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https://www.readbyqxmd.com/read/27922719/markov-mixed-effects-modeling-using-electronic-adherence-monitoring-records-identifies-influential-covariates-to-hiv-preexposure-prophylaxis
#1
Kumpal Madrasi, Ayyappa Chaturvedula, Jessica E Haberer, Mark Sale, Michael J Fossler, David Bangsberg, Jared M Baeten, Connie Celum, Craig W Hendrix
Adherence is a major factor in the effectiveness of preexposure prophylaxis (PrEP) for HIV prevention. Modeling patterns of adherence helps to identify influential covariates of different types of adherence as well as to enable clinical trial simulation so that appropriate interventions can be developed. We developed a Markov mixed-effects model to understand the covariates influencing adherence patterns to daily oral PrEP. Electronic adherence records (date and time of medication bottle cap opening) from the Partners PrEP ancillary adherence study with a total of 1147 subjects were used...
December 6, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27917873/dose-biomarker-response-modeling-of-the-anticancer-effect-of-ethaselen-in-a-human-non-small-cell-lung-cancer-xenograft-mouse-model
#2
Suo-Fu Ye, Jian Li, Shuang-Min Ji, Hui-Hui Zeng, Wei Lu
Thioredoxin reductase (TrxR) is a component of several redox-sensitive signaling cascades that mediate important biological processes such as cell survival, maturation, growth, migration and inhibition of apoptosis. The expression levels of TrxR1 in some human carcinoma cell lines are nearly 10 times higher than those in normal cells. Ethaselen is a novel antitumor candidate that exerts potent inhibition on non-small cell lung cancer (NSCLC) by targeting TrxR. In this study we explored the relationship between the ethaselen dose and TrxR activity level and the relationship between TrxR degradation and tumor apoptosis in a human lung carcinoma A549 xenograft model...
December 5, 2016: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/27909740/clinical-pharmacokinetics-of-magnesium-sulfate-in-the-treatment-of-children-with-severe-acute-asthma
#3
Joseph E Rower, Xiaoxi Liu, Tian Yu, Michael Mundorff, Catherine M T Sherwin, Michael D Johnson
PURPOSE: Intravenous (IV) magnesium sulfate (MgSO4) is used as adjunct therapy to treat acute asthma exacerbations. Despite its clinical use, there is a limited understanding of the disposition of magnesium in children. METHODS: To explore the pharmacokinetics (PK) of IV MgSO4 in this population, we collected retrospective data from 54 children who received IV MgSO4 for treatment of an acute asthma exacerbation at Primary Children's Hospital in Salt Lake City, UT...
December 2, 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27896683/population-pharmacokinetics-of-an-extended-release-formulation-of-exenatide-following-single-and-multiple-dose-administration
#4
Brenda Cirincione, Jeffrey Edwards, Donald E Mager
Exenatide is a glucagon-like peptide-1 receptor agonist with both immediate- and extended-release (ER) formulations that are approved for the treatment of type 2 diabetes mellitus. Long-term exposure from the ER formulation is achieved through slow peptide release from a degradable microsphere formulation. The goal of this analysis was to develop a pharmacokinetic model for the ER formulation following single and once-weekly multiple-dose administration. Pharmacokinetic data were collected from two clinical trials-one that evaluated single-dose administration of 2...
November 28, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27865605/population-pharmacokinetic-model-of-lithium-and-drug-compliance-assessment
#5
Isabel Pérez-Castelló, Víctor Mangas-Sanjuan, Ignacio González-García, Isabel Gonzalez-Alvarez, Marival Bermejo, Jose Luis Marco-Garbayo, Iñaki F Trocóniz
Population pharmacokinetic analysis of lithium during therapeutic drug monitoring and drug compliance assessment was performed in 54 patients and 246 plasma concentrations levels were included in this study. Patients received several treatment cycles (1-9) and one plasma concentration measurement for each patient was obtained always before starting next cycle (pre-dose) at steady state. Data were analysed using the population approach with NONMEM version 7.2. Lithium measurements were described using a two-compartment model (CL/F=0...
