Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis.
Limited information exists on the pharmacokinetic (PK)-pharmacodynamic (PD) relationships of drugs against Mycobacterium tuberculosis. Our aim was to identify the PK-PD parameter that best describes the efficacy of rifampin on the basis of in vitro and PK properties. Consistent with 83.8% protein binding by equilibrium dialysis, the rifampin MIC for M. tuberculosis strain H37Rv rose from 0.1 in a serum-free system to 1.0 mg/ml when it was tested in the presence of 50% serum. In time-kill studies, rifampin exhibited area under the concentration-time curve (AUC)-dependent killing in vitro, with maximal killing seen on all days and with the potency increasing steadily over a 9-day exposure period. MIC and time-kill studies performed with intracellular organisms in a macrophage monolayer model yielded similar results. By use of a murine aerosol infection model with dose ranging and dose fractionation over 6 days, the PD parameter that best correlated with a reduction in bacterial counts was found to be AUC/MIC (r(2) = 0.95), whereas the maximum concentration in serum/MIC (r(2) = 0.86) and the time that the concentration remained above the MIC (r(2) = 0.44) showed lesser degrees of correlation.
Jayaram
Ramesh
R
AstraZeneca India Pvt Ltd, Malleswaram, Bangalore 560003, India.
Gaonkar
Sheshagiri
S
Kaur
Parvinder
P
Suresh
B L
BL
Mahesh
B N
BN
Jayashree
R
R
Nandi
Vrinda
V
Bharat
Sowmya
S
Shandil
R K
RK
Kantharaj
E
E
Balasubramanian
V
V
D000336:Aerosols; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics*; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D008264:Macrophages / Q000166:cytology / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012293:Rifampin / Q000493:pharmacokinetics*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
D000336:Aerosols; D000904:Antibiotics, Antitubercular; D012293:Rifampin