering Na reabsorption in the PT, which would lead to favorable renal hemodynamic changes...
November 16, 2017: Journal of Clinical Pharmacology
Sudam Pathirana, Shyamalie Jayawardena, Suzanne Meeves, Gary A Thompson
Two pediatric studies characterized brompheniramine and chlorpheniramine pharmacokinetics in a total of 72 subjects, aged 2 to 17 years. A single age-/weight-based oral dose, ranging from 1 to 4 mg, was administered with 2 to 6 oz of water at least 2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed using high-pressure liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods; relationships with age were assessed using linear regression...
November 14, 2017: Journal of Clinical Pharmacology
Chi-Chung Li, Marissa Dockendorf, Ken Kowalski, Bei Yang, Yang Xu, Iris Xie, Huub Jan Kleijn, Rolien Bosch, Christopher Jones, Bob Thornton, Eugene E Marcantonio, Tiffini Voss, Kevin P Bateman, Prajakti A Kothare
Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late-stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late-stage clinical program: ubrogepant (MK-1602), a novel oral calcitonin gene-related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure-response modeling...
November 14, 2017: Journal of Clinical Pharmacology
Anna E Kersh, Spencer Ng, Yun Min Chang, Maiko Sasaki, Susan N Thomas, Haydn T Kissick, Gregory B Lesinski, Ragini R Kudchadkar, Edmund K Waller, Brian P Pollack
Two pharmacologic approaches that are currently at the forefront of treating advanced cancer are those that center on disrupting critical growth/survival signaling pathways within tumor cells (commonly referred to as "targeted therapies") and those that center on enhancing the capacity of a patient's immune system to mount an antitumor response (immunotherapy). Maximizing responses to both of these approaches requires an understanding of the oncogenic events present in a given patient's tumor and the nature of the tumor-immune microenvironment...
November 14, 2017: Journal of Clinical Pharmacology
Tobias Getzin, Marcus May, Martina Schmidbauer, Marcel Gutberlet, Petros Martirosian, Reinhard Oertel, Frank Wacker, Christoph Schindler, Katja Hueper
The purpose of this study was to evaluate contrast-media-free arterial spin labeling, a technique of functional magnetic resonance imaging (MRI), for assessment of kidney perfusion in a clinical study. We examined renal perfusion by arterial spin labeling in 15 healthy adults using a clinical 1.5-T MRI system, twice under baseline conditions and 60 minutes after a single oral dose of 50 mg captopril. Data evaluation included assessment of interstudy and interrater reproducibility in addition to the pharmacological effect of captopril on kidney perfusion and a sample size calculation for potential application of the technique in pharmacological intervention studies...
November 10, 2017: Journal of Clinical Pharmacology
Kristell Marzin, Gunther Kretschmar, Doreen Luedtke, Sandrine Kraemer, Raimund Kuelzer, Rozsa Schlenker-Herceg, Ulrike Schmid, David Schnell, Claudia Dallinger
Nintedanib is an intracellular inhibitor of tyrosine kinases used in the treatment of non-small cell lung cancer and idiopathic pulmonary fibrosis (IPF). This phase 1 open-label study investigated the influence of mild and moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of nintedanib following oral administration of a single 100-mg dose. Subjects with hepatic impairment classified as Child-Pugh A (mild hepatic impairment) or Child-Pugh B (moderate hepatic impairment) were eligible...
November 6, 2017: Journal of Clinical Pharmacology
Richard G Langley, Sree Kasichayanula, Mona Trivedi, Girish A Aras, Arunan Kaliyaperumal, Theresa Yuraszeck, John Gibbs, Megan Gibbs, Greg Kricorian, Amy S Paller
Etanercept has been recently approved in the United States for the treatment of moderate to severe plaque psoriasis in patients aged 4-17 years. The objective of this study was to characterize etanercept pharmacokinetics, immunogenicity, and efficacy in pediatric patients. Data from a phase 3 study and open-label extension study were analyzed. Etanercept serum concentrations in pediatric patients receiving etanercept 0.8 mg/kg (maximum, 50 mg) weekly were compared with adult psoriasis patients and pediatric patients with juvenile idiopathic arthritis (JIA) who received etanercept 0...
November 6, 2017: Journal of Clinical Pharmacology
Yasuyoshi Ishiwata, Masashi Nagata, Kohta Tsuge, Hiromitsu Takahashi, Sayo Suzuki, Kohsuke Imai, Masatoshi Takagi, Hirokazu Kanegane, Tomohiro Morio, Masato Yasuhara
No abstract text is available yet for this article.
October 27, 2017: Journal of Clinical Pharmacology
Ka Lai Yee, Mengyao Li, Tamara Cabalu, Vaishali Sahasrabudhe, Jian Lin, Ping Zhao, Pravin Jadhav
Dose recommendations for specific populations are not always provided and, when available, typically rely on empirical derivation from a small fraction of the general population. In this study, a prediction/confirmation framework was applied to 2 model-based methods, physiologically based pharmacokinetics (PBPK) and a static model, to evaluate their ability to predict clearance in mild, moderate, and severe renal impairment populations and to inform dosing recommendations in these populations. Simulated renal impairment/healthy subject AUC ratios (AUCRs) from PBPK and static models were compared with observed AUCRs from dedicated clinical studies in renal impairment subjects for 7 drugs eliminated primarily by renal clearance...
October 27, 2017: Journal of Clinical Pharmacology
Shota Muraki, Kuniaki Moriki, Saki Shigematsu, Masato Fukae, Makoto Kakara, Daiki Yamashita, Takeshi Hirota, Hiroshi Takane, Miki Shimada, Masaaki Hirakawa, Ichiro Ieiri
The aim of this study was to develop a population pharmacodynamic (PPD) model to describe uric acid (UA)-lowering effects in patients treated with febuxostat based on electronic medical records in 2 independent hospitals (university and city hospitals). Interhospital differences in the PPD model were also evaluated. We conducted the following 2 approaches to build the PPD models. A PPD model was developed separately using individual hospital data, and structural models and covariates between the two hospitals were compared (approach A)...
October 18, 2017: Journal of Clinical Pharmacology
Indranil Bhattacharya, Zorayr Manukyan, Phylinda Chan, Anne Heatherington, Lutz Harnisch
Domagrozumab, a monoclonal antibody that binds to myostatin, is being developed for Duchenne muscular dystrophy (DMD) boys following a first-in-human study in healthy adults. Literature reporting pharmacokinetic parameters of monoclonal antibodies suggested that body-weight- and body-surface-area-adjusted clearance and volume of distribution estimates between adults and children are similar for subjects older than 6 years. Population modeling identified a Michaelis-Menten binding kinetics model to optimally characterize the target mediated drug disposition profile of domagrozumab and identified body mass index on the volume of distribution as the only significant covariate...
October 12, 2017: Journal of Clinical Pharmacology
Leonardo C Welling, Eberval Gadelha Figueiredo
No abstract text is available yet for this article.
October 11, 2017: Journal of Clinical Pharmacology
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