Prothionamide, a second-line drug for multidrug-resistant tuberculosis (MDR-TB), has been in use for a few decades. However, its pharmacokinetic (PK) profile remains unclear. This study aimed to develop a population PK model for prothionamide and then apply the model to determine the optimal dosing regimen for MDR-TB patients. Multiple plasma samples were collected from 27 MDR-TB patients who had been treated with prothionamide at 2 different study hospitals. Prothionamide was administered according to the weight-band dose regimen (500 mg/day for weight <50 kg and 750 mg/day for weight >50 kg) recommended by the World Health Organization. The population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment, based on systemic exposure and MIC, was used as a response target. Fixed-dose regimens (500 or 750 mg/day) were simulated to compare the efficacies of various dosing regimens. PK profiles adequately described the two-compartment model with first-order elimination and the transit absorption compartment model with allometric scaling on clearance. All dosing regimens had effectiveness >90% for MIC values <0.4 μg/mL in 1.0-log kill target. However, a fixed dose of 750 mg/day was the only regimen that achieved the target resistance suppression of ≥90% for MIC values of <0.2 μg/mL. In conclusion, fixed-dose prothionamide (750 mg/day), regardless of weight-band, was appropriate for adult MDR-TB patients with weights of 40 to 67 kg.

Background

Moxifloxacin (MOX) is used as a first-choice drug to treat multidrug-resistant tuberculosis (MDR-TB); however, evidence-based dosing optimization should be strengthened by integrative analysis. The primary goal of this study was to evaluate MOX efficacy and toxicity using integrative model-based approaches in MDR-TB patients.

Methods

In total, 113 MDR-TB patients from 5 different clinical trials were analyzed for the development of a population pharmacokinetics (PK) model. A final population PK model was merged with a previously developed lung-lesion distribution and QT prolongation model. Monte Carlo simulation was used to calculate the probability target attainment value based on concentration. An area under the concentration-time curve (AUC)-based target was identified as the minimum inhibitory concentration (MIC) of MOX isolated from MDR-TB patients.

Results

The presence of human immunodeficiency virus (HIV) increased clearance by 32.7% and decreased the AUC by 27.4%, compared with HIV-negative MDR-TB patients. A daily dose of 800 mg or a 400-mg, twice-daily dose of MOX is expected to be effective in MDR-TB patients with an MIC of ≤0.25 µg/mL, regardless of PK differences resulting from the presence of HIV. The effect of MOX in HIV-positive MDR-TB patients tended to be decreased dramatically from 0.5 µg/mL, in contrast to the findings in HIV-negative patients. A regimen of twice-daily doses of 400 mg should be considered safer than an 800-mg once-daily dosing regimen, because of the narrow fluctuation of concentrations.

Conclusions

Our results suggest that a 400-mg, twice-daily dose of MOX is an optimal dosing regimen for MDR-TB patients because it provides superior efficacy and safety.