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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
S W Johnny Lau, Jan-Frederik Schlender, Darrell R Abernethy, Gilbert J Burckart, Adam Golden, Patricia W Slattum, Sven Stegemann, Thomas Eissing
No abstract text is available yet for this article.
October 11, 2017: Journal of Clinical Pharmacology
James F Burris, J Thomas Puglisi
The Federal Policy for the Protection of Human Subjects, generally referred to as the "Common Rule," is the basis for the human research protection policies of 16 signatory federal agencies and governs virtually all federally funded research involving humans. The Common Rule was originally published in 1991. It has been recognized that changes to the Common Rule are needed to accommodate changes in the research environment and advances in information technology. The Department of Health & Human Services (HHS) issued an Advance Notice of Proposed Rulemaking in the Federal Register in 2011 and a Notice of Proposed Rulemaking in 2015...
October 5, 2017: Journal of Clinical Pharmacology
Soyeon Cho, Jeong Yee, Jae Youn Kim, Sandy Jeong Rhie, Hye Sun Gwak
Gefitinib is a drug used for the treatment of non-small cell lung cancer (NSCLC) patients. Severe hepatotoxicity was observed, but only a few cases have been reported on the hepatotoxicity of gefitinib. This study aimed to investigate the association between gefitinib-induced hepatotoxicity and various factors including concomitant medications in lung cancer patients. From January 2013 to December 2014, a retrospective study was performed with NSCLC patients who were treated with gefitinib. Associations between hepatotoxicity and various factors including concomitant drugs were analyzed...
October 5, 2017: Journal of Clinical Pharmacology
Borje Darpo, Hongqi Xue, Nikki Adetoro, Barbara G Matthews, Helen S Pentikis
SYM-1219, a novel oral granule formulation of secnidazole, is under development as single-dose treatment for bacterial vaginosis. This 4-way, randomized, crossover study evaluated the effects of SYM-1219 on electrocardiographic (ECG) parameters in 52 healthy subjects. Subjects were administered single doses of SYM-1219, 2 g (proposed therapeutic dose), 6 g (supratherapeutic dose), placebo, and moxifloxacin (positive control). Serial digital 12-lead ECGs were recorded pre- and postdose; blood samples were taken to determine plasma secnidazole concentrations...
October 2, 2017: Journal of Clinical Pharmacology
Xiaoyun Liu, Yifan Zhang, Qian Chen, Yan Zhan, Quanren Wang, Chaoying Hu, Chen Yu, Zitao Guo, Xiaoyan Chen, Dafang Zhong
Apatinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with advanced-stage gastric cancer or gastroesophageal junction cancer who have progressed or recurred after at least 2 kinds of systemic chemotherapy. In vitro data indicate that cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of apatinib. Pharmacokinetic drug-drug interactions of apatinib and (1) a CYP3A4 inducer (rifampin) or (2) a CYP3A inhibitor (itraconazole) were clinically evaluated in healthy volunteers...
October 2, 2017: Journal of Clinical Pharmacology
Saibal Das, Jayanta Kumar Dey, Niranjan Prabhu Ss, Sachin David, Aniket Kumar, Deepa Braganza, Margaret Shanthi Fx
This study was performed to examine the association of 2 functional polymorphisms of the promoter region of the serotonin 5-HTR2C receptor gene: -759C/T (rs3813929) and -97G/C (rs518147) with risperidone-induced insulin resistance syndrome in an Indian population. In this case-control study, 52 adult patients of either sex, having no insulin resistance syndrome before initiating treatment, who were previously drug naive and who received risperidone monotherapy for ≥1 year, were recruited in 2 arms. Of them, 26 had risperidone-induced insulin resistance syndrome, and 26 did not have risperidone-induced insulin resistance syndrome...
September 22, 2017: Journal of Clinical Pharmacology
Lisa D Coles, Paul J Tuite, Gülin Öz, Usha R Mishra, Reena V Kartha, Kathleen M Sullivan, James C Cloyd, Melissa Terpstra
Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3)...
September 22, 2017: Journal of Clinical Pharmacology
Barbara Schütt, Marcus-Hillert Schultze-Mosgau, Corinna Draeger, Xinying Chang, Stephanie Löwen, Andreas Kaiser, Beate Rohde
This randomized, double-blind, parallel-group study in healthy young women investigated the effect of treatment with vilaprisan (0.5, 1, 2, or 4 mg/day for 12 weeks) on ovarian function by assessing the Hoogland score, which is based on the size of follicle-like structures as determined by transvaginal ultrasound and on estradiol and progesterone serum concentrations. Ovulation inhibition (ie, Hoogland score <6 in treatment weeks 1-4 and 8-12) was observed in >80% of the subjects receiving vilaprisan ≥1 mg/day...
September 21, 2017: Journal of Clinical Pharmacology
Mario González-Sales, Lanyan Fang, Myong-Jin Kim, Liang Zhao
We evaluated whether the current bioequivalence limit is adequate to ensure safety and efficacy of rivaroxaban in patients under total hip arthroplasty and total knee arthroplasty based on its model informed benefit/risk profile. Clinical data from a total of 7145 patients from 3 phase 2 and 4 phase 3 clinical trials were included in the current model-based exposure-response analysis. The relationships between rivaroxaban exposure measurements (ie, minimum or trough, maximum, average concentration, and area under the concentration-time curve [AUC] at steady state) and clinical outcomes (ie, the probabilities of major bleeding [MB] and venous thromboembolism [VTE]) were modeled using NONMEM 7...
