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https://www.readbyqxmd.com/read/28543084/population-pharmacokinetics-and-exposure-response-assessment-of-cc-292-a-potent-btk-inhibitor-in-patients-with-chronic-lymphocytic-leukemia
#1
Yan Li, Francisco Ramírez-Valle, Yongjun Xue, Judith I Ventura, Olivier Gouedard, Jay Mei, Kenichi Takeshita, Maria Palmisano, Simon Zhou
CC-292, a potent Bruton tyrosine kinase inhibitor, is under development for the treatment of B-cell malignancies. An analysis was performed to develop a population pharmacokinetic model of CC-292 and assess the influence of demographics and disease-related covariates on CC-292 exposure and to assess the exposure-response (overall response rate) relationship in patients with chronic lymphocytic leukemia. Population pharmacokinetic analysis was based on a 2-compartment base model conducted in NONMEM. Categorical exposure-response analysis was performed using logistic regression in SAS...
May 19, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28536776/development-of-improved-dosing-regimens-for-mycophenolate-mofetil-based-on-population-pharmacokinetic-analyses-in-adults-with-lupus-nephritis
#2
Azrin N Abd Rahman, Susan E Tett, Halim A Abdul Gafor, Brett C McWhinney, Christine E Staatz
BACKGROUND AND OBJECTIVE: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim of this study was to develop a population pharmacokinetic model of MPA and its metabolite, 7-O-MPA-β-glucuronide (MPAG), to identify important covariate influences and better predict patient dosing requirements. METHODS: MPA and MPAG concentration-time profiles were collected from 25 patients receiving mycophenolate mofetil (MMF) with or without cyclosporine (CsA) co-therapy...
May 23, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28526601/model-based-precision-dosing-of-sirolimus-in-pediatric-patients-with-vascular-anomalies
#3
Tomoyuki Mizuno, Chie Emoto, Tsuyoshi Fukuda, Adrienne M Hammill, Denise M Adams, Alexander A Vinks
Sirolimus is the first drug to show efficacy in the treatment of patients with complicated vascular anomalies. The current study expands on the evolution of a PK model-based strategy for the precision dosing of sirolimus as part of prospective concentration controlled clinical trials in pediatric patients with vascular anomalies. Twelve month follow up data collected from 52 pediatric patients participating in the Phase 2 clinical trial were analyzed. Target attainment across the age range of 3weeks to 18years after 2-3months of therapy was 94% (49 out of 52 patients)...
May 16, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28522373/population-pharmacokinetics-of-carvedilol-enantiomers-and-their-metabolites-in-type-2-diabetes-and-healthy-subjects
#4
Glauco H B Nardotto, Vera L Lanchote, Eduardo B Coelho, Oscar Della Pasqua
Carvedilol, a drug available as a racemic mixture, is eliminated as hydroxyphenylcarvedilol (OHC) by CYP2D6 and O-desmethylcarvedilol (DMC) by CYP2C9 followed by conjugation to glucuronides. In contrast to other β-adrenergic receptor antagonists, carvedilol does not induce insulin resistance or worsen glycaemic control in the diabetic hypertensive patients. This study aims to investigate the implications of type 2 diabetes (T2DM) on the pharmacokinetics of carvedilol enantiomers using an integrated population pharmacokinetic modelling approach...
May 15, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28513427/population-pharmacokinetics-of-lyophilized-recombinant-glucagon-like-peptide-1-receptor-agonist-recombinant-exendin-4-re-4-in-chinese-patients-with-type-2-diabetes-mellitus%C3%A2
#5
Yan-Nan Zang, Min-Jie Zhang, Yi-Tong Wang, Chen Wang, Qian Wang, Qing-Shan Zheng, Li-Nong Ji, Wei Guo, Yi Fang
OBJECTIVE: To investigate the population pharmacokinetics of lyophilized recombinant glucagon-like peptide-1 receptor agonist (rE-4) in Chinese patients with type 2 diabetes mellitus (T2DM) for plasma concentration estimation and individualized treatment. METHODS: Twelve patients with T2DM were enrolled to receive subcutaneous injections of rE-4 at 5 µg twice daily for 84 days. Administration dosage was adjusted from 5 µg to 10 µg twice daily at day 29 in case of glycated albumin (GA) ≥ 17%...
