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Clinical Pharmacokinetics

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https://www.readbyqxmd.com/read/29139042/obesity-and-altered-aspirin-pharmacology
#1
REVIEW
Nicholas B Norgard
Obesity is an independent risk factor for cardiovascular morbidity and mortality due to atherothrombotic events and represents a group of patients who are in need of optimized antithrombotic therapy. Central to the obesity-related risk of atherothrombosis is a pro-thrombotic state characterized by increased levels of coagulation factors, impaired fibrinolysis, and platelet hyper-reactivity, which results from the interaction among the features clustering in obesity: insulin resistance, inflammation, oxidative stress, and endothelial dysfunction...
November 14, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29134570/evaluation-of-tobramycin-exposure-predictions-in-three-bayesian-forecasting-programmes-compared-with-current-clinical-practice-in-children-and-adults-with-cystic-fibrosis
#2
Marc Burgard, Indy Sandaradura, Sebastiaan J van Hal, Sonya Stacey, Stefanie Hennig
BACKGROUND AND OBJECTIVES: Bayesian forecasting (BF) methods for tobramycin dose individualisation has not seen widespread clinical adoption, despite being endorsed by clinical practice guidelines. Several freeware and commercial programmes using BF methods are available to support personalised dosing. This study evaluated exposure estimates, dose recommendations, and predictive performance compared with current clinical practice. METHODS: Data from 105 patients (50 adults and 55 children) with cystic fibrosis who received intravenous tobramycin treatment and had paired concentration-time measurements were analysed using (1) log-linear regression analysis, and (2) three BF programmes: TDMx, InsightRX, and DoseMe...
November 13, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29086344/clinical-pharmacokinetic-and-pharmacodynamic-profile-of-riociguat
#3
REVIEW
Reiner Frey, Corina Becker, Soundos Saleh, Sigrun Unger, Dorina van der Mey, Wolfgang Mück
Oral riociguat is a soluble guanylate cyclase (sGC) stimulator that targets the nitric oxide (NO)-sGC-cyclic guanosine monophosphate pathway with a dual mode of action: directly by stimulating sGC, and indirectly by increasing the sensitivity of sGC to NO. It is rapidly absorbed, displays almost complete bioavailability (94.3%), and can be taken with or without food and as crushed or whole tablets. Riociguat exposure shows pronounced interindividual (60%) and low intraindividual (30%) variability in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH), and is therefore administered using an individual dose-adjustment scheme at treatment initiation...
October 30, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29080937/population-pharmacokinetics-and-dosing-considerations-for-the-use-of-linezolid-in-overweight-and-obese-adult-patients
#4
Piergiorgio Cojutti, Manjunath P Pai, Federico Pea
BACKGROUND: Linezolid is an anti-Gram-positive antimicrobial agent used at a fixed dose of 600 mg every 12 h. OBJECTIVES: The objective of this study was to assess the population pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of overweight and obese hospitalized patients. PATIENTS AND METHODS: Population pharmacokinetic and Monte Carlo simulations were conducted to assess the probability of target attainment (PTA) of an area under the concentration-time curve from time zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) ratio > 100, defined as the pharmacodynamic target of efficacy, with incremental candidate dosages...
October 28, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29076110/population-pharmacokinetics-of-upadacitinib-in-healthy-subjects-and-subjects-with-rheumatoid-arthritis-analyses-of-phase-i-and-ii-clinical-trials
#5
Ben Klünder, Mohamed-Eslam F Mohamed, Ahmed A Othman
BACKGROUND AND OBJECTIVES: Upadacitinib is a janus kinase (JAK) 1 inhibitor being developed for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. This work characterized upadacitinib population pharmacokinetics in healthy subjects and RA patients and the effects of covariates on upadacitinib exposure. METHODS: Upadacitinib plasma concentrations (n = 6399) from 107 healthy subjects and 466 RA patients from three phase I and two 12-week RA phase IIb trials (1-48 mg immediate-release doses across studies) were analyzed using non-linear mixed-effects modeling...