September 19, 2017: Journal of Clinical Pharmacology
Min Zhu, Andrea Kratzer, Jessica Johnson, Chris Holland, Christian Brandl, Indrajeet Singh, Andreas Wolf, Sameer Doshi
We evaluated blinatumomab pharmacokinetics, pharmacodynamics (CD3+ T-cell, CD19+ B-cell, and cytokine levels), and their associations with efficacy or safety in relapsed/refractory acute lymphoblastic leukemia. Blinatumomab pharmacokinetics (continuous intravenous infusion) from a phase 2 study (n = 189; NCT01466179) were assessed noncompartmentally. Associations between steady-state concentration (Css ) and efficacy (complete remission [CR] or CR with partial hematologic recovery [CRh]) or safety (cytokine release syndrome [CRS] and neurologic events [NEs]) were evaluated with statistical models...
September 18, 2017: Journal of Clinical Pharmacology
Naveen Mangal, Margaret O James, Peter W Stacpoole, Stephan Schmidt
Dichloroacetate (DCA) is an investigational drug used to treat congenital lactic acidosis and other mitochondrial disorders. Response to DCA therapy in young children may be suboptimal following body weight-based dosing. This is because of autoinhibition of its metabolism, age-dependent changes in pharmacokinetics, and polymorphisms in glutathione transferase zeta 1 (GSTZ1), its primary metabolizing enzyme. Our objective was to predict optimal DCA doses for the treatment of congenital lactic acidosis in children...
September 15, 2017: Journal of Clinical Pharmacology
Preet Mohinder Singh, Anuradha Borle, Jeetinder Kaur Makkar, Anjan Trikha, David Fish, Ashish Sinha
Haloperidol is an antipsychotic with well-known antiemetic potential. It is underutilized for postoperative nausea vomiting due to reported corrected QT interval (QTc) prolongation. This meta-analysis evaluates its safety and efficacy as an antiemetic in the perioperative period. Trials comparing haloperidol to 5-HT3 -receptor antagonists (5-HT3 -RA) for 24 postoperative vomiting incidences published up to May 2017 were searched in the medical database. Comparisons were made for antiemetic efficiency variables (vomiting incidence, rescue antiemetic need, and patients with complete response) during early (until 6 hours) and late postoperative phases...
September 15, 2017: Journal of Clinical Pharmacology
Xiaodong Wang, Zhi-Yi Zhang, Daniel Powers, Jing Wang, Sharon Lu, Sujata Arora, Lorraine Hughes, Jennifer Christensen, Vikram Kansra
Rolapitant, a selective and long-acting neurokinin-1 receptor antagonist, is approved in an oral formulation for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. The objective of this pivotal study was to assess the bioequivalence of a single intravenous infusion of rolapitant versus a single oral dose of rolapitant. In this randomized, open-label phase 1 study, healthy volunteers were administered rolapitant as a 180-mg oral dose or a 30-minute 166.5-mg intravenous infusion. Blood samples for pharmacokinetic analysis were collected predose and at points up to 912 hours postdose...
September 14, 2017: Journal of Clinical Pharmacology
Xiaodong Wang, Zhi-Yi Zhang, Sujata Arora, Lorraine Hughes, Jing Wang, Daniel Powers, Jennifer Christensen, Sharon Lu, Vikram Kansra
Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. Four open-label phase 1 studies evaluated the safety and drug-drug interactions of a single dose of rolapitant given intravenously (166.5 mg) or orally (180 mg) with oral digoxin (0.5 mg) or sulfasalazine (500 mg), probe substrates for the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively...
September 14, 2017: Journal of Clinical Pharmacology
Richard N Re
A variety of peptide signaling moieties that we have termed intracrines can act in the interiors of their cells of synthesis or of target cells after internalization. These intracrine factors are known to be upregulated in such disorders as diabetic nephropathy, systolic heart failure, and age-related macular degeneration. Indeed, a similar set of intracrines is upregulated in each of these disorders, suggesting a commonality of mechanism. In addition, several chronic neurodegenerative disorders such as Alzheimer disease and Parkinson disease involve intercellular trafficking of intracellular disease-causing proteins...
September 8, 2017: Journal of Clinical Pharmacology
Rajesh Krishna, Ferdous Gheyas, Yang Liu, Josee Cote, Omar Laterza, Jon L Ruckle, John A Wagner, Andrew E Denker
Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo...
September 8, 2017: Journal of Clinical Pharmacology
James P Franciosi, Edward B Mougey, Andre Williams, Roberto A Gomez-Suarez, Cameron Thomas, Christa L Creech, Katherine George, Diana Corao, John J Lima
Esophageal pH monitoring remains a primary diagnostic tool for detecting gastroesophageal reflux disease (GERD). GERD that is refractory to proton pump inhibitor (PPI) medications may be related to CYP2C19 variants. Current PPI dosing practices in children do not take into account CYP2C19 allelic variants, which may lead to underdosing and subsequently to a misperception of PPI therapy failure. We hypothesized that pH probe acid exposure outcomes associate with CYP2C19*17 alleles among children with clinical concern for GERD...
September 8, 2017: Journal of Clinical Pharmacology
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