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Approaches for modeling within subject variability in pharmacometric count data analysis: dynamic inter-occasion variability and stochastic differential equations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Pfizer China Res & Dev Ctr, Shanghai, Peoples R China..
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.
2016 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 43, no 3, 305-314 p.Article in journal (Refereed) Published
Abstract [en]

Parameter variation in pharmacometric analysis studies can be characterized as within subject parameter variability (WSV) in pharmacometric models. WSV has previously been successfully modeled using inter-occasion variability (IOV), but also stochastic differential equations (SDEs). In this study, two approaches, dynamic inter-occasion variability (dIOV) and adapted stochastic differential equations, were proposed to investigate WSV in pharmacometric count data analysis. These approaches were applied to published count models for seizure counts and Likert pain scores. Both approaches improved the model fits significantly. In addition, stochastic simulation and estimation were used to explore further the capability of the two approaches to diagnose and improve models where existing WSV is not recognized. The results of simulations confirmed the gain in introducing WSV as dIOV and SDEs when parameters vary randomly over time. Further, the approaches were also informative as diagnostics of model misspecification, when parameters changed systematically over time but this was not recognized in the structural model. The proposed approaches in this study offer strategies to characterize WSV and are not restricted to count data.

Place, publisher, year, edition, pages
2016. Vol. 43, no 3, 305-314 p.
Keyword [en]
Within subject variability, Count data, Dynamic inter-occasion variability, Stochastic differential equations
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-302713DOI: 10.1007/s10928-016-9473-1ISI: 000380277200006PubMedID: 27165151OAI: oai:DiVA.org:uu-302713DiVA: diva2:964907
Available from: 2016-09-08 Created: 2016-09-08 Last updated: 2016-09-08Bibliographically approved

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Plan, Elodie L.Karlsson, Mats O.
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