October 26, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29063519/clinical-pharmacokinetics-and-pharmacodynamics-of-oxazolidinones
#6
REVIEW
Claire Roger, Jason A Roberts, Laurent Muller
Oxazolidinones are a class of synthetic antimicrobial agents with potent activity against a wide range of multidrug-resistant Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Oxazolidinones exhibit their antibacterial effects by inhibiting protein synthesis acting on the ribosomal 50S subunit of the bacteria and thus preventing formation of a functional 70S initiation complex. Currently, two oxazolidinones have been approved by the US Food and Drug Administration: linezolid and more recently tedizolid...
October 23, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29063518/clinical-pharmacokinetics-and-safety-of-alz-801-a-novel-prodrug-of-tramiprosate-in-development-for-the-treatment-of-alzheimer-s-disease
#7
John A Hey, Jeremy Y Yu, Mark Versavel, Susan Abushakra, Petr Kocis, Aidan Power, Paul L Kaplan, John Amedio, Martin Tolar
BACKGROUND: ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor that was evaluated extensively in preclinical and clinical investigations for the treatment of Alzheimer's disease (AD). Tramiprosate has been found to inhibit β-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Aβ42 monomers, resulting in the inhibition of formation of oligomers and subsequent aggregation...
October 23, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29063517/parp-inhibitors-in-the-treatment-of-triple-negative-breast-cancer
#8
REVIEW
Jill J J Geenen, Sabine C Linn, Jos H Beijnen, Jan H M Schellens
Breast cancer is a heterogeneous disease, manifesting in a broad differentiation in phenotypes and morphologic profiles, resulting in variable clinical behavior. Between 10 and 20% of all breast cancers are triple negative. Triple-negative breast cancer (TNBC) lacks the expression of human epidermal growth factor receptor 2 (HER2) and hormone receptors; therefore, to date, chemotherapy remains the backbone of treatment. TNBC tends to be aggressive and has a high histological grade, resulting in a poor 5-year prognosis...
October 23, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29032486/population-pharmacokinetics-of-subcutaneous-pasireotide-in-healthy-volunteers-and-cushing-s-disease-patients
#9
Jerry Nedelman, Roland Fisch, Ke Hu, Ines Paule, Jocelyn Zhou
BACKGROUND AND OBJECTIVE: Pasireotide (SOM230, Signifor(®)) is a somatostatin analog approved in a subcutaneous formulation for the treatment of Cushing's disease. This analysis characterizes the population pharmacokinetics (PopPK) of subcutaneous pasireotide jointly in healthy volunteers (HVs) and Cushing's disease patients (CDPs), evaluating the effects of age, body size, and population on pasireotide pharmacokinetics. METHODS: The analysis dataset included five phase I studies and one each from phase II and phase III...
October 14, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28983805/influence-of-disease-and-patient-characteristics-on-daratumumab-exposure-and-clinical-outcomes-in-relapsed-or-refractory-multiple-myeloma
#10
Xiaoyu Yan, Pamela L Clemens, Thomas Puchalski, Sagar Lonial, Henk Lokhorst, Peter M Voorhees, Saad Usmani, Paul G Richardson, Torben Plesner, Kevin Liu, Robert Z Orlowski, Nedjad Losic, Richard Jansson, Tahamtan Ahmadi, Kristen Lantz, Juan Jose Perez Ruixo, Honghui Zhou, Xu Steven Xu
OBJECTIVE: The aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM). PATIENTS AND METHODS: Baseline myeloma type, albumin levels, renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group (ECOG) status, refractory status, and number of prior therapies were evaluated using data from two clinical studies-GEN501 (N = 104) and SIRIUS (N = 124)...
