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Assessing Pharmacodynamic Interactions in Mice using the Multistate Tuberculosis Pharmacometric and General Pharmacodynamic Interaction Models
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Northeast Agr Univ, Coll Vet Med, 600 Changjiang Rd, Harbin 150030, Heilongjiang, Peoples R China. Heilongjiang Key Lab Anim Dis Control & Pharmaceu, 600 Changjiang Rd, Harbin 150030, Heilongjiang, Peoples R China..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Erasmus MC, Department of Medical Microbiology and Infectious Disease, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.
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2017 (English)In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 6, no 11, p. 787-797Article in journal (Other academic) Published
Abstract [en]

The aim of this study was to investigate pharmacodynamic (PD) interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics (PKs), the Multistate Tuberculosis Pharmacometric (MTP) model, and the General Pharmacodynamic Interaction (GPDI) model. Rifampicin, isoniazid, ethambutol, or pyrazinamide were administered in monotherapy for 4 weeks. Rifampicin and isoniazid showed effects in monotherapy, whereas the animals became moribund after 7 days with ethambutol or pyrazinamide alone. No PD interactions were observed against fast-multiplying bacteria. Interactions between rifampicin and isoniazid on killing slow and non-multiplying bacteria were identified, which led to an increase of 0.86 log(10) colony-forming unit (CFU)/lungs at 28 days after treatment compared to expected additivity (i.e., antagonism). An interaction between rifampicin and ethambutol on killing non-multiplying bacteria was quantified, which led to a decrease of 2.84 log(10) CFU/lungs at 28 days after treatment (i.e., synergism). These results show the value of pharmacometrics to quantitatively assess PD interactions in preclinical tuberculosis drug development.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017. Vol. 6, no 11, p. 787-797
Keywords [en]
tuberculosis, pharmacokinetics-pharmacodynamics, drug-drug interactions, mixed effect models, pharmacometrics
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-318770DOI: 10.1002/psp4.12226ISI: 000418823400010PubMedID: 28657202OAI: oai:DiVA.org:uu-318770DiVA, id: diva2:1085400
Available from: 2017-03-28 Created: 2017-03-28 Last updated: 2018-02-23Bibliographically 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. p. 58
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 231
Keywords
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)
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Supervisors
Available from: 2017-04-27 Created: 2017-03-29 Last updated: 2018-01-13

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