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T Preijers, I van Moort, K Fijnvandraat, F W G Leebeek, M H Cnossen, R A A Mathôt
BACKGROUND:  Patients with severe and moderate haemophilia A are treated prophylactically with factor VIII (FVIII) concentrate. Individualization of prophylaxis can be achieved by pharmacokinetic (PK)-guided dosing. AIM:  In this study, the performance of three PK tools (myPKFiT, Web-Accessible Population Pharmacokinetic Service-Hemophilia [WAPPS] and NONMEM) is compared. METHODS:  In 39 patients, with severe or moderate haemophilia A, blood samples were collected 4, 24 and 48 hours after administration of 50 IU kg-1 of recombinant FVIII (Advate [ n  = 30] or Kogenate [ n  = 9])...
March 2018: Thrombosis and Haemostasis
Alexis Viel, Jérôme Henri, Salim Bouchène, Julian Laroche, Jean-Guy Rolland, Jacqueline Manceau, Michel Laurentie, William Couet, Nicolas Grégoire
PURPOSE: The objective was the development of a whole-body physiologically-based pharmacokinetic (WB-PBPK) model for colistin, and its prodrug colistimethate sodium (CMS), in pigs to explore their tissue distribution, especially in kidneys. METHODS: Plasma and tissue concentrations of CMS and colistin were measured after systemic administrations of different dosing regimens of CMS in pigs. The WB-PBPK model was developed based on these data according to a non-linear mixed effect approach and using NONMEM software...
March 12, 2018: Pharmaceutical Research
Pelle Hanberg, Kristina Öbrink-Hansen, Anders Thorsted, Mats Bue, Mikkel Tøttrup, Lena E Friberg, Tore Forsingdal Hardlei, Kjeld Søballe, Jakob Gjedsted
The objectives of this study were to describe meropenem pharmacokinetics (PK) in plasma and/or subcutaneous adipose tissue (SCT) in critically ill patients receiving ECMO treatment, and to develop a population PK model to simulate alternative dosing regimens and modes of administration. We conducted a prospective observational study. Ten patients on ECMO treatment received meropenem (1 or 2 g) intravenously over 5 min every 8 hours. Serial SCT concentrations were determined using microdialysis and compared with plasma concentrations...
March 12, 2018: Antimicrobial Agents and Chemotherapy
Harm-Jan de Grooth, Wai-Ping Manubulu-Choo, Anthe S Zandvliet, Angélique M E Spoelstra-de Man, Armand R Girbes, Eleonora L Swart, Heleen M Oudemans-van Straaten
BACKGROUND: Early high-dose intravenous vitamin-C is being investigated as adjuvant therapy in critically ill patients, but the optimal dose and infusion method are unclear. The primary aim of this study was to describe the dose-plasma concentration relationship and safety of four different dosing regimens. METHODS: Four-group randomized pharmacokinetic trial. Critically ill patients with multiple organ dysfunction were randomized to receive 2g/day or 10g/day vitamin-C as a twice daily bolus infusion or continuous infusion for 48 hours...
March 6, 2018: Chest
Brady S Moffett, Charissa Kam, Marianne Galati, Lindsay Schmees, Gideon A Stitt, Paula A Revell, Debra L Palazzi
BACKGROUND: Obese pediatric patients often require dose reductions when initiating gentamicin therapy. An appropriate method for calculating ideal body weight for dosing gentamicin in pediatric patients has not been validated. METHODS: A retrospective, population pharmacokinetic study was designed and included non-intensive care pediatric patients who received gentamicin and had serum gentamicin concentrations sampled. Actual body weight, adjusted body weight, and fat-free mass were used to describe the pharmacokinetic variables...
March 6, 2018: Therapeutic Drug Monitoring
V Goti, A Chaturvedula, M J Fossler, S Mok, J T Jacob
BACKGROUND: Despite being in clinical use for about six decades, vancomycin dosing remains perplexing and complex. METHODS: A population pharmacokinetic modeling and simulation approach was used to evaluate the efficiency of the current nomogram-based dosing of vancomycin. Serum vancomycin concentrations were obtained as a part of routine therapeutic drug monitoring (TDM) from two 500-bed academic medical centers. A population pharmacokinetic model was first built using these TDM data...