October 5, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28980166/population-pharmacokinetic-model-to-optimize-cefotaxime-dosing-regimen-in-critically-ill-children
#11
Agathe Béranger, Mehdi Oualha, Saïk Urien, Mathieu Genuini, Sylvain Renolleau, Radia Aboura, Déborah Hirt, Claire Heilbronner, Julie Toubiana, Jean-Marc Tréluyer, Sihem Benaboud
BACKGROUND: During sepsis, optimal plasma antibiotic concentrations are mandatory. Modifications of pharmacokinetic parameters could lead to low drug concentrations and therefore, insufficient therapeutic levels. OBJECTIVE: The aim of this study was to build a population pharmacokinetic model for cefotaxime and its metabolite desacetylcefotaxime in order to optimize individual dosing regimens for critically ill children. METHODS: All children aged < 18 years, weighing more than 2...
October 4, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28924743/a-physiologically-based-pharmacokinetic-model-for-pregnant-women-to-predict-the-pharmacokinetics-of-drugs-metabolized-via-several-enzymatic-pathways
#12
André Dallmann, Ibrahim Ince, Katrin Coboeken, Thomas Eissing, Georg Hempel
BACKGROUND: Physiologically based pharmacokinetic modeling is considered a valuable tool for predicting pharmacokinetic changes in pregnancy to subsequently guide in-vivo pharmacokinetic trials in pregnant women. The objective of this study was to extend and verify a previously developed physiologically based pharmacokinetic model for pregnant women for the prediction of pharmacokinetics of drugs metabolized via several cytochrome P450 enzymes. METHODS: Quantitative information on gestation-specific changes in enzyme activity available in the literature was incorporated in a pregnancy physiologically based pharmacokinetic model and the pharmacokinetics of eight drugs metabolized via one or multiple cytochrome P450 enzymes was predicted...
September 18, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28921125/exogenous-cannabinoid-efficacy-merely-a-pharmacokinetic-interaction
#13
Jennifer H Martin, Jennifer Schneider, Catherine J Lucas, Peter Galettis
Endocannabinoid pharmacology is now relatively well understood with a number of endocannabinoids and endogenous cannabinoid neurotransmitters identified and the pharmacokinetics relatively well ascertained. Further, the cannabinoid receptors are now molecularly and pharmacologically characterised and the cell processes involved in endocannabinoid transcription, synthesis, post-translational modification and protein expression are reported. Endogenous cannabinoids have been shown to have key roles in immune and pain pathways and neuro-behavioural signalling including appetite regulation...
September 18, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28918602/population-pharmacokinetics-and-optimal-sampling-strategy-for-model-based-precision-dosing-of-melphalan-in-patients-undergoing-hematopoietic-stem-cell-transplantation
#14
Kana Mizuno, Min Dong, Tsuyoshi Fukuda, Sharat Chandra, Parinda A Mehta, Scott McConnell, Elias J Anaissie, Alexander A Vinks
BACKGROUND: High-dose melphalan is an important component of conditioning regimens for patients undergoing hematopoietic stem cell transplantation. The current dosing strategy based on body surface area results in a high incidence of oral mucositis and gastrointestinal and liver toxicity. Pharmacokinetically guided dosing will individualize exposure and help minimize overexposure-related toxicity. OBJECTIVE: The purpose of this study was to develop a population pharmacokinetic model and optimal sampling strategy...
September 16, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28905331/antibiotic-distribution-into-cerebrospinal-fluid-can-dosing-safely-account-for-drug-and-disease-factors-in-the-treatment-of-ventriculostomy-associated-infections
#15
Nilesh Kumta, Jason A Roberts, Jeffrey Lipman, Menino Osbert Cotta
Ventriculostomy-associated infections, or ventriculitis, in critically ill patients are associated with considerable morbidity. Efficacious antibiotic dosing for the treatment of these infections may be complicated by altered antibiotic concentrations in the cerebrospinal fluid due to variable meningeal inflammation and antibiotic properties. Therefore, doses used to treat infections with a higher degree of meningeal inflammation (such as meningitis) may often fail to achieve equivalent exposures in patients with ventriculostomy-associated infections such as ventriculitis...
