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Journal of Clinical Pharmacology

Derrick E Akpalu, Bart Frederick, Ivo P Nnane, Zhenling Yao, Fang Shen, Tatiana Ort, Damien Fink, Shannon Dogmanits, Donald Raible, Amarnath Sharma, Zhenhua Xu
The safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of JNJ-61178104, a novel anti-tumor necrosis factor-alpha (TNFα) and anti-interleukin-17A (IL-17A) bispecific antibody, were investigated in a placebo-controlled, first-in-human study. Healthy subjects (n = 54) received a single dose of JNJ-61178104 by either intravenous infusion (0.1, 0.3, 1, 3, and 10 mg/kg) or subcutaneous injection (1 mg/kg). Blood samples for measurement of serum JNJ-61178104 concentrations, total IL-17A, total TNFα, and detection of antidrug antibodies were collected for up to 16 weeks after dosing and assessed using electrochemiluminescence immunoassays...
February 18, 2019: Journal of Clinical Pharmacology
Ashley M Reilly, Michelle X Ding, Joseph E Rower, Tyree H Kiser
Concern for bacterial resistance and treatment failure with vancomycin trough concentrations < 10 μg/mL have led guidelines to increase goal concentrations. There is a paucity of data evaluating vancomycin dosage necessary to achieve goals in the neonatal intensive care unit (NICU). We aimed to evaluate the implementation of a new vancomycin dosing guideline in improving trough target attainment. This retrospective study evaluated neonates in the NICU treated with vancomycin between January 2009 and December 2015...
February 18, 2019: Journal of Clinical Pharmacology
Vera S Donnenberg, Philip Chaikin, Maja Mandic, Bernd Meibohm, John van den Anker, Erin Rhinehart, Anne N Nafziger, James F Burris
Although the medical profession strives for safe prescribing, most medications are unique challenges even when prescribed by an experienced provider. In this article we discuss the pitfalls associated with drug interactions between commonly used antibiotics and anticoagulants, the complexities associated with the administration of novel reversible anticoagulants, the often-overlooked severe adverse drug reactions from commonly used classes of medications such as corticosteroids, the nuances of managing an acetaminophen overdose, and uncommon yet serious adverse events associated with the use of contraceptive hormone drugs...
February 15, 2019: Journal of Clinical Pharmacology
Scott R Penzak, Carlos Rojas-Fernandez
A number of cytochrome P450 (CYP)3A phenotyping probes have been used to characterize the drug interaction potential of new molecular entities; of these, midazolam has emerged as the gold standard. Recently, plasma 4β-hydroxycholesterol (4β-OHC), the metabolite of CYP3A-mediated cholesterol metabolism, has been championed as an endogenous biomarker for CYP3A, particularly during chronic conditions where CYP3A activity is altered by disease and in long-term treatment studies where midazolam administration is not optimal...
February 12, 2019: Journal of Clinical Pharmacology
Chyi-Hung Hsu, Xu Steven Xu, Jian Wang, Liping Zhang, Chao Liu, Yaning Wang
In pediatric drug development, large amounts of adult data are often available before the start of a pediatric study. It is believed that borrowing this information will improve the efficiency. However, when adult information is not sufficiently similar to that of pediatrics, incorporating adult data will introduce bias and consequently result in efficiency loss. A Bayesian alternative-namely, commensurate prior approach where the level of information borrowing is based on the concordance of adult and pediatric data-was investigated...
February 12, 2019: Journal of Clinical Pharmacology
Panteleimon D Mavroudis, John van den Anker, Laurie S Conklin, Jesse M Damsker, Eric P Hoffman, Kanneboyina Nagaraju, Paula R Clemens, William J Jusko
Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder occurring in boys and caused by mutations in the dystrophin gene. Vamorolone is a first-generation delta-9,11 compound that has favorable efficacy and side effect profiles relative to classical glucocorticoids. The pharmacokinetics (PK) of oral vamorolone were assessed in parallel-group studies in healthy men (phase 1, n = 86) and boys with DMD (phase 2a, n = 48) during 14 days of once-daily dosing with a range of doses. Vamorolone exhibited moderate variability in PK, with the maximum plasma concentration usually occurring at 2-4 hours and a half-life of approximately 2 hours for all doses and days examined...
February 11, 2019: Journal of Clinical Pharmacology
C Michael White
Cannabidiol (CBD) is a highly touted product for many different disorders among the lay press. Numerous CBD products are available, ranging from a US Food and Drug Administration (FDA)-approved product called Epidiolex to products created for medical marijuana dispensaries and products sold in smoke shops, convenience stores, and over the Internet. The legal status of the non-FDA-approved products differs depending on the source of the CBD and the state, while the consistency and quality of the non-FDA-approved products vary markedly...
