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Implementation of a Transit Compartment Model for Describing Drug Absorption in Pharmacokinetic Studies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
2007 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 34, no 5, 711-726 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: To compare the performance of the standard lag time model (LAG model) with the performance of an analytical solution of the transit compartment model (TRANSIT model) in the evaluation of four pharmacokinetic studies with four different compounds. Methods: The population pharmacokinetic analyses were performed using NONMEM on concentration–time data of glibenclamide, furosemide, amiloride, and moxonidine. In the TRANSIT model, the optimal number of transit compartments was estimated from the data. This was based on an analytical solution for the change in drug concentration arising from a series of transit compartments with the same first-order transfer rate between each compartment. Goodness-of-fit was assessed by the decrease in objective function value (OFV) and by inspection of diagnostic graphs. Results: With the TRANSIT model, the OFV was significantly lower and the goodness-of-fit was markedly improved in the absorption phase compared with the LAG model for all drugs. The parameter estimates related to the absorption differed between the two models while the estimates of the pharmacokinetic disposition parameters were similar. Conclusion: Based on these results, the TRANSIT model is an attractive alternative for modeling drug absorption delay, especially when a LAG model poorly describes the drug absorption phase or is numerically unstable.

Place, publisher, year, edition, pages
2007. Vol. 34, no 5, 711-726 p.
Keyword [en]
TRANSIT model, LAG model, Absorption delay, NONMEM, Pharmacokinetics
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97509DOI: 10.1007/s10928-007-9066-0ISI: 000249665200007PubMedID: 17653836OAI: oai:DiVA.org:uu-97509DiVA: diva2:172488
Available from: 2008-09-12 Created: 2008-09-12 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Improved pharmacometric model building techniques
Open this publication in new window or tab >>Improved pharmacometric model building techniques
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pharmacometric modelling is an increasingly used method for analysing the outcome from clinical trials in drug development. The model building process is complex and involves testing, evaluating and diagnosing a range of plausible models aiming to make an adequate inference from the observed data and predictions for future studies and therapy.

The aim of this thesis was to advance the approaches used in pharmacometrics by introducing improved models and methods for application in essential parts of model building procedure: (i) structural model development, (ii) stochastic model development and (iii) model diagnostics.

As a contribution to the structural model development, a novel flexible structural model for drug absorption, a transit compartment model, was introduced and evaluated. This model is capable of describing various drug absorption profiles and yet simple enough to be estimable from data available from a typical trial. As a contribution to the stochastic model development, three novel methods for parameter distribution estimation were developed and evaluated; a default NONMEM nonparametric method, an extended grid method and a semiparametric method with estimated shape parameters. All these methods are useful in circumstances when standard assumptions of parameter distributions in the population do not hold. The new methods provide less biased parameter estimates, better description of variability and better simulation properties of the model. As a contribution to model diagnostics, the most commonly used diagnostics were evaluated for their usefulness. In particular, diagnostics based on individual parameter estimates were systematically investigated and circumstances which are likely to misguide modelers towards making erroneous decisions in model development, relating to choice of structural, covariate and stochastic model components were identified.

In conclusion, novel approaches, insights and models have been provided to the pharmacometrics community.

Implementation of these advances to make model building more efficient and robust has been facilitated by development of diagnostic tools and automated routines.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 98 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 80Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 80
Keyword
Model building, Absorption model, Transit compartment model, Nonparametric method, Extended grid method, Semiparametric, Distribution transformation, Shrinkage, Model diagnostics
Identifiers
urn:nbn:se:uu:diva-9272 (URN)978-91-554-7275-7 (ISBN)
Public defence
2008-10-03, Room B41, BMC, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-09-12 Created: 2008-09-12Bibliographically approved

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Karlsson, Mats O.

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