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A model informed pre-clinical approach for identification of exposure-response and pharmacodynamic interactions in early tuberculosis drug development
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.
Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
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(English)Manuscript (preprint) (Other academic)
Description
Abstract [en]

Tuberculosis treatment involves the use of multiple drugs and therefore there is a risk of not only pharmacokinetic interactions but also pharmacodynamic interactions. From many perspectives identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting. Thus, the aim of this work was to develop a model-informed pre-clinical approach for identification of exposure-response and pharmacodynamic interactions of drug combinations in order to inform early anti-tuberculosis drug development. In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations. The Multistate Tuberculosis Pharmacometric model was used to characterize the natural growth and exposure-response relationships of each drug after mono-exposure. Pharmacodynamic interactions during combination exposure were characterized using the General Pharmacodynamic Interaction model with successful separation of each drug’s effect on the potency (EC50) of the other drugs. The approach outlined in this work constitutes groundwork for model informed input to the development of new and enhancement of existing anti-tuberculosis combination regimens.

Keyword [en]
tuberculosis, pharmacodynamic interactions, multistate tuberculosis pharmacometric model, general pharmacodynamic interaction model, isoniazid, rifampicin, ethambutol
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-303870OAI: oai:DiVA.org:uu-303870DiVA: diva2:1010194
Available from: 2016-10-03 Created: 2016-09-26 Last updated: 2016-10-09
In thesis
1. Novel Pharmacometric Methods for Informed Tuberculosis Drug Development
Open this publication in new window or tab >>Novel Pharmacometric Methods for Informed Tuberculosis Drug Development
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

With approximately nine million new cases and the attributable cause of death of an estimated two millions people every year there is an urgent need for new and effective drugs and treatment regimens targeting tuberculosis. The tuberculosis drug development pathway is however not ideal, containing non-predictive model systems and unanswered questions that may increase the risk of failure during late-phase drug development. The aim of this thesis was hence to develop pharmacometric tools in order to optimize the development of new anti-tuberculosis drugs and treatment regimens.

The General Pulmonary Distribution model was developed allowing for prediction of both rate and extent of distribution from plasma to pulmonary tissue. A distribution characterization that is of high importance as most current used anti-tuberculosis drugs were introduced into clinical use without considering the pharmacokinetic properties influencing drug distribution to the site of action. The developed optimized bronchoalveolar lavage sampling design provides a simplistic but informative approach to gathering of the data needed to allow for a model based characterization of both rate and extent of pulmonary distribution using as little as one sample per subject. The developed Multistate Tuberculosis Pharmacometric model provides predictions over time for a fast-, slow- and non-multiplying bacterial state with and without drug effect. The Multistate Tuberculosis Pharmacometric model was further used to quantify the in vitro growth of different strains of Mycobacterium tuberculosis and the exposure-response relationships of three first line anti-tuberculosis drugs. The General Pharmacodynamic Interaction model was successfully used to characterize the pharmacodynamic interactions of three first line anti-tuberculosis drugs, showing the possibility of distinguishing drug A’s interaction with drug B from drug B’s interaction with drug A. The successful separation of all three drugs effect on each other is a necessity for future work focusing on optimizing the selection of anti-tuberculosis combination regimens.

With a focus on pharmacokinetics and pharmacodynamics, the work included in this thesis provides multiple new methods and approaches that individually, but maybe more important the combination of, has the potential to inform development of new but also to provide additional information of the existing anti-tuberculosis drugs and drug regimen.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 222
Keyword
pharmacokinetics, pharmacodynamics, PKPD, pharmacometric, nonlinear mixed-effects models, multistate tuberculosis pharmacometric model, general pharmacodynamic interaction model, general pulmonary distribution model, tuberculosis, rifampicin, isoniazid, ethambutol
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-303872 (URN)978-91-554-9718-7 (ISBN)
Public defence
2016-11-25, B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
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Supervisors
Available from: 2016-11-03 Created: 2016-09-26 Last updated: 2016-11-16

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Clewe, OskarSvensson, Ulrika S H

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