December 2016: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27855133/influence-of-genotype-on-warfarin-maintenance-dose-predictions-produced-using-a-bayesian-dose-individualization-tool
#6
Shamin M Saffian, Stephen B Duffull, Rebecca L Roberts, Robert C Tait, Leanne Black, Kirstin A Lund, Alison H Thomson, Daniel F B Wright
BACKGROUND: A previously established Bayesian dosing tool for warfarin was found to produce biased maintenance dose predictions. In this study, we aimed (1) to determine whether the biased warfarin dose predictions previously observed could be replicated in a new cohort of patients from 2 different clinical settings, (2) to explore the influence of CYP2C9 and VKORC1 genotype on predictive performance of the Bayesian dosing tool, and (3) to determine whether the previous population used to develop the kinetic-pharmacodynamic model underpinning the Bayesian dosing tool was sufficiently different from the test (posterior) population to account for the biased dose predictions...
December 2016: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/27832147/model-linking-plasma-and-intracellular-tenofovir-emtricitabine-with-deoxynucleoside-triphosphates
#7
Xinhui Chen, Sharon M Seifert, Jose R Castillo-Mancilla, Lane R Bushman, Jia-Hua Zheng, Jennifer J Kiser, Samantha MaWhinney, Peter L Anderson
The coformulation of the nucleos(t)ide analogs (NA) tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC) is approved for HIV-infection treatment and prevention. Plasma TFV and FTC undergo complicated hybrid processes to form, accumulate, and retain as their active intracellular anabolites: TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP). Such complexities manifest in nonlinear intracellular pharmacokinetics (PK). In target cells, TFV-DP/FTC-TP compete with endogenous deoxynucleoside triphosphates (dNTP) at the active site of HIV reverse transcriptase, underscoring the importance of analog:dNTP ratios for antiviral efficacy...
2016: PloS One
https://www.readbyqxmd.com/read/27822850/population-pharmacokinetics-pk-and-pharmacodynamics-pd-analysis-of-ly3015014-a-monoclonal-antibody-to-protein-convertase-subtilisin-kexin-type-9-pcsk9-in-healthy-subjects-and-hypercholesterolemia-patients
#8
Tong Shen, Douglas E James, Kathryn A Krueger
PURPOSE: LY3015014 is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds to the catalytic domain of PCSK9 and reduce low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia that is poorly controlled by maximally tolerated statin therapy. The objective of this pharmacokinetic/pharmacodynamics (PK/PD) analysis was to characterize the PK and PD properties of LY3015014 and assess the effect of covariates on the LY3015014 PK-PD profiles. METHODS: Single and multiple dose data from three phase1 studies in healthy subjects (n = 133), as well as a phase 2 study in hypercholesterolemia patients (n = 527) were combined into a single dataset for analysis...
November 7, 2016: Pharmaceutical Research
https://www.readbyqxmd.com/read/27816630/pharmacokinetic-analysis-of-modified-release-metoprolol-formulations-an-interspecies-comparison
#9
Elien De Thaye, Anouk Vervaeck, Eleonora Marostica, Jean Paul Remon, Jan Van Bocxlaer, Chris Vervaet, An Vermeulen
In the current study, we investigated the metoprolol absorption kinetics of an in-house produced oral sustained-release formulation, matrices manufactured via prilling, and two commercially available formulations, ZOK-ZID(®) (reservoir) and Slow-Lopresor(®) (matrix) in both New Zealand White rabbits and Beagle dogs, using a population pharmacokinetic analysis approach. The aim of this study was to compare the in vivo pharmacokinetic (PK) profiles of different formulations based on metoprolol, a selective adrenergic β1-receptor antagonist, in dogs and rabbits and to contrast the observed differences...
November 2, 2016: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27813241/population-pharmacokinetics-of-rifampicin-in-adult-patients-with-osteoarticular-infections-interaction-with-fusidic-acid
#10
A Marsot, A Ménard, J Dupouey, C Muziotti, R Guilhaumou, O Blin
AIMS: Rifampicin represents the key antibiotic for management of osteoarticular infections. An important pharmacokinetic variability has already been described, incriminating notably absorption and metabolism. All previous pharmacokinetic studies were only focused on patient treated for tuberculosis. The objective of this study was to describe a population pharmacokinetic model of rifampicin in patients with staphylococcal osteoarticular infections, data which have not been investigated to date...
