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https://www.readbyqxmd.com/read/28926095/model-based-assessment-using-conventional-bioequivalence-limits-to-ensure-safety-and-efficacy-of-rivaroxaban-in-patients-undergoing-hip-or-knee-replacement
#1
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
https://www.readbyqxmd.com/read/28925806/population-pharmacokinetics-of-arginine-glutamate-in-healthy-chinese-volunteers
#2
Jing Wang, Heng Zheng, Kun Wang, Zheng Wang, Yufeng Ding
1. The present study developed population pharmacokinetic models of arginine and glutamate in healthy Chinese volunteers. Two nonlinear mixed-effect models were developed using NONMEM® software (ICON Development Solutions, Ellicott City, MD) to describe the pharmacokinetic properties and to assess the relevant parameters as well as the inter-individual variability. The potential covariates were screened using stepwise approach and the stability and predictive capability of the models were performed using bootstrap and visual predictive check...
September 19, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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
#3
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/28918591/platform-model-describing-pharmacokinetic-properties-of-vc-mmae-antibody-drug-conjugates
#4
Matts Kågedal, Leonid Gibiansky, Jian Xu, Xin Wang, Divya Samineni, Shang-Chiung Chen, Dan Lu, Priya Agarwal, Bei Wang, Ola Saad, Neelima Koppada, Bernard M Fine, Jin Y Jin, Sandhya Girish, Chunze Li
Antibody-drug conjugates (ADCs) developed using the valine-citrulline-MMAE (vc-MMAE) platform, consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile vc linker. Recently, clinical data for a variety of vc-MMAE ADCs has become available. The goal of this analysis was to develop a platform model that simultaneously described antibody-conjugated MMAE (acMMAE) pharmacokinetic (PK) data from eight vc-MMAE ADCs, against different targets and tumor indications; and to assess differences and similarities of model parameters and model predictions, between different compounds...
September 16, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28914344/influence-of-genetic-co-factors-on-the-population-pharmacokinetic-model-for-clopidogrel-and-its-active-thiol-metabolite
#5
Dorota Danielak, Marta Karaźniewicz-Łada, Anna Komosa, Paweł Burchardt, Maciej Lesiak, Łukasz Kruszyna, Agnieszka Graczyk-Szuster, Franciszek Główka
PURPOSE: A high interindividual variability is observed in the pharmacokinetics of clopidogrel, a widely used antiplatelet drug. In the present study, a joint parent-metabolite population pharmacokinetic model was developed to adequately describe observed concentrations of clopidogrel and its active thiol metabolite (H4). METHODS: The study included 63 patients undergoing elective coronarography or percutaneous coronary intervention. The population pharmacokinetic model was developed in the NONMEM 7...
September 15, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28887801/population-pharmacokinetic-and-pharmacodynamic-analysis-of-belimumab-administered-subcutaneously-in-healthy-volunteers-and-patients-with-systemic-lupus-erythematosus
#6
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/28854543/dexmedetomidine-pharmacodynamics-in-healthy-volunteers-2-haemodynamic-profile
#7
P J Colin, L N Hannivoort, D J Eleveld, K M E M Reyntjens, A R Absalom, H E M Vereecke, M M R F Struys
Background: Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, with little respiratory depression and rousability during sedations. We characterized the haemodynamic properties of dexmedetomidine by developing a pharmacokinetic-pharmacodynamic (PKPD) model with a focus on changes in mean arterial blood pressure (MAP) and heart rate. Methods: Dexmedetomidine was delivered i.v. to 18 healthy volunteers in a step-up fashion by target-controlled infusion using the Dyck model...
August 1, 2017: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/28854538/dexmedetomidine-pharmacokinetic-pharmacodynamic-modelling-in-healthy-volunteers-1-influence-of-arousal-on-bispectral-index-and-sedation
#8
P J Colin, L N Hannivoort, D J Eleveld, K M E M Reyntjens, A R Absalom, H E M Vereecke, M M R F Struys
Background: Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, such as maintained respiratory drive and production of arousable sedation. We describe development of a pharmacokinetic-pharmacodynamic model of the sedative properties of dexmedetomidine, taking into account the effect of stimulation on its sedative properties. Methods: In a two-period, randomized study in 18 healthy volunteers, dexmedetomidine was delivered in a step-up fashion by means of target-controlled infusion using the Dyck model...
