Influence of Rifampin Pharmacokinetic Variability on Antibacterial Effect and Prevention of Resistance in Pulmonary Tuberculosis: a Simulation Study
S. Goutelle (1,2,3), L. Bourguignon (1,2), P.H. Maire (1,2), M. Van Guilder (3), R.W. Jelliffe (3), J.E. Conte Jr (4,5)
(1) Hospices Civils de Lyon, H˘pital A. Charial, ADCAPT - Service Pharmaceutique, Francheville, France ; (2) UniversitÚ Lyon 1, UMR CNRS 5558, Villeurbanne, France ; (3) Laboratory of Applied Pharmacokinetics, USC School of Medicine, Los Angeles, USA ; (4) Department of Epidemiology and Biostatistics, Infectious Disease Research Group, University of California San Francisco and (5) American Health Sciences, San Francisco, USA
Objectives: The pharmacokinetic-pharmacodynamic (PK-PD) relationships of rifampin (RIF) are a key issue in tuberculosis (TB) treatment. Both Mycobacterium tuberculosis (MTB) killing and prevention of drug resistance are related to RIF concentrations [1,2]. Our work examined the pulmonary PK-PD variability of RIF in adult subjects, using a simulation approach.
Methods: A Monte Carlo simulation was done using Matlab« (n = 10,000 subjects). A three compartment PK model was used to calculate RIF concentrations in plasma, epithelial lining fluid (ELF) and alveolar cells (AC). The simulation used the nonparametric distribution grid of RIF PK parameters estimated from a clinical dataset using the NPAG algorithm. Each NPAG support point was used as a mean vector, in accordance with its probability. Then, the random assignment process assumed a normal bounded distribution for each parameter. The covariance matrix of PK parameter obtained from NPAG was put around each support point. The ratio of the maximum concentration (Cmax, in mg.L-1) to the minimum inhibitory concentration (MIC, in mg.L-1) and the ratio of the area under the time-concentration curve (AUC0-24h, in mg.h.L-1) to the MIC were computed, for various MIC values, after one day and after ten days of oral RIF 600 mg/day for each subject. The results were compared with published targets: Cmax/MIC > 175 for the prevention of resistance (PR)  and AUC0-24h /MIC > 271 (ELF) or > 665 (AC) for the killing effect (K) .
Results: On the first day, mean (▒SD) values for Cmax were 1.57 (▒1.61) in ELF and 4.91 (▒5.91) in AC. For AUC0-24h, mean values were 12.64 (▒20.39) in ELF and 48.16 (▒91.58) in AC. When the MIC was set at 0.01, the percent values of target attainment were 31.2% and 67.1% for PR in ELF and AC, and 64.9% and 67.1% for K in ELF and AC, respectively. For both effects, in each compartment, the percent values of target attainment decreased to less than 50% when the MIC was set at 0.025, and were less than 25% when the MIC was set at 0.1. On the tenth day, target attainment values were only slightly better. Concentration decrease due to RIF auto-induction was not considered in the simulation.
Conclusions: With a standard adult dose of 600 mg/day, concentrations of RIF in ELF and AC are too low in most patients to prevent resistance and to insure a significant antibacterial effect, even against MTB with low MIC values. This shows the need to evaluate higher doses of RIF to treat patients with TB.
 Jayaram R, Gaonkar S, Kaur P, Suresh BL, Mahesh BN, Jayashree R, et al. Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis. Antimicrob Agents Chemother 2003;47(7):2118-24.
 Gumbo T, Louie A, Deziel MR, Liu W, Parsons LM, Salfinger M, et al. Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. Antimicrob Agents Chemother 2007;51(11):3781-8.