May 17, 2017: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28512056/combined-proportional-and-additive-residual-error-models-in-population-pharmacokinetic-modelling
#6
Johannes H Proost
INTRODUCTION: In pharmacokinetic modelling, a combined proportional and additive residual error model is often preferred over a proportional or additive residual error model. Different approaches have been proposed, but a comparison between approaches is still lacking. METHODS: The theoretical background of the methods is described. Method VAR assumes that the variance of the residual error is the sum of the statistically independent proportional and additive components; this method can be coded in three ways...
May 13, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28510797/influence-of-morbid-obesity-on-the-pharmacokinetics-of-morphine-morphine-3-glucuronide-and-morphine-6-glucuronide
#7
Sjoerd de Hoogd, Pyry A J Välitalo, Albert Dahan, Simone van Kralingen, Michael M W Coughtrie, Eric P A van Dongen, Bert van Ramshorst, Catherijne A J Knibbe
INTRODUCTION: Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers. METHODS: In this analysis, data from 20 morbidly obese patients [mean body mass index 49.9 kg/m(2) (range 37...
May 16, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28510304/flip-flop-phenomenon-in-epidural-sufentanil-pharmacokinetics-a-population-study-in-children-and-infants
#8
Agnieszka Borsuk, Bogumiła Wołoszczuk-Gębicka, Alicja Bartkowska-Śniatkowska, Jowita Rosada-Kurasińska, Agnieszka Bienert, Paweł Wiczling
The aims of this study were to develop a population pharmacokinetic model of sufentanil coadministered with 0.2% ropivacaine as an epidural infusion in infants and describe the sufentanil absorption profile from epidural space. Data from 2 previously published studies were merged for analysis-20 infants aged 3-36 months receiving sufentanil as an epidural infusion and 41 children 0-17 years old receiving sufentanil as a long-term intravenous infusion. A population nonlinear mixed-effects model was built in NONMEM...
May 16, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28509794/an-allometric-model-of-remifentanil-pharmacokinetics-and-pharmacodynamics
#9
Douglas J Eleveld, Johannes H Proost, Hugo Vereecke, Anthony R Absalom, Erik Olofsen, Jaap Vuyk, Michel M R F Struys
BACKGROUND: Pharmacokinetic and pharmacodynamic models are used to predict and explore drug infusion schemes and their resulting concentration profiles for clinical application. Our aim was to develop a pharmacokinetic-pharmacodynamic model for remifentanil that is accurate in patients with a wide range of age and weight. METHODS: Remifentanil pharmacokinetic data were obtained from three previously published studies of adults and children, one of which also contained pharmacodynamic data from adults...
June 2017: Anesthesiology
https://www.readbyqxmd.com/read/28508378/population-pharmacokinetic-and-pharmacodynamic-modeling-of-etelcalcetide-in-patients-with-chronic-kidney-disease-and-secondary-hyperparathyroidism-receiving-hemodialysis
#10
Ping Chen, Adimoolam Narayanan, Benjamin Wu, Per Olsson Gisleskog, John P Gibbs, Andrew T Chow, Murad Melhem
INTRODUCTION: Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). METHODS: To assess titrated dosing regimens, population pharmacokinetic (PK) and PK/pharmacodynamic (PKPD) modeling of etelcalcetide was performed using NONMEM 7.2. In this analysis, plasma etelcalcetide, serum parathyroid hormone (PTH) and calcium (Ca) concentration-time data were collected from five phase I, II, and III clinical trials following single or multiple intravenous doses of etelcalcetide ranging from 2...
