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The multistate tuberculosis pharmacometric model: a semi-mechanistic pharmacokinetic-pharmacodynamic model for studying drug effects in an acute tuberculosis mouse model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Madrid, Spain.
Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Madrid, Spain.
Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Madrid, Spain.
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2017 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 44, no 2, 133-141 p.Article in journal (Refereed) Published
Abstract [en]

The Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin on Mycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected with M. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day). Twenty-five mice received oral rifampicin (1, 3, 9, 26 or 98 mg·kg-1·day-1; Days 1–8; 5 each dose level) and were sacrificed on Day 9. Twenty mice received oral rifampicin (30 mg·kg-1·day-1; up to 8 days) and were sacrificed on Days 2, 3, 4 and 9 (5 each day). The MTP model was linked to a rifampicin population pharmacokinetic model to describe the change in colony forming units (CFU) in the lungs over time. The transfer rates between the different bacterial states were fixed to estimates from in vitro data. The MTP model described well the change in CFU over time after different exposure levels of rifampicin in an acute tuberculosis mouse model. Rifampicin significantly inhibited the growth of fast-multiplying bacteria and stimulated the death of fast- and slow-multiplying bacteria. The data did not support an effect of rifampicin on non-multiplying bacteria possibly due to the short duration of the study. The pharmacometric modelling framework using the MTP model can be used to perform investigations and predictions of the efficacy of anti-tubercular drugs against different bacterial states.

Place, publisher, year, edition, pages
2017. Vol. 44, no 2, 133-141 p.
Keyword [en]
Mouse, Rifampicin, Tuberculosis, Pharmacokinetics, Pharmacodynamics
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-318691DOI: 10.1007/s10928-017-9508-2ISI: 000399036400006PubMedID: 28205025OAI: oai:DiVA.org:uu-318691DiVA: diva2:1085399
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme, 115337
Available from: 2017-03-28 Created: 2017-03-28 Last updated: 2017-05-18Bibliographically approved
In thesis
1. Pharmacokinetic-Pharmacodynamic Evaluations and Experimental Design Recommendations for Preclinical Studies of Anti-tuberculosis Drugs
Open this publication in new window or tab >>Pharmacokinetic-Pharmacodynamic Evaluations and Experimental Design Recommendations for Preclinical Studies of Anti-tuberculosis Drugs
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tuberculosis is an ancient infectious disease and a leading cause of death globally. Preclinical research is important for defining drugs and regimens which should be carried forward to human studies. This thesis aims to characterize the population pharmacokinetics and exposure-response relationships of anti-tubercular drugs alone and in combinations, and to suggest experimental designs for preclinical settings.

The population pharmacokinetics of rifampicin, isoniazid, ethambutol and pyrazinamide were described for the first time in two mouse models. This allowed for linking the population pharmacokinetic model to the Multistate Tuberculosis Pharmacometric (MTP) model for biomarker response, which was used to characterize exposure-response relationships in monotherapy. Pharmacodynamic interactions in combination therapies were quantitatively described by linking the MTP model to the General Pharmacodynamic Interaction (GPDI) model, which provided estimates of single drug effects together with a quantitative model-based evaluation framework for evaluation of pharmacodynamic interactions among drugs in combinations. Synergism (more than expected additivity) was characterized between rifampicin and ethambutol, while antagonism (less than expected additivity) was characterized between rifampicin and isoniazid in combination therapies.

The new single-dose pharmacokinetic design with enrichened individual sampling was more informative than the original design, in which only one sample was taken from each mouse in the pharmacokinetic studies. The new oral zipper design allows for informative pharmacokinetic sampling in a multiple-dose administration scenario for characterizing pharmacokinetic-pharmacodynamic relationships, with similar or lower bias and imprecision in parameter estimates and with a decreased total number of animals required by up to 7-fold compared to the original design. The optimized design for assessing pharmacodynamic interactions in the combination therapies, which was based on EC20, EC50 and EC80 of the single drug, provided lower bias and imprecision than a conventional reduced four-by-four microdilution checkerboard design at the same total number of samples required, which followed the 3Rs of animal welfare.

In summary, in this thesis the population pharmacokinetic-pharmacodynamic models of first-line drugs in mice were characterized through linking each population pharmacokinetic model to the MTP model. Pharmacodynamic interactions were quantitatively illustrated by the MTP-GPDI model. Lastly, experimental designs were optimized and recommended to both pharmacokinetic and pharmacodynamic studies for preclinical settings.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 231
Keyword
tuberculosis, pharmacokinetics, pharmacodynamics, pharmacometrics, the Multistate Tuberculosis Pharmacometric model, the General Pharmacodynamic Interaction model, optimized design, rifampicin, isoniazid, ethambutol, pyrazinamide
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-318845 (URN)978-91-554-9877-1 (ISBN)
Public defence
2017-05-19, B/B42, Biomedicinskt Centrum, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2017-04-27 Created: 2017-03-29 Last updated: 2017-05-05

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