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Journal of Clinical Pharmacology

Christoph P Hornik, Daniel Gonzalez, John van den Anker, Andrew M Atz, Ram Yogev, Brenda B Poindexter, Kee Chong Ng, Paula Delmore, Barrie L Harper, Chiara Melloni, Andrew Lewandowski, Casey Gelber, Michael Cohen-Wolkowiez, Jan Hau Lee
Ketamine is an N-methyl D-aspartate receptor antagonist used off-label to facilitate dissociative anesthesia in children undergoing invasive procedures. Available for both intravenous and intramuscular administration, ketamine is commonly used when vascular access is limited. Pharmacokinetic (PK) data in children are sparse, and the bioavailability of intramuscular ketamine in children is unknown. We performed 2 prospective PK studies of ketamine in children receiving either intramuscular or intravenous ketamine and combined the data to develop a pediatric population PK model using nonlinear mixed-effects methods...
April 20, 2018: Journal of Clinical Pharmacology
J Rick Turner, Ignacio Rodriguez, Emily Mantovani, Gary Gintant, Peter R Kowey, Ralph J Klotzbaugh, Krishna Prasad, Philip T Sager, Norman Stockbridge, Colette Strnadova
Multiple marketing withdrawals due to proarrhythmic concerns occurred in the United States, Canada, and the United Kingdom in the late 1980s to early 2000s. This primer reviews the clinical implications of a drug's identified proarrhythmic liability, the issues associated with these safety-related withdrawals, and the actions taken by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and by regulatory agencies in terms of changing drug development practices and introducing new nonclinical and clinical tests to asses proarrhythmic liability...
April 19, 2018: Journal of Clinical Pharmacology
Jincheng Yang, Maulik Patel, Mina Nikanjam, Edmund V Capparelli, Shirley M Tsunoda, Howard E Greenberg, Scott R Penzak, S Aubrey Stoch, Joseph S Bertino, Anne N Nafziger, Joseph D Ma
Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single-concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed-effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated...
April 17, 2018: Journal of Clinical Pharmacology
Dionna J Green, Janelle M Burnham, Paul Schuette, Xiaomei I Liu, Brian M Maas, Lynne Yao, Susan K McCune, Joseph Chen, John N van den Anker, Gilbert J Burckart
The selection of appropriate endpoints in pediatric drug development trials is a critical aspect of trial design. Given the high pediatric trial failure rate, selecting optimal trial design elements, such as the primary efficacy endpoint, is essential to ensuring increased potential for trial success. The objectives of this study were to identify the primary efficacy endpoints measured in pediatric drug development trials submitted to the US Food and Drug Administration and to relate endpoint attributes to trial and label outcome...
April 17, 2018: Journal of Clinical Pharmacology
Atsuko Kawazoe, Tomoo Funaki, Seongryul Kim
Busulfan is the most common chemotherapy agent used in allogeneic hematopoietic cell transplant (HCT) conditioning regimens. As narrow therapeutic index and interpatient variability exists in the effectiveness and toxicity of conditioning regimens, personalizing intravenous busulfan therapy is desirable. Population pharmacokinetic-based approaches have been applied to therapeutic drug monitoring for the purpose of personalizing therapy. A population pharmacokinetic analysis with the objective of personalizing therapy in Japanese patients was conducted by integrating pediatric patient data with adult patient data...
April 17, 2018: Journal of Clinical Pharmacology
Polina German, Yan Xin, Jason W Chien, Winnie Weng, Richard Mackman, Sandra A Lewis, Amy Meng, John Ling, Anita Mathias
Respiratory syncytial virus (RSV)-associated respiratory tract infection is a leading cause of hospitalizations in infants for which no effective treatment exists. RSV infection is also an important cause of respiratory disease in adults and immunocompromised patients. Presatovir (GS-5806) is an orally bioavailable antiviral agent that inhibits fusion of RSV with host cell membranes. Here, results from 2 phase 1 studies that evaluated safety, tolerability, and pharmacokinetics of presatovir in healthy adults following administration of single and multiple (7 days) once- or twice-daily ascending doses (first-in-human study) and in the presence or absence of food (food effect study) are described...
April 17, 2018: Journal of Clinical Pharmacology
Opeyemi Edema, Babatunde A Adeagbo, Ayorinde Adehin, Tiwalade A Olugbade
Amodiaquine (AQ) and pioglitazone (PGZ) are both metabolized by CYP2C8, an enzyme also inhibited by PGZ. These drugs are likely to be administered in instances of comorbidity of malaria with type 2 diabetes. This study, hence, evaluated the possibility of a drug interaction resulting from the concurrent use of both drugs. A 3-period crossover design in 10 healthy subjects, that assessed the disposition of AQ and PGZ alone and when coadministered, was implemented with the administration of single oral doses of AQ and PGZ...