May 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28506869/model-based-clinical-dose-optimization-for-phenobarbital-in-neonates-an-illustration-of-the-importance-of-data-sharing-and-external-validation
#11
Swantje Völler, Robert B Flint, Leo M Stolk, Pieter L J Degraeuwe, Sinno H P Simons, Paula Pokorna, David M Burger, Ronald de Groot, Dick Tibboel, Catherijne A J Knibbe
BACKGROUND: Particularly in the pediatric clinical pharmacology field, data-sharing offers the possibility of making the most of all available data. In this study, we utilize previously collected therapeutic drug monitoring (TDM) data of term and preterm newborns to develop a population pharmacokinetic model for phenobarbital. We externally validate the model using prospective phenobarbital data from an ongoing pharmacokinetic study in preterm neonates. METHODS: TDM data from 53 neonates (gestational age (GA): 37 (24-42) weeks, bodyweight: 2...
May 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28497294/a-two-step-deconvolution-analysis-informed-population-pharmacodynamic-modeling-approach-for-drugs-targeting-pulsatile-endogenous-compounds
#12
Michiel J van Esdonk, Jacobus Burggraaf, Piet H van der Graaf, Jasper Stevens
Pharmacodynamic modeling of pulsatile endogenous compounds (e.g. growth hormone [GH]) is currently limited to the identification of a low number of pulses. Commonly used pharmacodynamic models are not able to capture the complexity of pulsatile secretion and therefore non-compartmental analyses are performed to extract summary statistics (mean, AUC, Cmax). The aim of this study was to develop a new quantification method that deals with highly variable pulsatile data by using a deconvolution-analysis-informed population pharmacodynamic modeling approach...
May 11, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28483965/pharmacokinetics-of-efavirenz-in-2-3-years-old-children-a-high-dose-of-25-mg-kg-per-day
#13
Claire Pressiat, Madeleine Amorissani-Folquet, Caroline Yonaba, Jean-Marc Treluyer, Désiré Lucien Dahourou, François Eboua, Stéphane Blanche, Véronique Mea-Assande, Naïm Bouazza, Frantz Foissac, Karen Malateste, Sylvie Ouedraogo, Gabrielle Lui, Valériane Leroy, Déborah Hirt
Background: The MONOD ANRS 12206 trial was designated to assess simplification of a successful LPV-based antiretroviral treatment in young HIV-infected children using efavirenz (25 mg/kg/day) to preserve the protease inhibitors class before the age of 3. In this sub-study, EFV concentrations were measured to check the consistency of a 25 mg/kg EFV dose and to compare it with the 2016 FDA recommended dose.Methods: Fifty-two children underwent blood sampling for pharmacokinetic study at 6-month and 12-month after switching to EFV...
May 8, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28471911/application-of-population-pharmacokinetic-modeling-for-individualized-infliximab-dosing-strategies-in-crohn-s-disease
#14
Adam Frymoyer, Daniël R Hoekman, Travis L Piester, Tim G de Meij, Thalia Z Hummel, Marc A Benninga, Angelika Kindermann, K T Park
OBJECTIVES: The pharmacokinetics of infliximab are highly variable in children with Crohn's disease (CD), and a one-size-fits-all approach to dosing is inadequate. Model-based drug dosing can help individualize dosing strategies. We evaluated the predictive performance and clinical utility of a published population pharmacokinetic model of infliximab in children with CD. METHODS: Within a cohort of 34 children with CD who had infliximab trough concentrations measured, the pharmacokinetics of each patient was estimated in NONMEM® using a published population pharmacokinetic model...
May 3, 2017: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/28466367/model-based-meta-analysis-for-comparing-vitamin-d2-and-d3-parent-metabolite-pharmacokinetics
#15
Alanna S Ocampo-Pelland, Marc R Gastonguay, Matthew M Riggs
Association of Vitamin D (D3 & D2) and its 25OHD metabolite (25OHD3 & 25OHD2) exposures with various diseases is an active research area. D3 and D2 dose-equivalency and each form's ability to raise 25OHD concentrations are not well-defined. The current work describes a population pharmacokinetic (PK) model for D2 and 25OHD2 and the use of a previously developed D3-25OHD3 PK model [1] for comparing D3 and D2-related exposures. Public-source D2 and 25OHD2 PK data in healthy or osteoporotic populations, including 17 studies representing 278 individuals (15 individual-level and 18 arm-level units), were selected using search criteria in PUBMED...
