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Population pharmacokinetics, optimised design and sample size determination for rifampicin, isoniazid, ethambutol and pyrazinamide in the mouse
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
GlaxoSmithKline, DDW, Med Dev Campus,Severo Ochoa 2, Madrid 28760, Spain..
GlaxoSmithKline, DDW, Med Dev Campus,Severo Ochoa 2, Madrid 28760, Spain..
GlaxoSmithKline, DDW, Med Dev Campus,Severo Ochoa 2, Madrid 28760, Spain..
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2016 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 93, 319-333 p.Article in journal (Refereed) Published
Abstract [en]

The current first-line therapy for drug-susceptible tuberculosis consists of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). In this study, we determined the population pharmacokinetics (PopPK) of RIF, INH, EMB and PZA using original experimental sampling designs for single-dose intravenous (IV) and single- and multiple-dose oral administration studies in the mouse model, and used these PopPK models to develop and evaluate new, more informative sampling designs with the aim of reducing the number of animals required for each drug. The RIF, INH, EMB and PZA blood concentrations after single oral and IV doses and multiple-dose oral administrations based on the original designs were used in the PopPK analysis using NONMEM software. The final PopPK models described the data well, Stochastic simulation and estimation were used to optimise the designs. The relative bias and relative imprecision of each pharmacokinetic parameter for each drug were derived and assessed to choose the final designs. The final single-dose IV and oral designs included up to eight samples per mouse with a total of 24 mice required for RIF and EMB and 33 mice for INH and PZA. In the new multiple-dose (zipper) oral designs, the mice were divided into two groups of three per dose, and four samples were taken from each mouse to cover all seven or eight sampling time points. The final number of mice required for the multiple-dose oral designs was 30 for RIF, INH and EMB, 36 for PZA. The number of mice required in the new designs for RIF, INH and EMB was decreased by up to 7-fold and the relative bias and relative imprecision in the parameter estimates were at least similar to those in the original designs.

Place, publisher, year, edition, pages
2016. Vol. 93, 319-333 p.
Keyword [en]
Pharmacoldnetics, Design, Rifampicin, Isoniazid, Ethambutol, Pyrazinamide
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-307268DOI: 10.1016/j.ejps.2016.07.017ISI: 000384853200034PubMedID: 27473307OAI: oai:DiVA.org:uu-307268DiVA: diva2:1046408
Funder
Swedish Research CouncilEU, European Research CouncilGlaxoSmithKline (GSK)
Available from: 2016-11-14 Created: 2016-11-11 Last updated: 2017-03-29Bibliographically 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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