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Journal of Clinical Pharmacology

Sanjeev Pathak, Bradley Vince, Debra Kelsh, Megan J Shram, Beatrice Setnik, Hong Lu, Narinder Nangia, Arielle D Stanford, Elliot Ehrich
Buprenorphine/samidorphan combination (BUP/SAM) is an opioid system modulator being investigated as adjunctive treatment for major depressive disorder. BUP/SAM is a fixed-dose combination of buprenorphine, a partial μ-opioid receptor agonist and κ-opioid receptor antagonist, and samidorphan, a μ-opioid receptor antagonist added to address the abuse and dependence potential of buprenorphine. In this study, we assessed the effect of samidorphan on the abuse potential of buprenorphine in the BUP/SAM combination in nondependent, recreational, adult opioid users (ClinicalTrials...
August 13, 2018: Journal of Clinical Pharmacology
Xiao Tong, Hongmei Xu, David J Carlile, Helen Tomkinson, Nidal Al-Huniti, Diansong Zhou
Selumetinib (AZD6244, ARRAY-142886) is a mitogen-activated protein kinase kinase inhibitor that has been tested for treatment of non-small cell lung cancer (NSCLC). Selumetinib (75 mg twice daily) plus docetaxel in patients with advanced NSCLC has been assessed in phase 2 (SELECT-2) and phase 3 (SELECT-1) clinical trials. The objective of the current analysis was to investigate the exposure-response relationship of selumetinib in these 2 clinical trials, based on the development of a population pharmacokinetic (PopPK) model for selumetinib and its active metabolite, N-desmethyl selumetinib, in patients with NSCLC...
August 13, 2018: Journal of Clinical Pharmacology
Pierre-Eric Juif, Margaux Boehler, Michael Dobrow, Mike Ufer, Jasper Dingemanse
ACT-246475 is a selective and reversible P2Y12 receptor antagonist inducing inhibition of platelet aggregation (IPA). A randomized, double-blind, placebo-controlled, parallel-design study was performed to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating single subcutaneous doses of ACT-246475 (1, 2, 4, 8, 16, or 32 mg) in healthy male subjects (N = 8 per dose, 3:1 active:placebo ratio). Pharmacodynamic effects were assessed based on maximum platelet aggregation and P2Y12 reaction units using light transmission aggregometry and VerifyNow® assays, respectively...
August 8, 2018: Journal of Clinical Pharmacology
Jing Li, Jian Gu
We performed a systematic review and meta-analysis to fully investigate the rash and pruritus of programmed death-1 (PD-1) inhibitors in cancer patients. The relevant studies of the randomized controlled trials in cancer patients treated with PD-1 inhibitors were retrieved, and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published up to April 2018. Nineteen randomized controlled trials and 11,006 patients were included. The current meta-analysis suggests that the use of PD-1 inhibitors significantly increases the risk of developing the all-grade rash (risk ratio [RR] 1...
August 8, 2018: Journal of Clinical Pharmacology
Mayu Osawa, Takayo Ueno, Hiroki Ishikawa, Yasuhiko Imai, Tushar Garimella
Daclatasvir is a nonstructural protein 5A replication complex inhibitor, and asunaprevir is a nonstructural protein 3 protease inhibitor for hepatitis C virus (HCV). In 2014, the combination therapy of daclatasvir and asunaprevir received the first global approval in Japan as the first nonribavirin, all-oral therapy for HCV treatment. The population pharmacokinetics (popPK) of daclatasvir and asunaprevir were characterized by nonlinear mixed-effects modeling using 3801 and 2626 concentration data from 336 and 265 Japanese HCV subjects, respectively...
July 31, 2018: Journal of Clinical Pharmacology
Takayo Ueno, Mayu Osawa, Yasuhiko Imai, Hiroki Ishikawa, Tushar Garimella
The treatment of hepatitis C virus (HCV) infection has been revolutionized by the development of all-oral combination regimens of direct-acting antiviral agents. The current analysis characterized the relationship between exposures of daclatasvir (DCV; tablets) and asunaprevir (ASV; capsules) and sustained virologic response (SVR) in Japanese patients who are HCV genotype (GT) 1b nonresponders to pegylated interferon (IFN) α/ribavirin or IFNβ/ribavirin, and IFN-based therapy-ineligible naive/intolerant patients receiving DCV and ASV, and provided insight into patient covariates that were most closely associated with efficacy...