February 7, 2019: Journal of Clinical Pharmacology
Shiro Miyazaki, Takayuki Katsube, Helen Shen, Charles Tomek, Yukitoshi Narukawa
The objectives of this study were to characterize the concentration-time profiles of total radioactivity equivalent and unchanged cefiderocol, the route(s) of elimination and mass balance, and safety of cefiderocol after intravenous administration of a single 1000-mg (100 μCi) dose of [14 C]-cefiderocol as a 1-hour infusion in healthy adult male subjects. Unchanged cefiderocol accounted for the majority of total radioactivity in plasma, and the partitioning of total radioactivity into red blood cells was negligible...
February 7, 2019: Journal of Clinical Pharmacology
Hyewon Kim, Lanyan Fang, Jingyu Yu, Zhaoyu Meng, Mirjam N Trame, Stephan Schmidt, Lawrence J Lesko, Liang Zhao
Phenytoin demonstrates time-dependent and nonlinear pharmacokinetics (PK) within the therapeutic range of 10 to 20 μg/mL. There are discussions on the relevance of bioequivalence (BE) demonstrated in a single-dose BE study in healthy subjects to exposure under chronic use conditions in patients, particularly given that phenytoin has a narrow therapeutic index. The objective of this study was to quantitatively evaluate the appropriateness of single-dose PK BE through simulations for the phenytoin extended-capsule products...
February 4, 2019: Journal of Clinical Pharmacology
Jing Li
To fully investigate the diarrhea of human epidermal growth factor receptor 2 (HER2)-targeted agents in cancer patients. The relevant studies of the randomized, controlled trials (RCTs) in cancer patients treated with HER2-targeted agents were retrieved, and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until August 2018. Forty-two RCTs and 21 633 patients were included. The current meta-analysis suggested that the use of HER2-targeted agents significantly increases the risk of developing all-grade diarrhea (RR, 2...
February 1, 2019: Journal of Clinical Pharmacology
Douglas Cowart, Robert P Venuti, Kim Lynch, Jeffrey T Guptill, Robert J Noveck, Shi Yin Foo
Nitroxyl (HNO) is a reactive nitrogen molecule that has potential therapeutic benefits for patients with acute heart failure. The results of the first-in-human study for BMS-986231, a novel HNO donor, are reported. The aim of this sequential cohort study was to evaluate the safety, tolerability, and pharmacokinetic profile of BMS-986231 after 24- and 48-hour intravenous infusions in healthy volunteers. Eighty subjects were randomized and dosed. Seven cohorts (stratum A) received BMS-986231 0.1, 0.33, 1, 3, 5, 10, and 15 μg/kg/min or placebo, infused over 24 hours...
January 31, 2019: Journal of Clinical Pharmacology
Philip Krieter, Shwe Gyaw, C Nora Chiang, Roger Crystal, Phil Skolnick
Based on its high affinity for μ opiate receptors and reported half-life after oral administration, the pharmacokinetic properties of intranasal naltrexone were examined to evaluate its potential to treat opioid overdose. This study was prompted by the marked rise in overdose deaths linked to synthetic opioids like fentanyl, which may require more potent, longer-lived opiate antagonists than naloxone. Both the maximum plasma concentration (Cmax ) and the time (Tmax ) to reach Cmax for intranasal naltrexone (4 mg) were comparable to values reported for a Food and Drug Administration-approved 4-mg dose of intranasal naloxone...
January 30, 2019: Journal of Clinical Pharmacology
Phuong Thi Thu Nguyen, Md Masud Parvez, Min Jung Kim, Sung Eun Yoo, Sangzin Ahn, Jong-Lyul Ghim, Jae-Gook Shin
The widely used second-line antituberculosis drug ethionamide shows wide interindividual variability in its disposition; however, the relevant factors affecting this phenomenon have not been characterized. We previously reported the major contribution of flavin-containing monooxygenase 3 (FMO3) in the reductive elimination pathway of ethionamide. In this study, ethionamide metabolism was potentially inhibited by methimazole in vitro. The drug-drug interaction leading to methimazole affecting the disposition of ethionamide mediated by FMO3 was then quantitated using a bottom-up approach with a physiologically based pharmacokinetic framework...
January 28, 2019: Journal of Clinical Pharmacology
Heino Stass, John Lettieri, Konstantina M Vanevski, Stefan Willmann, Laura P James, Janice E Sullivan, Antonio C Arrieta, John S Bradley
The pharmacokinetics, safety, and tolerability of a single dose of moxifloxacin were characterized in 31 pediatric patients already receiving antibiotics for a suspected or proven infection in an open-label phase 1 study. A dosing strategy for each age cohort (Cohort 1: ≥6 years to ≤14 years; Cohort 2: ≥2 years to <6 years; Cohort 3: >3 month to <2 years) was developed using physiology-based pharmacokinetic modeling combined with a stepwise dosing scheme to obtain a similar exposure to adults receiving 400 mg of moxifloxacin...