November 4, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27799217/population-pharmacokinetics-and-pharmacogenetics-analysis-of-rilpivirine-in-hiv-1-infected-individuals
#11
Manel Aouri, Catalina Barcelo, Monia Guidi, Margalida Rotger, Matthias Cavassini, Cédric Hizrel, Thierry Buclin, Laurent A Decosterd, Chantal Csajka
BACKGROUND: Rilpivirine (RPV), the latest non nucleoside reverse transcriptase inhibitor active against HIV-1, is prescribed in a standard dosage of 25 mg once a day in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The aim of this observational study was to characterize RPV pharmacokinetic profile, to quantify interpatient variability and to identify potential factors that could influence drug exposure. METHODS: RPV concentrations data were collected from HIV patients as part of routine therapeutic drug monitoring performed in our centre...
October 31, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27795373/population-pharmacokinetics-and-dosing-considerations-for-gentamicin-in-newborns-with-suspected-or-proven-gram-negative-sepsis
#12
Yuma A Bijleveld, Maria E van den Heuvel, Caspar J Hodiamont, Ron A A Mathot, Timo R de Haan
AIM: To describe the population pharmacokinetics (PK) of gentamicin in neonates with suspected or proven gram-negative sepsis and determine the optimal dosage regimen in relation to the bacterial minimum inhibitory concentrations (MIC) found in this population. METHODS: Data were prospectively collected between October 2012 and January 2013 in the Neonatal Intensive Care unit (NICU) at the Academic Medical Centre (AMC), Amsterdam, The Netherlands. A single non-linear mixed-effects regression analysis (NONMEM®) was performed to describe the population PK of gentamicin...
October 24, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27783139/lack-of-effect-of-smoking-status-on-axitinib-pharmacokinetics-in-patients-with-non-small-cell-lung-cancer
#13
May Garrett, Timothy Taylor, Diane R Mould, Michael A Amantea, Ying Chen, Antonella Ingrosso, Yazdi K Pithavala
PURPOSE: Axitinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors 1-3, is approved for second-line treatment of advanced renal cell carcinoma. Axitinib is partially metabolized by cytochrome P450 1A2, which is induced by chronic heavy smoking. The effect of smoking on axitinib pharmacokinetics was evaluated in a non-small-cell lung cancer (NSCLC) patient population with a large number of active and ex-smokers. METHODS: Data were pooled from six clinical studies-serial pharmacokinetics from two healthy volunteer studies (n = 58) and sparse pharmacokinetics from four NSCLC studies (n = 152)-for a nonlinear mixed effects modeling (NONMEM v7...
October 25, 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27763679/theory-based-pkpd-of-s-and-r-warfarin-and-effects-on-inr-influence-of-body-size-composition-and-genotype-in-cardiac-surgery-patients
#14
Ling Xue, Nick Holford, Xiao-Liang Ding, Zhen-Ya Shen, Chen-Rong Huang, Hua Zhang, Jing-Jing Zhang, Zhe-Ning Guo, Cheng Xie, Ling Zhou, Zhi-Yao Chen, Lin-Sheng Liu, Li-Yan Miao
AIMS: The aims of this study are to apply a theory based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin. METHODS: Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population pharmacokinetic parameter with data method was used to describe the international normalized ratio (INR) time course...
October 20, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27743205/population-pharmacokinetics-of-a-novel-once-every-3-months-intramuscular-formulation-of-paliperidone-palmitate-in-patients-with-schizophrenia
#15
Mats O Magnusson, Mahesh N Samtani, Elodie L Plan, E Niclas Jonsson, Stefaan Rossenu, An Vermeulen, Alberto Russu
OBJECTIVES: Our objective was to characterize the population pharmacokinetics of paliperidone after intramuscular administration of its long-acting 3-month formulation palmitate ester at various doses and at different injection sites (deltoid and gluteal muscles). METHODS: This retrospective analysis included pooled data from 651 subjects from one phase I study (single injection of the 3-month formulation) and one phase III study (multiple injections of both 1- and 3-month formulations)...