July 31, 2018: Journal of Clinical Pharmacology
Min-Jee Kim, Mi-Sun Yum, Hye-Ryun Yeh, Tae-Sung Ko, Hyeong-Seok Lim
This study aimed to evaluate the safety and tolerability of intravenous (IV) levetiracetam (LEV) as a monotherapy in children aged 1 month-16 years and to explore the pharmacokinetics (PK) of IV LEV and the time to seizure after IV then oral administration of LEV in pediatric children with epilepsy. Children diagnosed with acute unprovoked seizures requiring in-hospital IV LEV administration were included. After administration, the clinical seizure outcomes, side effects, and the Korean-Child Behavior Checklist were monitored and the PK and repeated time to seizure were analyzed via modeling using NONMEM software...
July 27, 2018: Journal of Clinical Pharmacology
Peter N Morcos, Yumi Cleary, Carolina Sturm-Pellanda, Elena Guerini, Markus Abt, Massimiliano Donzelli, Faye Vazvaei, Bogdana Balas, Neil Parrott, Li Yu
Alectinib is approved and recommended as the preferred first-line treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of alectinib was assessed with physiologically based PK modeling prospectively and in a clinical study. An open-label study (NCT02621047) investigated a single 300-mg dose of alectinib in moderate (n = 8) and severe (n = 8) hepatic impairment (Child-Pugh B/C), and healthy subjects (n = 12) matched for age, sex, and body weight...
July 27, 2018: Journal of Clinical Pharmacology
Xun Bao, Jianmei Wu, Seongho Kim, Patricia LoRusso, Jing Li
The purpose of this study was to identify early circulating metabolite changes implicated in the mechanism of action of irinotecan, a DNA topoisomerase I inhibitor, in cancer patients. A liquid chromatography-tandem mass spectrometry-based targeted metabolomic platform capable of measuring 254 endogenous metabolites was applied to profile circulating metabolites in plasma samples collected pre- and post-irinotecan treatment from 13 cancer patients. To gain further mechanistic insights, metabolic profiling was also performed for the culture medium of human primary hepatocytes (HepatoCells) and 2 cancer cell lines on exposure to SN-38 (an active metabolite of irinotecan)...
July 27, 2018: Journal of Clinical Pharmacology
Jörg Täubel, Georg Ferber, Sara Fernandes, A John Camm
Understanding the physiological fluctuations in the corrected QT (QTc) interval is important to accurately interpret the variations in drug-induced prolongation. The present study aimed to define the time course of the effect of moxifloxacin on the QT interval to understand the duration of the responses to moxifloxacin. This retrospective analysis was performed on data taken from a thorough QT 4-way crossover study with 40 subjects. Each period consisted of a baseline electrocardiogram (ECG) day (day -1) and a treatment day (day 1)...
July 24, 2018: Journal of Clinical Pharmacology
Rajesh Krishna, Ferdous Gheyas, Christy Corr, Josee Cote, Yang Liu, John Wagner, David E Gutstein
Anacetrapib is a cholesteryl ester transfer protein inhibitor intended for the treatment of dyslipidemia. A phase 1 study was conducted to examine the pharmacokinetics and pharmacodynamics of multiple doses of anacetrapib in black compared to white healthy subjects. Although there was no apparent race-related pharmacokinetic effect, attenuation of the lipid response was observed in black subjects. Specifically, high-density lipoprotein cholesterol percentage increased 18.1% (absolute percentage points) less in black subjects (89...
July 20, 2018: Journal of Clinical Pharmacology
Evan J Zasowski, Thomas P Lodise
No abstract text is available yet for this article.
July 19, 2018: Journal of Clinical Pharmacology
Elia Gebran Malek, Johnny S Salameh
No abstract text is available yet for this article.
July 19, 2018: Journal of Clinical Pharmacology
Anne N Nafziger, Robert L Barkin
This is an article in the Core Entrustables in Clinical Pharmacology series that describes opioid therapy in acute and chronic pain. Opioid use during surgical procedures or anesthesia is not discussed. Basic pharmacokinetic and pharmacodynamic properties of opioids are reviewed. The safe and effective use of opioids, including clinical assessment and treatment plan, equianalgesic dosing, opioid rotation, opioid risks and side effects, and clinical adherence monitoring are discussed. Individualized opioid use can be a safe and effective component of a patient-specific multimodal treatment plan for acute or chronic pain...