January 25, 2019: Journal of Clinical Pharmacology
Yin Cheong Wong, Maddalena Centanni, Elizabeth C M de Lange
Receptor occupancy (RO) is a translational biomarker for assessing drug efficacy and safety. We aimed to apply a physiologically based pharmacokinetic (PBPK) modeling approach to predict the brain dopamine D2 RO time profiles of antipsychotics. Clozapine and risperidone were modeled together with their active metabolites, norclozapine and paliperidone, First, in PK-Sim a rat PBPK model was developed and optimized using literature plasma PK data. Then, blood-brain barrier parameters including the expression and efflux transport kinetics of P-glycoprotein were optimized using literature microdialysis data on brain extracellular fluid (brainECF), which were further adapted when translating the rat PBPK model into the human PBPK model...
January 24, 2019: Journal of Clinical Pharmacology
P Mian, A J Valkenburg, K Allegaert, B C P Koch, C V Breatnach, C A J Knibbe, D Tibboel, E H J Krekels
Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of acetaminophen in this special population, even though differences, as a result of altered hemodynamics and/or use of cardiopulmonary bypass, may be anticipated. Therefore, the aim of this study was to investigate the PK of intravenous acetaminophen in children after cardiac surgery with cardiopulmonary bypass. In the study, both children with and without Down syndrome were included...
January 11, 2019: Journal of Clinical Pharmacology
Mohamed-Eslam F Mohamed, Sheryl Trueman, Tian Feng, Jaclyn Anderson, Thomas C Marbury, Ahmed A Othman
Upadacitinib is a novel selective Janus kinase 1 inhibitor developed for treatment of rheumatoid arthritis and other autoimmune diseases. The objective of this study was to assess the pharmacokinetics and safety of a single upadacitinib dose in subjects with normal renal function and in subjects with renal impairment. A total of 24 subjects between the ages of 18 and 75 years were assigned to 1 of 4 renal function groups based on estimated glomerular filtration rate (normal, mild, moderate, severe; N = 6/group)...
January 11, 2019: Journal of Clinical Pharmacology
Michael J Sorich, Fayzah Mutlib, Madelé van Dyk, Ashley M Hopkins, Thomas M Polasek, Jean-Claude Marshall, A David Rodrigues, Andrew Rowland
Axitinib is a second-generation small-molecule vascular endothelial growth factor receptor inhibitor. An axitinib steady-state area under the plasma concentration-time curve (AUCSS ) >300 ng/mL/hr is associated with superior progression-free and overall survival. This study sought to characterize the physiological and molecular characteristics driving variability in axitinib AUCSS using physiologically based pharmacokinetic modeling to identify exposure biomarkers for this drug. The capacity to predict subjects likely to fail to achieve an axitinib AUCSS >300 ng/mL/hr was evaluated as a secondary outcome...
January 11, 2019: Journal of Clinical Pharmacology
Jörg Täubel, Georg Ferber, Leen Van Langenhoven, Teresa Del Bianco, Sara Fernandes, Dilshat Djumanov, Jørgen K Kanters, Claus Graff, A John Camm
Meal intake leads to a significant and prolonged increase in cardiac output to supply the splanchnic vasculature. A meal is associated with sympathetic activation of the cardiovascular system, and food ingestion is correlated with an increase in heart rate, an increase in cardiac stroke volume, and QTc interval shortening for up to 7 hours. Given the complexity of the system, one or several of many mechanisms could explain this observation. The shortening of the QTc interval was correlated with a rise of C-peptide following food ingestion, but the mechanisms by which C-peptide may be involved in the modulation of cardiac repolarization are still unknown...
January 11, 2019: Journal of Clinical Pharmacology
Niurys de Castro-Suárez, Leyanis Rodríguez-Vera, Carlos Villegas, José M Dávalos-Iglesias, Raymed Bacallao-Mendez, Betsy Llerena-Ferrer, Christian Leyva-de la Torre, Patricia Lorenzo-Luaces, Mayelin Troche-Concepción, Mayra Ramos-Suzarte
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression and mislocalization of epidermal growth factor receptor (EGFR) to the apical membranes of cystic epithelial cells. Nimotuzumab is a humanized antibody that recognizes an extracellular domain III of human EGFR. The aim of this study was to assess the pharmacokinetic behavior of nimotuzumab in patients with ADPKD given as a single dose. A phase I, single-center, and noncontrolled open clinical study was conducted...
January 11, 2019: Journal of Clinical Pharmacology
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