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Pharmacometrics

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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
#1
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/28688237/antibacterial-drug-development-program-successes-and-failures-a-pharmacometric-explanation
#2
REVIEW
Paul G Ambrose
My thesis is a simple one. We have not been doing a good enough job selecting dose regimens for serious infections during the drug development process. If we are to do a better job in the future, we need to revisit some uncomfortable places. That is, some notable program failures. To be clear, we are not revisiting program failures to make anyone uncomfortable or cast aspersions - but rather so that we sow the seeds for a better future. To that end, we will examine program failures and successes through a pharmacometric lens...
July 5, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28684136/open-innovation-towards-sharing-of-data-models-and-workflows
#3
Daniela J Conrado, Mats O Karlsson, Klaus Romero, Céline Sarr, Justin J Wilkins
Sharing of resources across organisations to support open innovation is an old idea, but which is being taken up by the scientific community at increasing speed, concerning public sharing in particular. The ability to address new questions or provide more precise answers to old questions through merged information is among the attractive features of sharing. Increased efficiency through reuse, and increased reliability of scientific findings through enhanced transparency, are expected outcomes from sharing...
July 3, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28662542/quantitative-disease-progression-model-of-alpha-1-proteinase-inhibitor-therapy-on-ct-lung-density-in-patients-with-alpha-1-antitrypsin-deficiency
#4
M A Tortorici, J A Rogers, O Vit, M Bexon, R A Sandhaus, J Burdon, J Chorostowska-Wynimko, P Thompson, J Stocks, N G McElvaney, K R Chapman, J M Edelman
AIMS: Early-onset emphysema attributed to alpha-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human alpha-1 proteinase inhibitor (A1 -PI; 60 mg/kg/wk) therapy completed to date, demonstrated for the first time that A1 -PI is clinically effective in slowing lung tissue loss in AATD. A post-hoc pharmacometric analysis was undertaken to further explore dose, exposure and response. METHODS: A disease progression model was constructed, utilizing observed A1 -PI exposure and lung density decline rates (measured by computed tomography) from RAPID-RCT/RAPID-OLE, to predict effects of population variability and higher doses on A1 -PI exposure and clinical response...
June 29, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28657202/assessing-pharmacodynamic-interactions-in-mice-using-the-multistate-tuberculosis-pharmacometric-and-general-pharmacodynamic-interaction-models
#5
Chunli Chen, Sebastian G Wicha, Gerjo J de Knegt, Fatima Ortega, Laura Alameda, Veronica Sousa, Jurriaan E M de Steenwinkel, Ulrika S H Simonsson
The aim of this study was to investigate pharmacodynamic interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics, the Multistate Tuberculosis Pharmacometric (MTP) model, and the General Pharmacodynamic Interaction (GPDI) model. Rifampicin, isoniazid, ethambutol or pyrazinamide were administered in monotherapy for 4 weeks. Rifampicin and isoniazid showed effects in monotherapy, whereas the animals became moribund after 7 days with ethambutol or pyrazinamide alone. No pharmacodynamic interactions were observed against fast-multiplying bacteria...
June 28, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28634883/a-minimal-continuous-time-markov-pharmacometric-model
#6
Emilie Schindler, Mats O Karlsson
In this work, an alternative model to discrete-time Markov model (DTMM) or standard continuous-time Markov model (CTMM) for analyzing ordered categorical data with Markov properties is presented: the minimal CTMM (mCTMM). Through a CTMM reparameterization and under the assumption that the transition rate between two consecutive states is independent on the state, the Markov property is expressed through a single parameter, the mean equilibration time, and the steady-state probabilities are described by a proportional odds (PO) model...
June 20, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28595492/current-mathematical-models-for-cancer-drug-discovery
#7
Letizia Carrara, Silvia Maria Lavezzi, Elisa Borella, Giuseppe De Nicolao, Paolo Magni, Italo Poggesi
Pharmacometric models represent the most comprehensive approaches for extracting, summarizing and integrating information obtained in the often sparse, limited, and less-than-optimally designed experiments performed in the early phases of oncology drug discovery. Whilst empirical methodologies may be enough for screening and ranking candidate drugs, modeling approaches are needed for optimizing and making economically viable the learn-confirm cycles within an oncology research program and anticipating the dose regimens to be investigated in the subsequent clinical development...
