A Population Pharmacokinetic Study of Plasma and Intrapulmonary Concentrations of Rifampin
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)
(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: In pulmonary tuberculosis (TB), Mycobacterium tuberculosis (MTB) is both extracellular and intracellular. Rifampin (RIF) is probably the most important drug in TB treatment since it is active against bacteria in both locations, but little is known about the pulmonary pharmacokinetics-pharmacodynamics (PK-PD) of RIF. The objective of this study was to explore the pulmonary PK of RIF, using a population modeling approach.
Methods: The population PK analysis was carried out using NPAG in MM-USCPACK software. Data included concentrations of RIF in plasma, epithelial lining fluid (ELF), and alveolar cells (AC) that were reported in a previous study . Forty subjects, without tuberculosis, received RIF 600 mg orally once daily for five days. RIF concentrations were determined in plasma at 2h and 4h and in ELF and AC by bronchoalveolar lavage (BAL) at 4h after the last dose. All concentrations were modelled simultaneously. Individual predicted concentrations were computed using Bayesian posterior parameter estimates. Goodness of fit was assessed by regression over the predicted-observed concentrations plots and coefficient of correlation. Bias (mean weighted error) and precision (bias-adjusted mean weighted squared error) were used to assess predictive performance.
Results: Six patients from the original group were discarded in this analysis. It is noteworthy that five of those six patients had AIDS. They seemed to have a much delayed absorption. Thirty-four patients were included in the final PK analysis. A three compartment model with first order processes for all transfers best fitted the data. Scatterplots of PK parameters versus available covariates showed no evident relationship. Graphical analysis of Bayesian posterior estimated and measured data showed coefficient of correlation values of 0.94, 0.99 and 0.99 for plasma, ELF, and AC levels, respectively. Bias values (mg/L) were -0.174, 0.183 and -0.038, while precision values (mg/L)2 were 1.818, 0.248 and 0.035 for RIF concentrations in plasma, ELF and AC, respectively. Large variability was found in pulmonary diffusion parameter values.
Conclusions: A compartmental model was created that adequately described the plasma, ELF and pulmonary intracellular PK of RIF. As ELF and AC levels are thought to reflect the antibacterial activity of drugs against MTB , this model can serve as benchmark for future PK-PD studies with RIF. A specific study is indicated to explore possible delayed absorbers.
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