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A Fast Method for Testing Covariates in Population PK/PD Models
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2011 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 13, no 3, 464-472 p.Article in journal (Refereed) Published
Abstract [en]

The development of covariate models within the population modeling program like NONMEM is generally a time-consuming and non-trivial task. In this study, a fast procedure to approximate the change in objective function values of covariate-parameter models is presented and evaluated. The proposed method is a first-order conditional estimation (FOCE)-based linear approximation of the influence of covariates on the model predictions. Simulated and real datasets were used to compare this method with the conventional nonlinear mixed effect model using both first-order (FO) and FOCE approximations. The methods were mainly assessed in terms of difference in objective function values (Delta OFV) between base and covariate models. The FOCE linearization was superior to the FO linearization and showed a high degree of concordance with corresponding nonlinear models in Delta OFV. The linear and nonlinear FOCE models provided similar coefficient estimates and identified the same covariate-parameter relations as statistically significant or non-significant for the real and simulated datasets. The time required to fit tesaglitazar and docetaxel datasets with 4 and 15 parameter-covariate relations using the linearization method was 5.1 and 0.5 min compared with 152 and 34 h, respectively, with the nonlinear models. The FOCE linearization method allows for a fast estimation of covariate-parameter relations models with good concordance with the nonlinear models. This allows a more efficient model building and may allow the utilization of model building techniques that would otherwise be too time-consuming.

Place, publisher, year, edition, pages
2011. Vol. 13, no 3, 464-472 p.
Keyword [en]
conditional estimation, covariate model building, NONMEM, population PK/PD
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-157007DOI: 10.1208/s12248-011-9289-2ISI: 000293186000015OAI: oai:DiVA.org:uu-157007DiVA: diva2:434888
Available from: 2011-08-16 Created: 2011-08-15 Last updated: 2017-12-08Bibliographically approved

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Harling, KajsaJonsson, Niclas E.Hooker, Andrew C.Karlsson, Mats O.

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