June 22, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28575552/supervised-machine-learning-reveals-that-old-and-obese-people-achieve-low-dapsone-concentrations
#8
Ronald G Hall, Jotam G Pasipanodya, Mark A Swancutt, Claudia Meek, Richard Leff, Tawanda Gumbo
The human species is becoming increasingly obese. Dapsone, which is extensively used across the globe for dermatological disorders, arachnid bites, and for treatment of several bacterial, fungal and parasitic diseases, could be affected by obesity. We performed a clinical experiment, using optimal design, in volunteers weighing 44-150 kilograms, to identify the effect of obesity on dapsone pharmacokinetic parameters based on maximum-likelihood solution via the expectation-maximization algorithm. Artificial intelligence-based multivariate adaptive regression splines were used for covariate selection, and identified weight and/or age as predictors of absorption, systemic clearance and volume of distribution...
June 2, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28575547/implications-for-drug-characterization-in-glucose-tolerance-tests-without-insulin-simulation-study-of-power-and-predictions-using-model-based-analysis
#9
Siti M Sheikh Ghadzi, Mats O Karlsson, Maria C Kjellsson
In anti-hyperglycemic drug development, drug effects are usually characterized using glucose provocations. Analyzing provocation data using pharmacometrics has been shown powerful, enabling small studies. In pre-clinical drug development, high power is attractive due to the experiment sizes, however insulin is not always available, which potentially impacts power and predictive performance. This simulation study was performed to investigate the implications of performing model-based drug characterization without insulin...
June 2, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28569042/exposure-response-analysis-of-necitumumab-efficacy-in-squamous-non-small-cell-lung-cancer-patients
#10
Emmanuel Chigutsa, Amanda J Long, Johan E Wallin
We sought to describe the exposure-response relationship of necitumumab efficacy in squamous non-small cell lung cancer patients and evaluate intrinsic and extrinsic patient descriptors that may guide dosing. SQUIRE was a phase 3 study comparing necitumumab in combination with gemcitabine and cisplatin versus gemcitabine and cisplatin alone in 1014 patients. An integrated model for tumor size dynamics and overall survival was developed, where reduction in tumor size results in a decrease in survival hazard...
May 31, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28565810/anti-atherogenic-properties-of-resveratrol-4-week-resveratrol-administration-associated-with-serum-concentrations-of-sirt1-adiponectin-s100a8-a9-and-vsmcs-contractility-in-a-rat-model
#11
Michał Wiciński, Bartosz Malinowski, Mateusz M Węclewicz, Elżbieta Grześk, Grzegorz Grześk
Resveratrol (3, 4', 5-trihydroxy-trans-stilbene) is a natural, non-flavonoid polyphenol that exerts protective properties against atherosclerosis-associated endothelial dysfunction and senescence. The present study aimed to assess the influence of resveratrol on vascular contractility and molecular factors including sirtuin-1 (SIRT1), adiponectin and calprotectin (S100A8/A9) that are considered to be important elements of atherogenesis. A total of 17 male rats were divided into a control and treatment group and administered resveratrol or a placebo...
May 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28548207/pharmacometric-modeling-of-naloxegol-efficacy-and-safety-impact-on-dose-and-label
#12
N Al-Huniti, D Zhou, H Xu, S Aksenov, K H Bui, R Fox, G Helmlinger, D Stanski
Naloxegol is a peripherally acting μ-opioid receptor antagonist that was developed for the treatment of opioid-induced constipation. Modeling and simulation of naloxegol efficacy and tolerability informed selection of doses for phase III studies and provided comprehensive dosage recommendations for the naloxegol US package insert.
May 26, 2017: Clinical Pharmacology and Therapeutics
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
#13
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
#14
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
#15
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 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
#16
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
#17
REVIEW
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...
July 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28425210/corrigendum-commentary-on-pharmacometrics-for-immunotherapy
#18
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
#19
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
#20
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...
May 2017: CPT: Pharmacometrics & Systems Pharmacology
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