Population Modeling and Monte Carlo Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Rifampin in Lungs

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Abstract
Little information exists on the pulmonary pharmacology of antituberculosis drugs. We used population pharmacokinetic modeling and Monte Carlo simulation to describe and explore the pulmonary pharmacokinetics and pharmacodynamics of rifampin (RIF; rifampicin). A population pharmacokinetic model that adequately described the plasma, epithelial lining fluid (ELF), and alveolar cell (AC) concentrations of RIF in a population of 34 human volunteers was made by use of the nonparametric adaptive grid (NPAG) algorithm. The estimated concentrations correlated well with the measured concentrations, and there was little bias and good precision. The results obtained with the NPAG algorithm were then imported into Matlab software to perform a 10,000-subject Monte Carlo simulation. The ability of RIF to suppress the development of drug resistance and to induce a sufficient bactericidal effect against Mycobacterium tuberculosis was evaluated by calculating the proportion of subjects achieving specific target values for the maximum concentration of drug ( C max )/MIC ratio and the area under the concentration-time curve from time zero to 24 h (AUC 0-24 )/MIC ratio, respectively. At the lowest MIC (0.01 mg/liter), after the administration of one 600-mg oral dose, the rates of target attainment for C max /MIC (≥175) were 95% in ACs, 48.8% in plasma, and 35.9% in ELF. Under the same conditions, the target attainment results for the killing effect were 100% in plasma (AUC 0-24 /MIC ≥ 271) but only 54.5% in ELF (AUC 0-24 /MIC ≥ 665). The use of a 1,200-mg RIF dose was associated with better results for target attainment. The overall results suggest that the pulmonary concentrations obtained with the standard RIF dose are too low in most subjects. This work supports the need to evaluate higher doses of RIF for the treatment of patients with tuberculosis.