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https://www.readbyqxmd.com/read/28520930/improved-power-for-tb-phase-iia-trials-using-a-model-based-pharmacokinetic-pharmacodynamic-approach-compared-with-commonly-used-analysis-methods
#1
Robin J Svensson, Stephen H Gillespie, Ulrika S H Simonsson
Background: The demand for new anti-TB drugs is high, but development programmes are long and costly. Consequently there is a need for new strategies capable of accelerating this process. Objectives: To explore the power to find statistically significant drug effects using a model-based pharmacokinetic-pharmacodynamic approach in comparison with the methods commonly used for analysing TB Phase IIa trials. Methods: Phase IIa studies of four hypothetical anti-TB drugs (labelled A, B, C and D), each with a different mechanism of action, were simulated using the multistate TB pharmacometric (MTP) model...
May 16, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28506868/drug-disease-modeling-in-the-pharmaceutical-industry-where-mechanistic-systems-pharmacology-and-statistical-pharmacometrics-meet
#2
Gabriel Helmlinger, Nidal Al-Huniti, Sergey Aksenov, Kirill Peskov, Melissa Hallow, Lulu Chu, David Boulton, Ulf Eriksson, Bengt Hamrén, Craig Lambert, Eric Masson, Helen Tomkinson, Donald Stanski
Modeling & simulation (M&S) methodologies are established quantitative tools, which have proven to be useful in supporting the research, development (R&D), regulatory approval, and marketing of novel therapeutics. Applications of M&S help design efficient studies and interpret their results in context of all available data and knowledge to enable effective decision-making during the R&D process. In this mini-review, we focus on two sets of modeling approaches: population-based models, which are well-established within the pharmaceutical industry today, and fall under the discipline of clinical pharmacometrics (PMX); and systems dynamics models, which encompass a range of models of (patho-)physiology amenable to pharmacological intervention, of signaling pathways in biology, and of substance distribution in the body (today known as physiologically-based pharmacokinetic models) - which today may be collectively referred to as quantitative systems pharmacology models (QSP)...
May 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28504472/thoughtflow-standards-and-tools-for-provenance-capture-and-workflow-definition-to-support-model-informed-drug-discovery-and-development
#3
J J Wilkins, Pls Chan, J Chard, G Smith, M K Smith, M Beer, A Dunn, C Flandorfer, C Franklin, R Gomeni, L Harnisch, R Kaye, S Moodie, M L Sardu, E Wang, E Watson, K Wolstencroft, Sya Cheung
Pharmacometric analyses are complex and multifactorial. It is essential to check, track, and document the vast amounts of data and metadata that are generated during these analyses (and the relationships between them) in order to comply with regulations, support quality control, auditing, and reporting. It is, however, challenging, tedious, error-prone, and time-consuming, and diverts pharmacometricians from the more useful business of doing science. Automating this process would save time, reduce transcriptional errors, support the retention and transfer of knowledge, encourage good practice, and help ensure that pharmacometric analyses appropriately impact decisions...
May 15, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28486094/a-pharmacodynamic-modelling-and-simulation-study-identifying-gender-differences-of-daily-olanzapine-dose-and-dopamine-d2-receptor-occupancy
#4
Andy R Eugene, Jolanta Masiak
BACKGROUND: Gender differences in treatment response rates for patients treated with antipsychotics are known. However, the literature lacks a pharmacodynamic model to allow for gender-based clinical trial simulations from modelling parameters for Olanzapine and dopamine D2 receptor occupancy. Thus, the primary aim of this analysis is to test and quantify the effect of gender on the pharmacodynamics of Olanzapine. METHODS: Population pharmacodynamic modelling was performed using non-linear mixed effects modelling in MONOLIX, while the Clinical Trial Simulations were performed using R for statistical programming...
May 9, 2017: Nordic Journal of Psychiatry
https://www.readbyqxmd.com/read/28447486/guidance-to-develop-individual-dose-recommendations-for-patients-on-chronic-hemodialysis
#5
Verena Gotta, Kim Dao, Frédérique Rodieux, Thierry Buclin, Françoise Livio, Marc Pfister
In addition to tailored clinical trials in patients on chronic hemodialysis (HD) during drug development, clinician-initiated post-marketing studies and case reports on individual pharmacokinetic (PK) assessments provide an important source of information about drug dialysability and individualized dose recommendations in this vulnerable population. Areas covered: First, factors that may alter drug exposure in HD patients are explained. Second, available regulatory and methodological guidelines for PK assessments in this population are summarized...
April 27, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28425210/corrigendum-commentary-on-pharmacometrics-for-immunotherapy
#6
M J Garrido, P Berraondo, I F Trocóniz
No abstract text is available yet for this article.
April 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28420580/comparative-pharmacodynamic-analysis-of-imidazoline-compounds-using-rat-model-of-ocular-mydriasis-with-a-test-of-quantitative-structure-activity-relationships
#7
Joanna Raczak-Gutknecht, Antoni Nasal, Teresa Frąckowiak, Anita Kornicka, Franciszek Sączewski, Renata Wawrzyniak, Łukasz Kubik, Roman Kaliszan
Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain...