August 1, 2017: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/28836585/population-pharmacokinetics-and-bayesian-estimation-of-mycophenolic-acid-concentrations-in-chinese-adult-renal-transplant-recipients
#9
Zi-Cheng Yu, Pei-Jun Zhou, Xiang-Hui Wang, Bressolle Françoise, Da Xu, Wei-Xia Zhang, Bing Chen
Mycophenolate mofetil (MMF) is an important immunosuppressant used in renal transplantation, and mycophenolic acid (MPA) is the active component released from the ester prodrug MMF. The objective of this study was to investigate the population pharmacokinetics of mycophenolic acid (MPA) following oral administration of MMF in Chinese adult renal transplant recipients and to identify factors that explain MPA pharmacokinetic variability. Pharmacokinetic data for MPA and covariate information were retrospectively collected from 118 patients (79 patients were assigned to the group for building the population pharmacokinetic model, while 39 patients were assigned to the validation group)...
August 24, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28833329/population-pharmacokinetics-and-bayesian-estimation-of-tacrolimus-exposure-in-chinese-liver-transplant-patients
#10
B Chen, H-Q Shi, X-X Liu, W-X Zhang, J-Q Lu, B-M Xu, H Chen
WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is widely used as part of immunosuppressive regimens. There is great interindividual variation on the disposition of TAC. The aim of this study was to develop a population pharmacokinetic (PPK) model for Chinese liver transplant patients and evaluate genetic polymorphism and other possible factors on the PK parameters. The exposure of TAC is to be estimated through Bayesian modelling. METHODS: A total of 47 sets of rich-time PK and 1234 conventional therapeutic drug monitoring (TDM) data were collected from 125 Chinese liver transplant patients...
August 17, 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/28815754/pharmacokinetic-interactions-and-dosing-rationale-for-antiepileptic-drugs-in-adults-and-children
#11
S C van Dijkman, W M Rauwé, M Danhof, O Della Pasqua
AIM: Population pharmacokinetic modelling has been widely used across many therapeutic areas to identify sources of variability, which are incorporated into models as covariate factors. Despite numerous publications on pharmacokinetic (PK) drug-drug interactions (DDIs) between antiepileptic drugs (AEDs), such data are not used to support the dose rationale for polytherapy in the treatment of epileptic seizures. Here we assess the impact of DDIs on plasma concentrations and evaluate the need for AED dose adjustment...
August 16, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28801680/population-pharmacokinetics-of-peginterferon-%C3%AE-2a-in-patients-with-chronic-hepatitis-b
#12
Jingfeng Bi, Xingang Li, Jia Liu, Dawei Chen, Shuo Li, Jun Hou, Yuxia Zhou, Shanwei Zhu, Zhigang Zhao, Enqiang Qin, Zhenman Wei
There were significant differences in response and pharmacokinetic characteristics to the peginterferon α2a treatment among Chronic Hepatitis B (CHB) patients. The aim of this study is to identify factors which could significantly impact the peginterferon α2a pharmacokinetic characteristics in CHB patients. There were 208 blood samples collected from 178 patients who were considered as CHB and had been treated with peginterferon α2a followed by blood concentration measurement and other laboratory tests. The covariates such as demographic and clinical characteristics of the patients were retrieved from medical records...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28761579/a-bayesian-approach-for-population-pharmacokinetic-modeling-of-alcohol-in-japanese-individuals
#13
Asuka Nemoto, Matsuura Masaaki, Kazue Yamaoka
BACKGROUND: Blood alcohol concentration data that were previously obtained from 34 healthy Japanese subjects with limited sampling times were reanalyzed. Characteristics of the data were that the concentrations were obtained from only the early part of the time-concentration curve. OBJECTIVE: To explore significant covariates for the population pharmacokinetic analysis of alcohol by incorporating external data using a Bayesian method, and to estimate effects of the covariates...
2017: Current Therapeutic Research, Clinical and Experimental
https://www.readbyqxmd.com/read/28711678/linezolid-in-liver-failure-exploring-the-value-of-the-maximal-liver-function-capacity-limax-test-in-a-pharmacokinetic-pilot-study
#14
Sebastian G Wicha, Otto R Frey, Anka C Roehr, Johann Pratschke, Martin Stockmann, Rawan Alraish, Tilo Wuensch, Magnus Kaffarnik
BACKGROUND: Patients in the intensive care unit frequently require antibiotic treatment. Liver impairment possesses substantial challenges for dose selection in these patients. The aim of the present pilot study was to assess the novel maximal liver function capacity (LiMAx test) in comparison to conventional liver function markers as covariates of drug clearance in liver failure using linezolid as model drug. METHODS: 28 patients with different degrees of liver failure were recruited and LiMAx test, plasma, dialysis and urine sampling was performed under linezolid steady-state therapy (600 mg BID)...
