Population Modeling and Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Isoniazid in Lungs

Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling. Then the model was used to simulate the EBA of INH in lungs and to investigate the influences of INH dose, acetylator status, and M. tuberculosis MIC on this effect. A three-compartment model adequately described INH concentrations in plasma and lungs. With an MIC of 0.0625 mg/liter, simulations showed that the mean bactericidal effect of a standard 300-mg daily dose of INH was only 11% lower for FA subjects than for SA subjects and that dose increases had little influence on the effects in either FA or SA subjects. With an MIC value of 1 mg/liter, the mean bactericidal effect associated with a 300-mg daily dose of INH in SA subjects was 41% greater than that in FA subjects. With the same MIC, increasing the daily INH dose from 300 mg to 450 mg resulted in a 22% increase in FA subjects. These results suggest that patients infected with M. tuberculosis with low-level resistance, especially FA patients, may benefit from higher INH doses, while dose adjustment for acetylator status has no significant impact on the EBA in patients with low-MIC strains.