April 6, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28418603/towards-quantitative-systems-pharmacology-models-of-chemotherapy-induced-neutropenia
#8
REVIEW
M Craig
Neutropenia is a serious toxic complication of chemotherapeutic treatment. For years, mathematical models have been developed to better predict hematological outcomes during chemotherapy in both the traditional pharmaceutical sciences and mathematical biology disciplines. An increasing number of quantitative systems pharmacology (QSP) models that combine systems approaches, physiology, and pharmacokinetics/pharmacodynamics have been successfully developed. Here, I detail the shift towards QSP efforts, emphasizing the importance of incorporating systems-level physiological considerations in pharmacometrics...
April 18, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28379635/pharmacometric-modeling-of-liver-metastases-diameter-volume-and-density-and-their-relation-to-clinical-outcome-in-imatinib-treated-gist-patients
#9
Emilie Schindler, Sreenath M Krishnan, Ron H J Mathijssen, Alessandro Ruggiero, Gaia Schiavon, Lena E Friberg
Three-dimensional and density-based tumor metrics have been suggested to better discriminate tumor response to treatment than unidimensional metrics, particularly for tumors exhibiting non-uniform size changes. In the developed pharmacometric modeling framework based on data from 77 imatinib-treated gastro-intestinal patients, the time-courses of liver metastases' maximum trans-axial diameters, software-calculated actual volumes (Vactual ) and calculated ellipsoidal volumes were characterized by logistic growth models, where imatinib induced a linear dose-dependent size reduction...
April 5, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28378945/translational-pharmacometric-evaluation-of-typical-antibiotic-broad-spectrum-combination-therapies-against-staphylococcus-aureus-exploiting-in-vitro-information
#10
Sebastian G Wicha, Wilhelm Huisinga, Charlotte Kloft
Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid or vancomycin combined with meropenem against Staphylococcus aureus as the most frequent causative pathogen of severe infections. A semi-mechanistic PK-PD model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of linezolid, vancomycin and meropenem alone and in dual combinations...
April 5, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28378918/a-pharmacometric-framework-for-axitinib-exposure-efficacy-and-safety-in-metastatic-renal-cell-carcinoma-patients
#11
Emilie Schindler, Michael A Amantea, Mats O Karlsson, Lena E Friberg
The relationships between exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble VEGF receptors (sVEGFR)-1, 2, 3, and soluble stem cell factor receptor (sKIT)), tumor sum of longest diameters (SLD), diastolic blood pressure (dBP) and overall survival (OS) were investigated in a modeling framework. The dataset included 64 metastatic renal cell carcinoma patients (mRCC) treated with oral axitinib. Biomarker time-courses were described by indirect response (IDR) models where axitinib inhibits sVEGFR-1, 2 and 3 production, and VEGF degradation...
April 5, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28353185/pk-pd-compass-bringing-infectious-diseases-pharmacometrics-to-the-patient-s-bedside
#12
Catharine C Bulik, Justin C Bader, Li Zhang, Scott A Van Wart, Christopher M Rubino, Sujata M Bhavnani, Kim L Sweeney, Paul G Ambrose
Antimicrobial stewardship programs face many challenges, one of which is a lack of guidance regarding antimicrobial dose, interval, and duration. There is no tool that considers patient demographic, pathogen susceptibility, and pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy in order to evaluate appropriate antimicrobial dosing regimens. The PK-PD Compass, an educational mobile application, was developed to address this unmet need. The application consists of a Monte Carlo simulation algorithm which integrates pharmacokinetic (PK) and PK-PD data, patient-specific characteristics, and pathogen susceptibility data...
April 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28304215/use-of-statistical-and-pharmacokinetic-pharmacodynamic-modeling-and-simulation-to-improve-decision-making-a-section-summary-report-of-the-trends-and-innovations-in-clinical-trial-statistics-conference
#13
Holly Kimko, Seth Berry, Michael O'Kelly, Nitin Mehrotra, Matthew Hutmacher, Venkat Sethuraman
The application of modeling and simulation (M&S) methods to improve decision-making was discussed during the Trends & Innovations in Clinical Trial Statistics Conference held in Durham, North Carolina, USA on May 1-4, 2016. Uses of both pharmacometric and statistical M&S were presented during the conference, highlighting the diversity of the methods employed by pharmacometricians and statisticians to address a broad range of quantitative issues in drug development. Five presentations are summarized herein, which cover the development strategy of employing M&S to drive decision-making; European initiatives on best practice in M&S; case studies of pharmacokinetic/pharmacodynamics modeling in regulatory decisions; estimation of exposure-response relationships in the presence of confounding; and the utility of estimating the probability of a correct decision for dose selection when prior information is limited...
