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A Target-Mediated Drug Disposition model integrated with a T lymphocyte pharmacodynamic model for Otelixizumab.
No full textObjectives: Otelixizumab is a monoclonal antibody currently being investigated in autoimmunity. It is directed against human CD3ε on T lymphocytes. Its pharmacological effects include 1) down modulation of the CD3/T cell receptor complex on T lymphocytes and 2) a decrease of T cells in blood. The aim of the present work was to integrate a mechanistic target-mediated drug disposition (TMDD) model [1] to a T lymphocyte pharmacodynamic (PD) model.
Methods: Free drug in serum and CD4+ and CD8+ T lymphocytes counts were measured using immunoassay and flow cytometry, respectively. Free, bound and total receptors were then obtained for both CD4+ and CD8+ T lymphocytes [2]. A QSS-TMDD model accounting for Otelixizumab binding to receptors on both CD4+ and CD8+ cells was implemented [3]. Direct and indirect inhibition models were investigated to describe the observed T cell reduction in blood. Analyses were conducted using NONMEM version 7.2. FOCEI and IMP estimation methods were used and compared. Final models were selected based upon change in OFV, precision estimates, diagnostic plots and visual predictive checks (VPCs).
Results: First, a simple one-compartment PK model with MM elimination was identified using available PK data. This PK model was used to drive a direct or an indirect lymphocyte PD model. Both sequential (IPP) and simultaneous PK-PD (T lymphocytes) analyses were implemented. Based on VPCs, the indirect model provided a slightly better description of lymphocyte time-course and variability. Then, our previous QSS-TMDD model [3] was improved including a ‘Study' covariate on linear elimination rate constant (K) with a consequent reduction of the estimated high BSV on K. This QSS-TMDD model was used as input for both lymphocyte PD models. Sequential and simultaneous TMDD-lymphocyte analyses were conducted. To overcome problems with OF minimization and covariance step failure with FOCEI the IMP method was used to achieve minimization with covariance step completion. Both TMDD+direct and TMDD+indirect models adequately described the lymphocyte data.
Conclusions: A QSS-TMDD model integrated either to a direct or an indirect inhibitory model was proposed to describe Otelixizumab binding to CD3/TCR on T lymphocytes and subsequent decrease of T lymphocytes in blood. The IMP estimation method proved a useful alternative to FOCEI in case of such complex PK/PD models. Further strategies to improve lymphocytes model integration into TMDD are discussed.
References:
[1] Gibiansky L, Gibiansky E, Target-Mediated Drug Disposition Model for Drugs That Bind to More than One Target. J Pharmacokinet Pharmacodyn 2010;37:323-346.
[2] Wiczling P, Rosenzweig M, Vaickus L, Jusko WJ. Pharmacokinetics and Pharmacodynamics of a Chimeric/Humanized Anti-CD3 Monoclonal Antibody, Otelixizumab (TRX4), in Subjects With Psoriasis and With Type 1 Diabetes Mellitus. J Clinical Pharmacol 2010;50(5):494-506.
[3] PAGE 21 (2012) Abstr 2463 [www.page-meeting.org/?abstract=2463
Integration of response, tolerability and dropout in flexible-dose trials: a case study in depression
No full textPrintable version
PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
ISSN 1871-6032
Reference:
PAGE 20 (2011) Abstr 2131 [www.page-meeting.org/?abstract=2131]
PDF poster/presentation:
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Poster: Other topics - Methodology
IV-01 Alberto Russu Integration of response, tolerability and dropout in flexible-dose trials: a case study in depression
A. Russu(1), E. Marostica(1), G. De Nicolao(1), A.C. Hooker(2), I. Poggesi(3,*), R. Gomeni(4), S. Zamuner(5)
(1) Department of Computer Engineering and Systems Science, University of Pavia, Pavia, Italy; (2) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (3) Clinical Pharmacology / Modelling & Simulation, GlaxoSmithKline, Verona, Italy; (4) Pharmacometrics, GlaxoSmithKline, King of Prussia, PA, USA; (5) Clinical Pharmacology / Modelling & Simulation, GlaxoSmithKline, Stockley Park, UK; * Current address: Advanced Modeling&Simulation, Janssen Pharmaceutical Companies of Johnson & Johnson, Milan, Italy
Objectives: The difficulties arising when analyzing depression trials are manifold, as a comprehensive model, in addition to the efficacy endpoints, should account for: (i) flexible dosing schemes, (ii) dropout events, and (iii) drug-related adverse effects. Simplified modelling approaches that neglect some of the above aspects may yield biased results. In this work we investigate an integrated approach based on the joint population modelling of response, tolerability and dropout. The proposed methodology is used to analyse data from a flexible-dose, placebo-controlled, Phase II depression trial. As an extension of previous work [1,2], in this study we account for flexible dosage regimen and adverse events as covariates in the dropout model.
Methods: The time course of the HAMD score was described as the sum of a Weibull and a linear function [3]. The dose escalation was included in the model as a covariate on two of the four structural parameters. We investigated three different dropout mechanisms: missing completely at random (MCAR), at random (MAR) and not at random (MNAR) [4]. The dropout probability was modulated using three covariates: the time course of the clinical outcome, dose escalation, and the occurrence of clinically relevant adverse events in the drug arm. The population model was implemented in WinBUGS 1.4.3 [5].
