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Population Pharmacokinetics of Rifampin in Pulmonary Tuberculosis Patients Including a Semi-mechanistic Model to Describe Variable Absorption
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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2008 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 6, 2138-2148 p.Article in journal (Refereed) Published
Abstract [en]

This article describes the population pharmacokinetics of rifampin in South African pulmonary tuberculosis patients. Three datasets containing 2,913 rifampin plasma concentration-time data points, collected from 261 South African pulmonary tuberculosis patients aged 18 to 72 years and weighing 28.5 to 85.5 kg and receiving regular daily treatment that included administration of rifampin (450 to 600 mg) for at least 10 days, were pooled. A compartmental pharmacokinetic model was developed using nonlinear mixed-effects modeling. Variability in the shape of the absorption curve was described using a flexible transit compartment model, in which a delay in the onset of absorption and a gradually changing absorption rate were modeled as the passage of drug through a chain of hypothetical compartments, ultimately reaching the absorption compartment. A previously described implementation was extended to allow its application to multiple-dosing data. The typical population estimate of oral clearance was 19.2 liters . h(-1), while the volume of distribution was estimated to be 53.2 liters. Interindividual variability was estimated to be 52.8% for clearance and 43.4% for volume of distribution. Interoccasional variability was estimated for CL/F (22.5%) and mean transit time during absorption (67.9%). The use of single-drug formulations was found to increase both the mean transit time (by 104%) and clearance (by 23.6%) relative to fixed-dose-combination use. A strong correlation between clearance and volume of distribution suggested substantial variability in bioavailability, which could have clinical implications, given the dependence of treatment effectiveness on exposure. The final model successfully described rifampin pharmacokinetics in the population studied and is suitable for simulation in this context.

Place, publisher, year, edition, pages
2008. Vol. 52, no 6, 2138-2148 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97511DOI: 10.1128/AAC.00461-07ISI: 000256272700031OAI: oai:DiVA.org:uu-97511DiVA: diva2:172490
Available from: 2008-09-12 Created: 2008-09-12 Last updated: 2016-01-15
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.
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
Model building, Absorption model, Transit compartment model, Nonparametric method, Extended grid method, Semiparametric, Distribution transformation, Shrinkage, Model diagnostics
urn:nbn:se:uu:diva-9272 (URN)978-91-554-7275-7 (ISBN)
Public defence
2008-10-03, Room B41, BMC, Uppsala, 09:15
Available from: 2008-09-12 Created: 2008-09-12Bibliographically approved

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Karlsson, Mats O.Simonsson, Ulrika
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