2017: Journal of Biopharmaceutical Statistics
https://www.readbyqxmd.com/read/28276649/precision-medicine-in-pharmacometrics-and-systems-pharmacology
#14
EDITORIAL
L Li
No abstract text is available yet for this article.
March 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28254068/phxnlme-an-r-package-that-facilitates-pharmacometric-workflow-of-phoenix-nlme-analyses
#15
Chay Ngee Lim, Shuang Liang, Kevin Feng, Jason Chittenden, Ana Henry, Samer Mouksassi, Angela K Birnbaum
BACKGROUND AND OBJECTIVE: Pharmacometric analyses are integral components of the drug development process, and Phoenix NLME is one of the popular software used to conduct such analyses. To address current limitations with model diagnostic graphics and efficiency of the workflow for this software, we developed an R package, Phxnlme, to facilitate its workflow and provide improved graphical diagnostics. METHODS: Phxnlme was designed to provide functionality for the major tasks that are usually performed in pharmacometric analyses (i...
March 2017: Computer Methods and Programs in Biomedicine
https://www.readbyqxmd.com/read/28211134/effect-of-age-on-the-performance-of-bispectral-and-entropy-indices-during-sevoflurane-pediatric-anesthesia-a-pharmacometric-study
#16
Alberto Sciusco, Joseph F Standing, Yucheng Sheng, Pasquale Raimondo, Gilda Cinnella, Michele Dambrosio
BACKGROUND: Bispectral index (BIS) and entropy monitors have been proposed for use in children, but research has not supported their validity for infants. However, effective monitoring of young children may be even more important than for adults, to aid appropriate anesthetic dosing and reduce the chance of adverse consequences. This prospective study aimed to investigate the relationships between age and the predictive performance of BIS and entropy monitors in measuring the anesthetic drug effects within a pediatric surgery setting...
April 2017: Paediatric Anaesthesia
https://www.readbyqxmd.com/read/28205374/developmental-pharmacokinetics-of-sirolimus-implications-for-precision-dosing-in-neonates-and-infants-with-complicated-vascular-anomalies
#17
Tomoyuki Mizuno, Tsuyoshi Fukuda, Chie Emoto, Paula S Mobberley-Schuman, Adrienne M Hammill, Denise M Adams, Alexander A Vinks
BACKGROUND: Sirolimus has recently been shown to be efficacious and tolerable in pediatric patients with complicated vascular anomalies. Nevertheless, dosing information remains very limited especially for neonates and infants. The purpose of this study was to develop an age-appropriate sirolimus starting dosing regimen based on the developmental changes in drug elimination capacity using data collected in neonates and infants. PROCEDURE: A recently developed sirolimus maturation model [Emoto et al...
February 16, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28205038/clinical-trial-simulations-and-pharmacometric-analysis-in-pediatrics-application-to-inhaled-loxapine-in-children-and-adolescents
#18
Min Dong, Tsuyoshi Fukuda, Sally Selim, Mark A Smith, Laura Rabinovich-Guilatt, James V Cassella, Alexander A Vinks
BACKGROUND AND OBJECTIVES: Loxapine for inhalation is a drug-device combination product approved in adults for the acute treatment of agitation associated with schizophrenia or bipolar I disorder. The primary objective of this study was to develop a clinical trial protocol to support a phase I pharmacokinetic study in children aged 10 years and older. In addition, this report details the results of the clinical study in relation to the predicted likelihood of achieving the target exposure associated with therapeutic effect in adults...
February 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28205025/the-multistate-tuberculosis-pharmacometric-model-a-semi-mechanistic-pharmacokinetic-pharmacodynamic-model-for-studying-drug-effects-in-an-acute-tuberculosis-mouse-model
#19
Chunli Chen, Fatima Ortega, Joaquin Rullas, Laura Alameda, Iñigo Angulo-Barturen, Santiago Ferrer, Ulrika Sh Simonsson
The Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin on Mycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected with M. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day)...
April 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28176362/interdisciplinary-pharmacometrics-linking-oseltamivir-pharmacology-influenza-epidemiology-and-health-economics-to-inform-antiviral-use-in-pandemics
#20
Mohamed A Kamal, Patrick F Smith, Nathorn Chaiyakunapruk, David B C Wu, Chayanin Pratoomsoot, Kenneth K C Lee, Huey Yi Chong, Richard E Nelson, Keith Nieforth, Georgina Dall, Stephen Toovey, David C M Kong, Aaron Kamauu, Carl M Kirkpatrick, Craig R Rayner
AIMS: A modular interdisciplinary platform was developed to investigate the economic impact of oseltamivir treatment by dosage regimen under simulated influenza pandemic scenarios. METHODS: The pharmacology module consisted of a pharmacokinetic distribution of oseltamivir carboxylate daily area under the concentration-time curve at steady state (simulated for 75 mg and 150 mg twice daily regimens for 5 days) and a pharmacodynamic distribution of viral shedding duration obtained from phase II influenza inoculation data...
February 8, 2017: British Journal of Clinical Pharmacology
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