May 2, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28461315/genetic-determinants-of-the-pharmacokinetic-variability-of-rifampicin-in-malawian-adults-with-pulmonary-tuberculosis
#16
Derek J Sloan, Andrew D McCallum, Alessandro Schipani, Deirdre Egan, Henry C Mwandumba, Steve A Ward, David Waterhouse, Gertrude Banda, Theresa J Allain, Andrew Owen, Saye H Khoo, Geraint R Davies
Variable exposure to anti-tuberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampicin. We evaluated the contribution of Single Nucleotide Polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC, CES-1) to inter-individual pharmacokinetic variability in Malawi. 174 adults with pulmonary TB underwent sampling of plasma rifampicin concentrations at 2- and 6-hours post-dose...
May 1, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28451709/a-dosing-algorithm-for-metformin-based-on-the-relationships-between-exposure-and-renal-clearance-of-metformin-in-patients-with-varying-degrees-of-kidney-function
#17
Janna K Duong, M Y A M Kroonen, S S Kumar, H L Heerspink, C M Kirkpatrick, G G Graham, K M Williams, R O Day
PURPOSE: The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CLR), and apparent non-renal clearance of metformin (CLNR/F) in patients with varying degrees of kidney function and to develop dosing recommendations. METHODS: Plasma and urine samples were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CLCR; range, 14-112 mL/min). A population pharmacokinetic model was built (NONMEM) in which the oral availability (F) was fixed to 0...
April 28, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28444697/population-pharmacokinetics-of-dexmedetomidine-in-infants
#18
Rachel G Greenberg, Huali Wu, Matthew Laughon, Edmund Capparelli, Stevie Rowe, Kanecia O Zimmerman, P Brian Smith, Michael Cohen-Wolkowiez
Despite limited pharmacokinetic (PK) data, dexmedetomidine is increasingly being used off-label for sedation in infants. We aimed to characterize the developmental PK changes of dexmedetomidine during infancy. In this open-label, single-center PK study of dexmedetomidine in infants receiving dexmedetomidine per clinical care, ≤10 blood samples per infant were collected. A set of structural PK models and residual error models were explored using nonlinear mixed-effects modeling in NONMEM. Covariates including postmenstrual age (PMA), serum creatinine, and recent history of cardiac surgery requiring cardiopulmonary bypass were investigated for their influence on PK parameters...
April 25, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28432468/population-pharmacokinetics-of-intravenous-acetaminophen-in-japanese-patients-undergoing-elective-surgery
#19
Tsuyoshi Imaizumi, Shinju Obara, Midori Mogami, Yuzo Iseki, Makiko Hasegawa, Masahiro Murakawa
INTRODUCTION: Intravenous (i.v.) acetaminophen is administered during surgery for postoperative analgesia. However, little information is available on the pharmacokinetics of i.v. acetaminophen in Japanese patients undergoing surgery under general anesthesia. METHODS: The study was approved by the Institutional Review Board and registered at UMIN-CTR (UMIN000013418). Patients scheduled to undergo elective surgery under general anesthesia were enrolled after obtaining written informed consent...
April 21, 2017: Journal of Anesthesia
https://www.readbyqxmd.com/read/28417561/population-pharmacokinetics-of-morphine-in-patients-with-nonalcoholic-steatohepatitis-nash-and-healthy-adults
#20
V Pierre, C K Johnston, B C Ferslew, Klr Brouwer, D Gonzalez
Altered expression and function of transporters in nonalcoholic steatohepatitis (NASH) patients may affect the pharmacokinetics (PK), efficacy, and safety of substrate drugs. A population pharmacokinetic (PopPK) analysis was performed to assess differences in morphine and morphine-3-glucuronide (M3G) disposition in NASH and healthy subjects. A total of 315 serum and 42 urine samples from 21 subjects (14 healthy; 7 NASH) were analyzed using NONMEM. Morphine and M3G PK were described by three- and one-compartment models, respectively...
April 18, 2017: CPT: Pharmacometrics & Systems Pharmacology
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