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Drug effect of clofazimine on persisters explain an unexpected increase in bacterial load from patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
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.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Tuberculosis (TB) drug development is dependent on informative trials to secure development of new antibiotics and combination regimens. Clofazimine (CFZ) and pyrazinamid (PZA) are important components of recommended standard multi-drug treatments of TB. Paradoxically, in a Phase IIa trial aiming to define the early bactericidal activity (EBA) of CFZ and PZA monotherapy over the first 14 days of treatment, no significant drug effect was demonstrated for the two drugs using traditional statistical analysis. Using a model-based analysis we characterized statistically significant exposure-response relationships for both drugs that could explain the original findings of increase in colony forming units (CFU) with CFZ treatment and no effect with PZA. Sensitive analyses are crucial for exploring drug effects in early clinical trials to make right decisions for advancement to further development. We propose that this quantitative semi-mechanistic approach provides a rational framework for analysing Phase IIa EBA studies, and can accelerate anti-TB drug development.

Keywords [en]
Pharmacometrics, Pharmacodynamics, Pharmacokinetics, Biomarker, Tuberculosis
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-379356OAI: oai:DiVA.org:uu-379356DiVA, id: diva2:1296390
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15
In thesis
1. Pharmacometric Models to Improve the Treatment and Development of Drugs against Tuberculosis
Open this publication in new window or tab >>Pharmacometric Models to Improve the Treatment and Development of Drugs against Tuberculosis
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

With 10 million new infections yearly, tuberculosis has a major impact on the human well-being of the world. Most patients have infections susceptible to a first-line treatment with a treatment success rate of 80%, a number that can potentially be improved by optimising the first-line treatment. Besides susceptible disease, each year half a million patients are infected by tuberculosis with resistance to first-line treatment where only 50% of patients get cured. Thus, new drugs against resistant tuberculosis are desperately needed but given the inefficiency of developing new anti-tuberculosis drugs, enough new drugs will not reach patients in time. The aim of this thesis was to develop pharmacometric models to optimise the development and use of current and future drugs for treating tuberculosis.

A population pharmacokinetic model for rifampicin, the most prominent first-line drug, was developed and later used for developing exposure-response models followed by clinical trial simulations. The developed exposure-response models were based on liquid culture data and were expanded to describe the relationship between liquid culture results and a new biomarker, the molecular bacterial load assay which is a quicker alternative to liquid culture and is also contamination-free.

The in vitro-derived semi-mechanistic Multistate Tuberculosis Pharmacometric (MTP) model was applied to clinical rifampicin and clofazimine colony forming unit datasets. This novel application of the MTP model allowed detection of statistically significant exposure-response relationships between rifampicin and clofazimine for the specific killing of non-multiplying, persister bacteria. Furthermore, the MTP model was compared to conventional statistical analyses for detecting drug effects in Phase IIa. If designing and analysing Phase IIa using the MTP model, the required sample size for detecting drug effects can be lowered. An improved design and analysis of pre-clinical treatment outcome assessments was developed which increased the information gain compared to a conventional design yet kept the animal use at a minimum. Lastly, a therapeutic drug monitoring approach was suggested based on updated targets for rifampicin, a framework easily expandable to second-line drugs.

In conclusion this thesis presents the development of pharmacometric models which will streamline both the development and use of drugs against tuberculosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 77
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 267
Keywords
Pharmacokinetics, Pharmacodynamics, Biomarkers, Rifampicin, Clofazimine, Therapeutic drug monitoring, Time-to-event, Time-to-positivity, Molecular bacterial load assay
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-379359 (URN)978-91-513-0598-1 (ISBN)
Public defence
2019-05-03, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-04-12 Created: 2019-03-15 Last updated: 2019-05-07

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Svensson, Robin J.Simonsson, Ulrika S H

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