Nonparametric Population Pharmacokinetic Modeling of Isoniazid in Colombian Patients With Tuberculosis

Isoniazid (INH) is a first-line antituberculosis (TB) agent with a pharmacokinetic profile characterized by high interindividual variation; however, population pharmacokinetic studies in patients with TB are scarce. The aim was to develop a population model for INH in Colombian patients with TB suitable for predicting drug exposure and assessing the probability of target attainment of pharmacodynamic goals.

Ten hospitalized adult patients with TB undergoing INH treatment were recruited. After an 8-hour fasting, subjects took 300 mg of INH, and 10 samples were taken from 0 to 12 hours. INH was quantified by high-performance liquid chromatography-UV, and data were analyzed with the Pmetrics R package software. A Monte Carlo simulation with the model parameters was run to determine the probability of target attainment for optimal efficacy.

The best model included 2 compartments, first-order absorption (Ka), delayed absorption (Tlag), and linear clearance (CL). Median Tlag was 0.25 hours, 5.54 hour for Ka, (Equation is included in full-text article.)for CL, (Equation is included in full-text article.)for the volume of the central compartment (Vc), 1.04 L/h for intercompartmental clearance (Q), and 788 L for the volume of the peripheral compartment (Vp). CL and Vc were allometrically scaled on basis of the normalized body weight.

The Monte Carlo simulation indicated that 300 mg of INH per day is appropriate for Mycobacterium tuberculosis strains with minimal inhibitory concentration (MIC) up to 0.03 mg/L (target: area under the concentration-time curve/MIC >597); however, to cover strains with MIC up to 0.125 mg/L (80% of clinical isolates), a dose of 900 mg per day would be required.