February 20, 2018: Therapeutic Drug Monitoring
Helgi Padari, Tuuli Metsvaht, Eva Germovsek, Charlotte I Barker, Karin Kipper, Koit Herodes, Joseph F Standing, Kersti Oselin, Tõnis Tasa, Hiie Soeorg, Irja Lutsar
Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but poorly for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We described PK of penicillin G in neonates with gestational age (GA) ≥32 weeks and postnatal age <72 h. Penicillin G was administered intravenously at a dose of 25,000 or 50,000 IU/kg/q12h. At steady state, PK blood samples were collected prior to and at 5 min, 1 h, 3 h, 8 h, 12 h after injection...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Satoshi Ueshima, Daiki Hira, Yuuma Kimura, Ryo Fujii, Chiho Tomitsuka, Takuya Yamane, Yohei Tabuchi, Tomoya Ozawa, Hideki Itoh, Seiko Ohno, Minoru Horie, Tomohiro Terada, Toshiya Katsura
AIMS: This study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolising enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban. METHODS: Data were collected from 81 Japanese patients with atrial fibrillation. Pharmacogenomic data were stratified by ABCB1, ABCG2, and CYP3A5 polymorphisms. The pharmacokinetic profile of apixaban was described by a one-compartment model with first-order absorption. Population pharmacokinetic analysis was conducted using non-linear mixed effect modelling (NONMEM™) program...
February 19, 2018: British Journal of Clinical Pharmacology
M H Kuizenga, P J Colin, K M E M Reyntjens, D J Touw, H Nalbat, F H Knotnerus, H E M Vereecke, M M R F Struys
BACKGROUND: Neural inertia is defined as the tendency of the central nervous system to resist transitions between arousal states. This phenomenon has been observed in mice and Drosophila anaesthetized with volatile anaesthetics: the effect-site concentration required to induce anaesthesia in 50% of the population (C50 ) was significantly higher than the effect-site concentration for 50% of the population to recover from anaesthesia. We evaluated this phenomenon in humans using propofol or sevoflurane (both with or without remifentanil) as anaesthetic agents...
March 2018: British Journal of Anaesthesia
Victor Mangas-Sanjuan, Carmen Navarro-Fontestad, Alfredo García-Arieta, Iñaki F Trocóniz, Marival Bermejo
A semi-physiological two compartment pharmacokinetic model with two active metabolites (primary (PM) and secondary metabolites (SM)) with saturable and non-saturable pre-systemic efflux transporter, intestinal and hepatic metabolism has been developed. The aim of this work is to explore in several scenarios which analyte (parent drug or any of the metabolites) is the most sensitive to changes in drug product performance (i.e. differences in in vivo dissolution) and to make recommendations based on the simulations outcome...
February 13, 2018: European Journal of Pharmaceutical Sciences
Nayoung Han, Jung-Woo Chae, Jihyun Jeon, Jaeyeon Lee, Hyun-Moon Back, Byungjeong Song, Kwang-Il Kwon, Sang Kyum Kim, Hwi-Yeol Yun
Background: Although alterations in the methionine metabolism cycle (MMC) have been associated with vascular complications of diabetes, there have not been consistent results about the levels of methionine and homocysteine in type 2 diabetes mellitus (T2DM). The aim of the current study was to predict changes in plasma methionine and homocysteine concentrations after simulated consumption of methionine-rich foods, following the development of a mathematical model for MMC in Zucker Diabetic Fatty (ZDF) rats, as a representative T2DM animal model...
2018: Nutrition & Metabolism
Iris K Minichmayr, Jason A Roberts, Otto R Frey, Anka C Roehr, Charlotte Kloft, Alexander Brinkmann
Background: Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients. Objectives: To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function. Methods: A population pharmacokinetic model was developed in NONMEM® 7.3 based on steady-state meropenem concentrations (CSS) collected during therapeutic drug monitoring...
February 7, 2018: Journal of Antimicrobial Chemotherapy
Suchaya Sanhajariya, Stephen B Duffull, Geoffrey K Isbister
Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974-present) and Medline (1946-present). For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, the disposition of snake venom was described by a two-compartment model consisting of a rapid distribution phase and a slow elimination phase, with half-lives of 5 to 48 min and 0...
February 7, 2018: Toxins
Luis I Cortínez, Pablo Sepúlveda, Augusto Rolle, Pauline Cottin, Alexandre Guerrini, Brian J Anderson
BACKGROUND: The aim of this study is to derive a propofol pharmacokinetic (PK) pharmacodynamic (PD) model to perform effect-site target-controlled infusion (TCI) in obese patients, and to analyze its performance along with that of other available PK models. METHODS: In the first step of the study, a 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (keo) was used to fit propofol concentration-bispectral index (BIS) data...