April 17, 2018: Journal of Clinical Pharmacology
Leslie Z Benet
Individualization of patient drug dosing to maximize efficacy and minimize toxicity is the goal of clinical pharmacology. Here we review the history of drug dosing individualization from early predictions for renally eliminated drugs based on kidney function through the introduction of clearance concepts for metabolic processes, the differentiation of volume of distribution between pharmacokinetics and chemistry, the role of transporters, the unique pharmacokinetic aspects of oral dosing, and the relevance of protein binding to the emergence of pharmacogenomics...
April 17, 2018: Journal of Clinical Pharmacology
Joanna C Masters, Peter H Wiernik
No abstract text is available yet for this article.
April 17, 2018: Journal of Clinical Pharmacology
Daohong Chen
Cancer is known to be often associated with autoimmunity/inflammation epidemically and pathologically. Although comprehensive mechanisms behind the link of these 2 medical conditions are yet to be elucidated, cumulated biological evidence has pointed to an array of molecular pathways that are shared in the pathogenesis of cancer and autoimmunity. Herein, this article presents the representative druggable cellular proteins that substantially contribute to the development of the 2 medical conditions, in particular highlighting the recently approved medications that target these molecular pathways to corroborate the link between autoimmunity and cancer from the therapeutic perspective...
April 17, 2018: Journal of Clinical Pharmacology
William B White, Christopher Chapple, Christian Gratzke, Sender Herschorn, Dudley Robinson, Jeffrey Frankel, Arwin Ridder, Matthias Stoelzel, Asha Paireddy, Robert van Maanen, Michael A Weber
There have been concerns that treatment of overactive bladder with β3 -adrenoceptor agonists may potentially have detrimental cardiovascular (CV) side effects. We evaluated the CV safety of mirabegron, a β3 -adrenoceptor agonist, alone and in combination therapy with the antimuscarinic agent solifenacin. The SYNERGY trial was a multinational, multicenter, randomized, double-blind, parallel-group, placebo and active-controlled phase 3 trial. Patients were randomized to receive solifenacin 5 mg + mirabegron 50 mg (combination 5 + 50 mg), solifenacin 5 mg + mirabegron 25 mg (combination 5 + 25 mg), solifenacin 5 mg monotherapy, mirabegron 25 mg monotherapy, mirabegron 50 mg monotherapy, or placebo for a 12-week double-blind treatment period...
April 12, 2018: Journal of Clinical Pharmacology
Weijiang Zhang, Christine McIntyre, Melissa Kuhn, Harper Forbes, Tae Min Kim, Jeeyun Lee, Lev Demidov, Dawn Colburn
The primary objective of this phase 1, open-label, multicenter, 3-period, fixed-sequence study was to evaluate the effect of multiple doses of vemurafenib on the pharmacokinetics of a single dose of digoxin, a probe P-glycoprotein (P-gp) substrate, in patients with BRAFV600 mutation-positive metastatic malignancy. Following a 28-day screening period, patients received a single oral dose of digoxin 0.25 mg on day 1 in period A, oral vemurafenib 960 mg twice daily for 21 days in period B (days 8-28), and a single oral dose of digoxin 0...
April 12, 2018: Journal of Clinical Pharmacology
Bertram Pitt, Vanessa Zann, Chris Roe, Jeffrey W Jacobs, James P Davidson, Christine Dowd, Padmapriya Kumaraswamy, Fangling Lin, Paul Korner, Robert C Blanks, David P Rosenbaum
Hyperkalemia is common in patients with heart failure or chronic kidney disease, particularly those taking renin-angiotensin-aldosterone system inhibitors, and can cause arrhythmias and sudden cardiac death. The most widely used treatment, sodium polystyrene sulfonate (SPS), limits gastrointestinal potassium absorption, but has poor palatability. RDX7675 (RDX227675) is the calcium salt of a reengineered polystyrene sulfonate-based resin with improved palatability over SPS. The pharmacodynamic effects and safety of RDX7675 were assessed in a phase 1, single-center, randomized, active-controlled study...
April 12, 2018: Journal of Clinical Pharmacology
Wonkyung Byon, Sunil Nepal, Alan E Schuster, Andrew Shenker, Charles E Frost
This study was conducted to investigate the extent of absorption in different regions of the gastrointestinal (GI) tract. The relative bioavailability of an apixaban crushed tablet was also assessed to investigate the effect of dissolution on absorption. This was an open-label, randomized, 4-period, 4-treatment crossover study with a 7-day washout period balanced for first-order residual effects in 12 healthy subjects. Subjects received a single dose of a 2.5-mg apixaban solution administered orally, released in the distal small intestine and in the ascending colon...
March 26, 2018: Journal of Clinical Pharmacology
Randall K Hoover, Harry Alcorn, Laura Lawrence, Susan K Paulson, Megan Quintas, David R Luke, Sue K Cammarata
Delafloxacin, a fluoroquinolone, has activity against Gram-positive organisms including methicillin-resistant S aureus and fluoroquinolone-susceptible and -resistant Gram-negative organisms. The intravenous formulation of delafloxacin contains the excipient sulfobutylether-β-cyclodextrin (SBECD), which is eliminated by renal filtration. This study examined the pharmacokinetics and safety of SBECD after single intravenous (IV) infusions in subjects with renal impairment. The study was an open-label, parallel-group, crossover study in subjects with normal renal function or mild, moderate, or severe renal impairment, and those with end-stage renal disease undergoing hemodialysis...
