Isoniazid pharmacokinetics-pharmacodynamics in an aerosol infection model of tuberculosis.
Limited data exist on the pharmacokinetic-pharmacodynamic (PK-PD) parameters of the bactericidal activities of the available antimycobacterial drugs. We report on the PK-PD relationships for isoniazid. Isoniazid exhibited concentration (C)-dependent killing of Mycobacterium tuberculosis H37Rv in vitro, with a maximum reduction of 4 log10 CFU/ml. In these studies, 50% of the maximum effect was achieved at a C/MIC ratio of 0.5, and the maximum effect did not increase with exposure times of up to 21 days. Conversely, isoniazid produced less than a 0.5-log10 CFU/ml reduction in two different intracellular infection models (J774A.1 murine macrophages and whole human blood). In a murine model of aerosol infection, isoniazid therapy for 6 days produced a reduction of 1.4 log10 CFU/lung. Dose fractionation studies demonstrated that the 24-h area under the concentration-time curve/MIC (r2 = 0.83) correlated best with the bactericidal efficacy, followed by the maximum concentration of drug in serum/MIC (r2 = 0.73).
Jayaram
Ramesh
R
AstraZeneca India Pvt. Ltd., Hebbal, Bangalore 560 024, India.
Shandil
Radha K
RK
Gaonkar
Sheshagiri
S
Kaur
Parvinder
P
Suresh
B L
BL
Mahesh
B N
BN
Jayashree
R
R
Nandi
Vrinda
V
Bharath
Sowmya
S
Kantharaj
E
E
Balasubramanian
V
V
D000336:Aerosols; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011485:Protein Binding; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology*
D000336:Aerosols; D000995:Antitubercular Agents; D001798:Blood Proteins; D007538:Isoniazid