July 9, 2018: Journal of Clinical Pharmacology
James Truong, Shawn R Smith, John J Veillette, Steven C Forland
Dosing vancomycin in critically ill patients often results in subtherapeutic and supratherapeutic trough concentrations. In this retrospective study, we compared the time to goal trough attainment and incidence of acute kidney injury in intensive care unit (ICU) patients whose vancomycin was dosed by a pharmacy pharmacokinetic (PK) dosing and monitoring service to the standard of care. Three-hundred fifty adult ICU patients at a Level 1 trauma, teaching hospital who received vancomycin for >24 hours from February 1, 2016, to November 30, 2016, were screened...
June 29, 2018: Journal of Clinical Pharmacology
Gerda M de Kuijper, Pieter J Hoekstra
Although physicians are aware of the risks of prescribing long-term off-label antipsychotics in people with intellectual disability, attempts to discontinue often fail. This study aimed to identify potential determinants of successful and failed discontinuation. Long-term off-label antipsychotics were tapered in 14 weeks, with 12.5% of baseline dose every 2 weeks. Participants living in facilities offered by intellectual disability service providers, ≥6 years, with an IQ <70 were eligible to discontinue antipsychotic use, as judged by their physicians...
June 19, 2018: Journal of Clinical Pharmacology
Maiko Nomoto, Jim Ferry, Ziad Hussein
Avatrombopag, a c-Mpl agonist, has been developed to provide an alternative therapy to standard platelet transfusion care for the treatment of thrombocytopenia. The main objectives of this article were to describe the pharmacokinetics (PK) of avatrombopag, to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship between plasma avatrombopag concentrations and platelet count, and to identify potential intrinsic and extrinsic factors affecting PK or PK/PD in patients with chronic liver disease (CLD)...
June 15, 2018: Journal of Clinical Pharmacology
Melanie R Nicol, Joseph A Corbino, Mackenzie L Cottrell
Preexposure prophylaxis (PrEP) is a powerful tool that, as part of a comprehensive prevention package, has potential to significantly impact the HIV epidemic. PrEP effectiveness is believed to be dependent on the exposure and efficacy of antiretrovirals at the site of HIV transmission. Clinical trial results as well as modeling and simulation indicate the threshold of adherence required for PrEP efficacy of emtricitabine/tenofovir disoproxil fumarate may differ between sites of HIV transmission with less forgiveness for missed doses in women exposed through genital tissue compared to people exposed through colorectal tissue...
June 14, 2018: Journal of Clinical Pharmacology
Yan Xu, Chuanpu Hu, Yanli Zhuang, Benjamin Hsu, Zhenhua Xu, Amarnath Sharma, Honghui Zhou
To characterize the dose-exposure-response relationship of sirukumab, an anti-interleukin 6 human monoclonal antibody, in the treatment of moderately to severely active rheumatoid arthritis (RA), we conducted exposure-response (E-R) modeling analyses based on data from two pivotal phase 3 placebo-controlled trials of sirukumab in patients with RA who were inadequate responders to nonbiologic disease-modifying antirheumatic drugs or anti-tumor necrosis factor α agents. A total of 2176 patients were included for the analyses and received subcutaneous administration of either placebo or sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks...
June 14, 2018: Journal of Clinical Pharmacology
Phuong Thi Thu Nguyen, Md Masud Parvez, Min Jung Kim, Jung Ho Lee, Sangzin Ahn, Jong-Lyul Ghim, Jae-Gook Shin
Currently, ethionamide is the most frequently prescribed second-line antituberculosis drug in children. After extensive metabolism by flavin-containing monooxygenase (FMO) isoform 3 in the liver, the drug may exert cytotoxic effects. The comparison of children in different age groups revealed a significant age-related increase in ethionamide elimination in vivo. However, to date, the exact mechanism underlying this dynamic increase in ethionamide elimination has not been elucidated. We hypothesized that the age-dependent changes in ethionamide elimination were predominantly a result of the progressive increases in the expression and metabolic capacity of FMO3 during childhood...
June 7, 2018: Journal of Clinical Pharmacology
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