September 13, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28889370/semi-mechanistic-model-for-predicting-the-dosing-rate-in-children-and-neonates-for-drugs-mainly-eliminated-by-cytochrome-metabolism
#16
Lena Cerruti, Nathalie Bleyzac, Michel Tod
BACKGROUND AND OBJECTIVE: A simple approach is proposed to predict drug clearance in children when no paediatric data are available for drugs metabolised by cytochromes. METHODS: The maturation functions of cytochrome activity and binding proteins in plasma were combined with several measures of body size to describe drug clearance increase with age. The complete model and different reduced models were evaluated on a large panel of drug clearance data in children...
September 9, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28887801/population-pharmacokinetic-and-pharmacodynamic-analysis-of-belimumab-administered-subcutaneously-in-healthy-volunteers-and-patients-with-systemic-lupus-erythematosus
#17
Herbert Struemper, Mita Thapar, David Roth
BACKGROUND: Intravenous belimumab 10 mg/kg every 4 weeks is indicated in patients with active, autoantibody-positive systemic lupus erythematosus receiving standard systemic lupus erythematosus care. Subcutaneous 200-mg weekly administration, which may prove more convenient for patients and improve adherence, is currently under investigation. OBJECTIVE: The objective of this study was to characterize the population pharmacokinetics and exposure-efficacy response of subcutaneous belimumab in a pooled analysis of pharmacokinetic data [phase I: BEL114448 (NCT01583530) and BEL116119 (NCT01516450) in healthy subjects (n = 134); phase III: BEL112341 (NCT01484496) in adults with systemic lupus erythematosus (n = 554)] and pharmacodynamic data [BEL112341 in adults with systemic lupus erythematosus (n = 833)]...
September 8, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28884437/extrapolation-of-a-brivaracetam-exposure-response-model-from-adults-to-children-with-focal-seizures
#18
Rik Schoemaker, Janet R Wade, Armel Stockis
INTRODUCTION: Prediction of brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for brivaracetam to children, using an existing population PK model for brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration-effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A). METHODS: The existing adult PK/PD model for brivaracetam was applied to a combined adult-pediatric dataset of levetiracetam...
September 7, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28875477/effects-of-pon1-gene-promoter-dna-methylation-and-genetic-variations-on-the-clinical-outcomes-of-dual-antiplatelet-therapy-for-patients%C3%A2-undergoing-percutaneous-coronary-intervention
#19
He-Ping Lei, Xi-Yong Yu, Hong Wu, Yan-Hong Kang, Wan-Ping Zhong, Li-Yun Cai, Meng-Zhen Zhang, Ji-Yan Chen, Li-Ping Mai, Qing-Shan Ding, Min Yang, Shi-Long Zhong
INTRODUCTION AND OBJECTIVE: The relationship between either paraoxonase 1 (PON1) gene promoter DNA methylation or genetic variations and bleeding or major adverse cardiac events after dual antiplatelet therapy has been incompletely characterized. We aimed to systematically investigate the role of genetic variations and DNA methylation of the PON1 CpG island promoter on the clinical outcomes of dual antiplatelet therapy for patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI)...
September 5, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28866861/effects-of-the-proton-pump-inhibitors-omeprazole-and-pantoprazole-on-the-cytochrome-p450-mediated-metabolism-of-venlafaxine
#20
Maxim Kuzin, Georgios Schoretsanitis, Ekkehard Haen, Benedikt Stegmann, Christoph Hiemke, Gerhard Gründer, Michael Paulzen
BACKGROUND AND OBJECTIVE: An increasing trend in prescribing proton pump inhibitors (PPIs) inevitably increases the risk of unwanted drug-drug interactions (DDIs). The aim of this study was to uncover pharmacokinetic interactions between two PPIs-omeprazole and pantoprazole-and venlafaxine. METHODS: A therapeutic drug monitoring database contained plasma concentrations of venlafaxine and its active metabolite O-desmethylvenlafaxine. We considered three groups: a group of patients who received venlafaxine without confounding medications (non-PPI group, n = 906); a group of patients who were comedicated with omeprazole (n = 40); and a group of patients comedicated with pantoprazole (n = 40)...
September 2, 2017: Clinical Pharmacokinetics
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