February 2, 2018: Anesthesia and Analgesia
Sandra Matovic, Jasmina R Milovanovic, Katerina Dajic, Anđelka Stojkovic, Slobodan M Jankovic
OBJECTIVES: Asthma and vitamin D deficiency are widespread in the pediatric and adolescent population. The aim of this study was to develop a population pharmacokinetic (PPK) model and to evaluate the most important factors that can significantly affect clearance of 25-hydroxy vitamin D in asthmatic children using PPK analysis. MATERIALS AND METHODS: The study population included school children and adolescents from 7 to 18 years of age of both sexes. PPK analysis was performed by non-linear mixed-effects modeling (NONMEM), and 19 covariates were assessed...
February 2, 2018: International Journal of Clinical Pharmacology and Therapeutics
Yun Seob Jung, Soon Min Lee, Min Soo Park, Kyungsoo Park
OBJECTIVE: This study was conducted to develop a population pharmacokinetic (PK) model of levetiracetam in Korean neonates with seizures. MATERIALS AND METHODS: Data were obtained from a retrospective study of 18 neonates with seizures admitted to the Neonatal Intensive Care Unit (NICU) of Severance Children's Hospital for the period of from 2013 to 2015. Sampling and dosing times were recorded by clinical research coordinators on case report forms. Demographic factors and laboratory results were tested as potential covariates for PK parameters...
February 2, 2018: International Journal of Clinical Pharmacology and Therapeutics
Alexander Eser, Christian Primas, Sieglinde Reinisch, Harald Vogelsang, Gottfried Novacek, Diane R Mould, Walter Reinisch
Despite a robust exposure-response relationship of infliximab in inflammatory bowel disease (IBD), attempts to adjust dosing to individually predicted serum concentrations of infliximab (SICs) are lacking. Compared with labor-intensive conventional software for pharmacokinetic (PK) modeling (eg, NONMEM) dashboards are easy-to-use programs incorporating complex Bayesian statistics to determine individual pharmacokinetics. We evaluated various infliximab detection assays and the number of samples needed to precisely forecast individual SICs using a Bayesian dashboard...
January 30, 2018: Journal of Clinical Pharmacology
Elsa Maksoud, Berengere Koehl, Aude Facchin, Phuong Ha, Wei Zhao, Florentia Kaguelidou, Malika Benkerrou, Patricia Mariani, Albert Faye, Mathie Lorrot, Evelyne Jacqz-Aigrain
The pharmacokinetic profile of most drugs is dependent on patient's covariates and may be influenced by the disease. Cefotaxime is frequently prescribed in pediatric patients with sickle-cell disease (SCD), characterized by vaso-occlusive complications, chronic haemolytic anaemia and defective immunological function predisposing to severe infection. Data on the impact of the disease on cefotaxime disposition are missing. In the present study, our aims were to determine cefotaxime pharmacokinetics when prescribed in SCD children for suspected or proven bacterial infection, identify significant covariates and perform Monte-Carlo simulations to optimize drug dosage...
January 29, 2018: Antimicrobial Agents and Chemotherapy
Zhong-Ren Shi, Xing-Kai Chen, Li-Yuan Tian, Ya-Kun Wang, Gu-Ying Zhang, Lei Dong, Totsapol Jirasomprasert, Evelyne Jacqz-Aigrain, Wei Zhao
Objective: Ceftazidime, a third-generation cephalosporin, can be used for thetreatment of adults and children with infections due to susceptible bacteria. To date, the pediatric pharmacokinetic data is limited in infants, and therefore we aimed to evaluate the population pharmacokinetics of ceftazidime in infants and define the appropriate dose to optimize ceftazidime treatment.Methods: Blood samples were collected from children treated with ceftazidime, and concentrations of drug were quantified by HPLC-UV...
January 29, 2018: Antimicrobial Agents and Chemotherapy
Wei Zhao, Stéphanie Leroux, Valérie Biran, Evelyne Jacqz-Aigrain
BACKGROUND: Although substantial progress has been made in understanding of ontogeny of drug metabolism, there is still a gap of knowledge in developmental pharmacogenetics in neonates. We hypothesized that both age and pharmacogenetics might explain the developmental pattern of CYP2C19. We conducted a population pharmacokinetic-pharmacogenetic study to quantify the developmental pharmacogenetics of CYP2C19 in neonates and young infants using omeprazole as a probe drug. METHODS: Pharmacokinetic samples were collected from 51 Caucasian neonates and young infants, who were receiving omeprazole treatment...
January 28, 2018: British Journal of Clinical Pharmacology
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