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The use of clinical irrelevance criteria in covariate model building with application to dofetilide pharmacokinetic data
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (Farmakometri)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (Farmakometri)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
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2008 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, no 5, 503-526 p.Article in journal (Refereed) Published
Abstract [en]

To characterise the pharmacokinetics of dofetilide in patients and to identify clinically relevant parameter-covariate relationships. To investigate three different modelling strategies in covariate model building using dofetilide as an example: (1) using statistical criteria only or in combination with clinical irrelevance criteria for covariate selection, (2) applying covariate effects on total clearance or separately on non-renal and renal clearances and (3) using separate data sets for covariate selection and parameter estimation. Pooled concentration-time data (1,445 patients, 10,133 observations) from phase III clinical trials was used. A population pharmacokinetic model was developed using NONMEM. Stepwise covariate model building was applied to identify important covariates using the strategies described above. Inclusion and exclusion of covariates using clinical irrelevance was based on reduction in interindividual variability and changes in parameters at the extremes of the covariate distribution. Parametric separation of the elimination pathways was accomplished using creatinine clearance as an indicator of renal function. The pooled data was split in three parts which were used for covariate selection, parameter estimation and evaluation of predictive performance. Parameter estimations were done using the first-order (FO) and the first-order conditional estimation (FOCE) methods. A one-compartment model with first order absorption adequately described the data. Using clinical irrelevance criteria resulted in models containing less parameter-covariate relationships with a minor loss in predictive power. A larger number of covariates were found significant when the elimination was divided into a renal part and a non-renal part, but no gain in predictive power could be seen with this data set. The FO and FOCE estimation methods gave almost identical final covariate model structures with similar predictive performance. Clinical irrelevance criteria may be valuable for practical reasons since stricter inclusion/exclusion criteria shortens the run times of the covariate model building procedure and because only the covariates important for the predictive performance are included in the model.

Place, publisher, year, edition, pages
2008. Vol. 35, no 5, 503-526 p.
Keyword [en]
Covariates, Dofetilide, Modelling, NONMEM
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94379DOI: 10.1007/s10928-008-9099-zISI: 000262699200002PubMedID: 19011957OAI: oai:DiVA.org:uu-94379DiVA: diva2:168209
Available from: 2006-04-21 Created: 2006-04-21 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Development, Application and Evaluation of Statistical Tools in Pharmacometric Data Analysis
Open this publication in new window or tab >>Development, Application and Evaluation of Statistical Tools in Pharmacometric Data Analysis
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pharmacometrics uses models based on pharmacology, physiology and disease for quantitative analysis of interactions between drugs and patients. The availability of software implementing modern statistical methods is important for efficient model building and evaluation throughout pharmacometric data analyses.

The aim of this thesis was to facilitate the practical use of available and new statistical methods in the area of pharmacometric data analysis. This involved the development of suitable software tools that allows for efficient use of these methods, characterisation of basic properties and demonstration of their usefulness when applied to real world data. The thesis describes the implementation of a set of statistical methods (the bootstrap, jackknife, case-deletion diagnostics, log-likelihood profiling and stepwise covariate model building), made available as tools through the software Perl-speaks-NONMEM (PsN). The appropriateness of the methods and the consistency of the software tools were evaluated using a large selection of clinical and nonclinical data. Criteria based on clinical relevance were found to be useful components in automated stepwise covariate model building. Their ability to restrict the number of included parameter-covariate relationships while maintaining the predictive performance of the model was demonstrated using the antiarrythmic drug dofetilide. Log-likelihood profiling was shown to be equivalent to the bootstrap for calculating confidence intervals for fixed-effects parameters if an appropriate estimation method is used. The condition number of the covariance matrix for the parameter estimates was shown to be a good indicator of how well resampling methods behave when applied to pharmacometric data analyses using NONMEM. The software developed in this thesis equips modellers with an enhanced set of tools for efficient pharmacometric data analysis.

Place, publisher, year, edition, pages
Uppsala: Avdelningen för farmakokinetik och läkemedelsterapi, 2006. 46 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 33
Keyword
Pharmaceutical biosciences, pharmacometrics, pharmacokinetics, pharmacodynamics, methodology, statistics, model evaluation, resampling methods, Farmaceutisk biovetenskap
Identifiers
urn:nbn:se:uu:diva-6825 (URN)91-554-6544-7 (ISBN)
Public defence
2006-05-12, B22, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-04-21 Created: 2006-04-21Bibliographically approved

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Karlsson, Mats O

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