March 26, 2018: Journal of Clinical Pharmacology
Tiago Furtado Sampaio, Erinaldo Ubirajara Damasceno Dos Santos, Gessica Dayane Cordeiro de Lima, Rute Salgues Gueiros Dos Anjos, Ronaldo Celerino da Silva, Amdore Guescel C Asano, Nadja Maria Jorge Asano, Sergio Crovella, Paulo Roberto Eleutério de Souza
The most commonly used Parkinson's disease (PD) treatment is the replacement of dopamine by its levodopa precursor (l-dopa). Monoamine oxidase-B (MAO-B) and catechol-o-methyl transferase (COMT) are enzymes involved in the metabolism and regulation of dopamine availability. In our study we investigated the possible relation among selected single-nucleotide polymorphisms (SNPs) in the MAO-B (rs1799836) and COMT (rs4680) genes and the therapeutic response to levodopa (l-dopa). A total of 162 Brazilian patients from the Pro-Parkinson service of Clinics Hospital of Pernambuco diagnosed with sporadic PD and treated with levodopa were enrolled...
March 26, 2018: Journal of Clinical Pharmacology
Yan Xu, Chuanpu Hu, Yanli Zhuang, Benjamin Hsu, Zhenhua Xu, Honghui Zhou
The population pharmacokinetics of sirukumab, a human immunoglobulin G1κ monoclonal antibody against interleukin-6, were characterized in patients with moderately to severely active rheumatoid arthritis in 4 phase 3 studies (SIRROUND-D, -T, -H, and -M). A total of 17 034 serum concentrations were analyzed from 1991 rheumatoid arthritis patients who received subcutaneous administration of sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. A stepwise confirmatory population PK analysis was conducted to accommodate the staged data release and the sparse sampling nature of phase 3 studies and to assess the potential covariate influences in an unbiased and timely manner...
March 26, 2018: Journal of Clinical Pharmacology
William L Marshall, Jacqueline B McCrea, Sreeraj Macha, Karsten Menzel, Fang Liu, Arne van Schanke, Joanna I Udo de Haes, Azra Hussaini, Heather R Jordan, Melissa Drexel, Bhavna S Kantesaria, Christine Tsai, Carolyn R Cho, Ellen G J Hulskotte, Joan R Butterton, Marian Iwamoto
Letermovir is a human cytomegalovirus terminase inhibitor for cytomegalovirus infection prophylaxis in hematopoietic stem cell transplant recipients. Posaconazole (POS), a substrate of glucuronosyltransferase and P-glycoprotein, and voriconazole (VRC), a substrate of CYP2C9/19, are commonly administered to transplant recipients. Because coadministration of these azoles with letermovir is expected, the effect of letermovir on exposure to these antifungals was investigated. Two trials were conducted in healthy female subjects 18 to 55 years of age...
March 26, 2018: Journal of Clinical Pharmacology
Randall Hoover, Harry Alcorn, Laura Lawrence, Susan K Paulson, Megan Quintas, Sue K Cammarata
This was an open-label, parallel-group, crossover study that examined the pharmacokinetics and safety of delafloxacin, an anionic fluoroquinolone, after a single intravenous infusion in subjects with end-stage renal disease (ESRD; creatinine clearance <15 mL/min) undergoing hemodialysis compared with healthy subjects. Subjects received 300 mg delafloxacin containing sulfobutylether-β-cyclodextrin in 2 periods separated by ≥14-day washouts. Blood and urine samples were collected, and pharmacokinetic parameters were calculated using noncompartmental methods...
March 14, 2018: Journal of Clinical Pharmacology
Yong-Soon Cho, Yook-Hwan Noh, Hyeong-Seok Lim, Sang-Heon Cho, Jong-Lyul Ghim, Sangmin Choe, Soon-Bae Kim, Jung-Sik Park, Sang-Koo Lee, Won-Seok Yang, Jai-Won Chang, Mi-Young Bahng, Kyun-Seop Bae
Udenafil is a phosphodiesterase-5 inhibitor used to treat erectile dysfunction. Although udenafil is not predominantly eliminated by the kidney, renal impairment can alter its secretion/transport pathways. Drug pharmacokinetics and safety must therefore be assessed in subjects with a renal impairment. We investigated the effects of impaired renal function on the pharmacokinetics and safety of a single 100-mg oral dose of udenafil in a single-dose, open-label, parallel-group study of 31 subjects. Cockcroft-Gault creatinine clearance was used to stratify these subjects into healthy controls (>80 mL·min-1 ) and individuals with mild (50 to ≤80 mL·min-1 ), moderate (30 to ≤50 mL·min-1 ), and severe (<30 mL·min-1 ) renal impairment...
March 14, 2018: Journal of Clinical Pharmacology
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