July 12, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28681225/a-population-pharmacokinetic-model-to-predict-the-individual-starting-dose-of-tacrolimus-following-pediatric-renal-transplantation
#15
Louise M Andrews, Dennis A Hesselink, Teun van Gelder, Birgit C P Koch, Elisabeth A M Cornelissen, Roger J M Brüggemann, Ron H N van Schaik, Saskia N de Wildt, Karlien Cransberg, Brenda C M de Winter
BACKGROUND: Multiple clinical, demographic, and genetic factors affect the pharmacokinetics of tacrolimus in children, yet in daily practice, a uniform body-weight based starting dose is used. It can take weeks to reach the target tacrolimus pre-dose concentration. OBJECTIVES: The objectives of this study were to determine the pharmacokinetics of tacrolimus immediately after kidney transplantation and to find relevant parameters for dose individualization using a population pharmacokinetic analysis...
July 5, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28681176/population-pharmacokinetics-of-haloperidol-in-terminally-ill-adult-patients
#16
L G Franken, R A A Mathot, A D Masman, F P M Baar, D Tibboel, T van Gelder, B C P Koch, B C M de Winter
PURPOSE: Over 80% of the terminally ill patients experience delirium in their final days. In the treatment of delirium, haloperidol is the drug of choice. Very little is known about the pharmacokinetics of haloperidol in this patient population. We therefore designed a population pharmacokinetic study to gain more insight into the pharmacokinetics of haloperidol in terminally ill patients and to find clinically relevant covariates that may be used in developing an individualised dosing regimen...
July 5, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28631514/pharmacokinetics-and-dosing-requirements-of-digoxin-in-pregnant-women-treated-for-fetal-supraventricular-tachycardia
#17
Ana Martin-Suarez, J German Sanchez-Hernandez, Fabiola Medina-Barajas, J Samuel Pérez-Blanco, Jose M Lanao, Luisa Garcia-Cuenllas Alvarez, M Victoria Calvo
BACKGROUND: The objective of this study was to characterize the pharmacokinetics (PK) of digoxin in pregnant women and its potential implications for drug dosing. METHODS: Serum digoxin concentrations (SDCs) obtained in pregnant women treated for fetal supraventricular tachycardia (SVT) was retrospectively collected. PK analysis was comparatively performed using a two-stage approach (PKS™) and a Population PK approach (NONMEM™). As clinical outcome the fetal heart rate was recorded...
August 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28631179/population-pharmacokinetics-of-volasertib-administered-in-patients-with-acute-myeloid-leukaemia-as-a-single-agent-or-in-combination-with-cytarabine
#18
Belén P Solans, Angèle Fleury, Matthias Freiwald, Holger Fritsch, Karin Haug, Iñaki F Trocóniz
BACKGROUND: Volasertib, a potent and selective polo-like kinase inhibitor, has shown to increase response rates and improve survival with a clinically manageable safety profile, administered alone and in combination with cytarabine in patients with acute myeloid leukaemia. OBJECTIVES: The objectives of this analysis were to describe the pharmacokinetics of volasertib and cytarabine, administered as single agents or in combination. METHODS: Three thousand, six hundred and six plasma volasertib concentrations from 501 patients receiving either volasertib alone, or in combination with cytarabine, and 826 plasma cytarabine concentrations from 650 patients receiving cytarabine as multiple subcutaneous injections per cycle either alone, or in combination with volasertib, were analysed using NONMEM Version 7...
June 19, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28620891/population-pharmacokinetic-modeling-of-olaratumab-an-anti-pdgfr%C3%AE-human-monoclonal-antibody-in-patients-with-advanced-and-or-metastatic-cancer
#19
Gary Mo, John R Baldwin, Debra Luffer-Atlas, Robert L Ilaria, Ilaria Conti, Michael Heathman, Damien M Cronier
BACKGROUND AND OBJECTIVES: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population...
June 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28618035/population-pharmacokinetics-of-imatinib-in-nigerians-with-chronic-myeloid-leukemia-clinical-implications-for-dosing-and-resistance
#20
Babatunde Ayodeji Adeagbo, Tiwalade Adewale Olugbade, Muheez Alani Durosinmi, Rahman Ayodele Bolarinwa, Kayode Ogungbenro, Oluseye Oladotun Bolaji
Imatinib, a tyrosine kinase inhibitor, is the drug of choice for the treatment of chronic myeloid leukemia in Nigeria. Several studies have established interindividual and interpopulation variations in imatinib disposition although no pharmacokinetic study have been conducted in an African population since the introduction of the drug. This study explored a population pharmacokinetic approach to investigate the disposition of imatinib in Nigerians and examined the involvement of some covariates including genetic factors in the variability of the drug disposition with a view to optimize the use of the drug in this population...
June 15, 2017: Journal of Clinical Pharmacology
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