October 14, 2016: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/27734584/population-pharmacokinetics-of-thrombomodulin-alfa-in-pediatric-patients-with-hematological-malignancy-and-disseminated-intravascular-coagulation
#16
Masanobu Takeuchi, Reo Tanoshima, Naoyuki Miyagawa, Takeo Sarashina, Hiromi Kato, Ryosuke Kajiwara, Shinya Ito, Hiroaki Goto
BACKGROUND: Thrombomodulin alfa (TM-α) is a new class of anticoagulant drug for patients with disseminated intravascular coagulation (DIC). This study aimed to determine the pharmacokinetics of TM-α and determine the optimal dose in pediatric patients with hematological malignancy and DIC. PROCEDURE: Pediatric patients with hematological malignancy and DIC were administered TM-α at a dose of 0.06 mg/kg (380 U/kg) over 30 min every 24 hr. Blood samples were taken at steady state before the start, immediately after the end, and 24 hr after the start of the sixth administration...
October 12, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27713650/glibenclamide-population-pharmacokinetic-pharmacodynamic-modeling-in-south-african-type-2-diabetic-subjects
#17
Virendra Rambiritch, Poobalan Naidoo, Goonaseelan Pillai
AIM: To determine the effective dose of glibenclamide by quantifying the dose-response relationship in South African type 2 diabetic patients. PATIENTS AND METHODS: A total of 24 type 2 diabetic patients participated in a glibenclamide dose-escalation study during which glibenclamide, glucose, and insulin concentrations were quantified, while the dose of glibenclamide was progressively increased. All except four subjects contributed data on all dose-escalation steps; however, data from all 24 patients were included in the model-based analysis...
2016: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/27709284/population-pharmacokinetic-pharmacodynamic-modeling-and-model-based-prediction-of-docetaxel-induced-neutropenia-in-japanese-patients-with-non-small-cell-lung-cancer
#18
Masato Fukae, Yoshimasa Shiraishi, Takeshi Hirota, Yuka Sasaki, Mika Yamahashi, Koichi Takayama, Yoichi Nakanishi, Ichiro Ieiri
PURPOSE: Docetaxel is used to treat many cancers, and neutropenia is the dose-limiting factor for its clinical use. A population pharmacokinetic-pharmacodynamic (PK-PD) model was introduced to predict the development of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer (NSCLC). METHODS: Forty-seven advanced or recurrent Japanese patients with NSCLC were enrolled. Patients received 50 or 60 mg/m(2) docetaxel as monotherapy, and blood samples for a PK analysis were collected up to 24 h after its infusion...
October 5, 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27707991/effect-of-diurnal-variation-cyp2b6-genotype-and-age-on-the-pharmacokinetics-of-nevirapine-in-african-children
#19
Andrzej Bienczak, Adrian Cook, Lubbe Wiesner, Veronica Mulenga, Cissy Kityo, Addy Kekitiinwa, A Sarah Walker, Andrew Owen, Diana M Gibb, David Burger, Helen McIlleron, Paolo Denti
OBJECTIVES: To characterize the effects of CYP2B6 polymorphisms, diurnal variation and demographic factors on nevirapine pharmacokinetics in African children. METHODS: Non-linear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration-time data from 414 children aged 0.3-15 years. RESULTS: Nevirapine pharmacokinetics was best described using a one-compartment disposition model with elimination through a well-stirred liver model accounting for a first-pass effect and transit-compartment absorption...
October 5, 2016: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/27683090/a-population-pharmacokinetic-model-to-predict-oxypurinol-exposure-in-patients-on-haemodialysis
#20
Daniel Fb Wright, Matthew P Doogue, Murray L Barclay, Peter T Chapman, Nicholas B Cross, John H Irvine, Lisa K Stamp
PURPOSE: The aims of this study were to characterise the population pharmacokinetics of oxypurinol in patients receiving haemodialysis and to compare oxypurinol exposure in dialysis and non-dialysis patients. METHODS: Oxypurinol plasma concentrations from 6 gout people receiving haemodialysis and 19 people with gout not receiving dialysis were used to develop a population pharmacokinetic model in NONMEM. Deterministic simulations were used to predict the steady-state area under the oxypurinol plasma concentration time curve over 1 week (AUC7days)...
September 28, 2016: European Journal of Clinical Pharmacology
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