Results: With respect to previous approaches [1,2], which used only the HAMD score as a covariate in the hazard model, the proposed method achieved comparable goodness-of-fit to HAMD data. However, the inclusion of dose escalation and drug-related adverse events in the hazard function yielded a substantial benefit in the description of the dropout process, as witnessed by the Deviance Information Criterion [6], parameter estimates, and the modified Cox-Snell residuals [4]. Comparison of the dropout mechanisms suggested a MNAR dropout process in both treatment arms. The ability of the proposed model to reproduce realistic dropout patterns was assessed via Kaplan-Meier visual predictive checks [7].
Conclusions: Our results show the feasibility of a joint model accounting for the HAMD time course, discontinuities in the dosing schedule, dropouts and adverse events. Indeed, in the study here analyzed, the dropout process was influenced by all the above aspects. Thorough modelling approaches that integrate all the relevant information are necessary to provide a more comprehensive assessment of antidepressant drug response.
References:
[1] Russu A, Marostica E, De Nicolao G, Hooker AC, Poggesi I, Gomeni R, Zamuner S (2010), Integrated model for clinical response and dropout in depression trials: a state-space approach, Population Approach Group Europe (PAGE) 19th Meeting, Abstract 1852
[2] Hooker C, Gomeni R, Zamuner S (2009), Time to event modeling of dropout events in clinical trials, Population Approach Group Europe (PAGE) 18th Meeting, Abstract 1656
[3] Gomeni R, Lavergne A, Merlo-Pich E (2009), Modelling placebo response in depression trials using a longitudinal model with informative dropout, European Journal of Pharmaceutical Sciences 36, pp. 4-10
[4] Hu C, Sale ME (2003), A joint model for longitudinal data with informative dropout, Journal of Pharmacokinetics and Pharmacodynamics 30, pp. 83-103
[5] Lunn DJ, Thomas A, Best N, Spiegelhalter D (2000), WinBUGS - A Bayesian modelling framework: concepts, structure and extensibility. Statistics and Computing 10, pp. 325-337
[6] Spiegelhalter DJ, Best NG, Carlin BP, van der Linde A (2002), Bayesian measures of model complexity and fit (with discussion), Journal of the Royal Statistics Society 64, pp. 583-639
[7] Holford N (2005), The visual predictive check: superiority to standard diagnostic (Rorschach) plots, Population Approach Group Europe (PAGE) 14th Meeting, Abstract 73
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
A Target-Mediated Drug Disposition model to quantify the relationship between Otelixizumab in vitro concentration and TCR/CD3 engagement
No full textObjectives: Otelixizumab is a monoclonal antibody (mAb) directed against CD3ε, a protein forming part of the CD3/T-cell receptor (TCR) complex on T lymphocytes [1]. An in vitro culture system was proposed to investigate Otelixizumab binding characteristics in a static situation. Specifically, the objective of this work was to quantify the relationship between Otelixizumab in vitro concentration and TCR/CD3 engagement. Within this framework, the Target Mediated Drug Disposition (TMDD) hypothesis [2] was investigated for Otelixizumab disposition.
Methods: A wide range of doses was proposed in order to detect and properly quantify nonlinearities in Otelixizumab PK. For this purpose, peripheral blood mononuclear cells (PBMCs) from two donors were incubated with titrated Otelixizumab initial concentrations in the range 0.001-10 μg/ml. To investigate the kinetics of CD3/TCR re-expression, cells were washed on day 2 to remove exogenous Otelixizumab and thereby allow CD3/TCR complex re-expression to be monitored. At each time point free, bound and total TCR/CD3 expression on both CD4+ and CD8+ T cells and the amount of free antibody in the supernatant were measured. A TMDD model [3] accounting for Otelixizumab binding on both CD4+ and CD8+ lymphocytes was proposed with the intent to describe in vitro experimental data. Analyses were conducted using NONMEM version 7.2. Final models were selected based upon change in OFV, precision of estimates and diagnostic goodness-of-fit plots.
Results: All parameters were estimated with reasonable precision (<40%). The proposed Target Mediated Drug Disposition model well captured the PK and PD profiles of Otelixizumab. No significant difference was found in the binding constants for binding on CD4+ or CD8+ lymphocytes (Kon=51.5/nM/day and Koff=4.64/day). The estimated values for binding parameters suggested high Otelixizumab affinity to TCR/CD3 receptor (KD = Koff/Kon = 90 pM). Estimated internalization rates (Kint4=1.26/day and Kint8=1.29/day) were 5 times higher than degradation rates (Kdeg4=0.273/day and Kdeg8=0.275/day).
Conclusions: The TCR/CD3 receptor has been shown to have a major role in determining the non-linear PK of Otelixizumab. A TMDD model accounting for Otelixizumab binding to TCR/CD3 on both CD4+ and CD8+ lymphocytes successfully captured the PK and PD in vitro data, confirming that the assumptions of this model are reasonable for Otelixizumab.
References:
[1] Routledge EG, Lloyd I, Gorman SD, Clark M, Waldmann H. A humanized monovalent CD3 antibody which can activate homologous complement. Eur J Immunol. 21, 2717-2725 (1991)
[2] Gerhard Levy. Pharmacologic target-mediated drug disposition. Clinical pharmacology and therapeutics, 56(3):248, 1994.
[3] Donald E. Mager and William J. Jusko. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. Journal of Pharmacokinetics and Pharmacodynamics, 28(6):507-532, 2001
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