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: 4.57). 01/2013; 57(4). DOI: 10.1128/AAC.01567-12
Source: PubMed

ABSTRACT 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.

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    ABSTRACT: The induction of cytochrome P450 enzymes (CYPs) is an important source of drug-drug interaction (DDI) and can result in pronounced changes in pharmacokinetics (PK). Rifampicin (RIF) is a potent inducer of CYP3A4 and also acts as a competitive inhibitor which can partially mask the induction. The objective of this study was to determine a clinical DDI study design for RIF resulting in maximum CYP3A4 induction. A physiologically based pharmacokinetic (PBPK) model was developed to project the dynamics and magnitude of CYP3A4 induction in vivo from in vitro data generated with primary human hepatocytes. The interaction model included both inductive and inhibitory effects of RIF on CYP3A4 in gut and liver and accounting for the observed RIF auto-induction. The model has been verified for 4 CYP3A4 substrates: midazolam, triazolam, alfentanil and nifedipine using plasma concentration data from 20 clinical study designs with intravenous (n=7) and oral (n=13) administrations. Finally, the influence of the time between RIF and substrate administration was explored for the interaction between midazolam and RIF. The model integrating in vitro induction parameters correctly predicted intravenous induction but underestimated oral induction with 30% of simulated concentrations more than 2 fold higher than of observed data. The use of a 1.6 fold higher value for the maximum induction effect (Emax) improved significantly the accuracy and precision of oral induction with 82% of simulated concentrations and all predicted PK parameters within 2 fold of observed data. Our simulations suggested that a concomitant administration of RIF and midazolam resulted in significant competitive inhibition limited to intestinal enzyme. Accordingly, a maximum induction effect could be achieved with a RIF pretreatment of 600 mg/day during 5 days and a substrate administration at least 2 h after the last RIF dose. A period of 2 weeks after RIF removal was found sufficient to allow return to baseline levels of enzyme.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 02/2014; DOI:10.1016/j.ejps.2014.02.002 · 2.61 Impact Factor
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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.
    American Journal of Respiratory and Critical Care Medicine 03/2013; 187(10). DOI:10.1164/rccm.201207-1210OC · 11.04 Impact Factor


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