A Physiologically Based Pharmacokinetic Model of Rifampin in Mice

Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 01/2013; 57(4). DOI: 10.1128/AAC.01567-12
Source: PubMed


One problem associated with regimen-based development of anti-tuberculosis (anti-TB) drugs is the difficulty of a systematic and thorough in vivo evaluation of the large number of possible regimens that arise from consideration of multiple drugs tested together. A mathematical model capable of simulating the pharmacokinetics and pharmacodynamics of experimental combination chemotherapy of TB offers a way to mitigate this problem by extending the use of available data to investigate regimens that are not initially tested. In order to increase the available mathematical tools needed to support such a model for preclinical anti-TB drug development, we constructed a preliminary whole-body physiologically based pharmacokinetic (PBPK) model of rifampin in mice, using data from the literature. Interindividual variability was approximated using Monte Carlo (MC) simulation with assigned probability distributions for the model parameters. An MC sensitivity analysis was also performed to determine correlations between model parameters and plasma concentration to inform future model development. Model predictions for rifampin concentrations in plasma, liver, kidneys, and lungs, following oral administration, were generally in agreement with published experimental data from multiple studies. Sensitive model parameters included those descriptive of oral absorption, total clearance, and partitioning of rifampin between blood and muscle. This PBPK model can serve as a starting point for the integration of rifampin pharmacokinetics in mice into a larger mathematical framework, including the immune response to Mycobacterium tuberculosis infection, and pharmacokinetic models for other anti-TB drugs.


Available from: Brad Reisfeld, Oct 25, 2015
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    ABSTRACT: RATIONALE: The dosage of 10 mg/kg/day rifampin, as currently used in the treatment of tuberculosis (TB), is not an optimal dose. Shortening of treatment duration might be achievable using an increased rifampin dose. OBJECTIVES: Determination of optimal rifampin dosage in mice, resulting in maximum therapeutic effect and without adverse effects. Assessment of associated pharmacokinetic (PK) parameters and pharmacokinetic/pharmacodynamic (PK/PD) indices. METHODS: A murine TB infection using a Beijing genotype Mycobacterium tuberculosis strain was established by intratracheal bacterial instillation followed by proper inhalation, while keeping mice in a vertical position. We assessed dose-dependent activity of rifampin in single-drug treatment during 3 weeks. Also the maximum tolerated dosage (MTD), PK parameters and PK/PD index were determined. Secondly, therapeutic efficacy of a range of rifampin (R) dosages added to a regimen of isoniazid (H) and pyrazinamide (Z) was assessed. MEASUREMENTS AND MAIN RESULTS: MTD of rifampin in the murine TB was 160 mg/kg/day. PK measurement in HR(10)Z and HR(160)Z therapy regimens showed for rifampin a Cmax of 16.2 and 157.3 mg/L, an AUC0-24h of 132 and 1782 h*mg/L and AUC0-24h /MIC ratios of 528 and 7129, respectively. A clear dose-effect correlation was observed for rifampin after 3-weeks single-drug treatment. Administration of HR(80)Z allowed 9-week treatment duration to be effective without relapse of infection. CONCLUSION: Our findings indicate that the currently used rifampin dosage in the therapy of TB is too low. In our murine TB model a rifampin dosage of 80 mg/kg/day enabled a significant reduction in therapy duration without adverse effects.
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