Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis

Abstract

Pyrazinamide is used in the treatment of tuberculosis (TB) because its sterilizing effect against tubercle bacilli allows the shortening of treatment. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multidrug-resistant tuberculosis (MDR-TB). Pyrazinamide pharmacokinetic (PK) data from 61 HIV/TB-coinfected patients in South Africa were used in the analysis. The patients were administered weight-adjusted doses of pyrazinamide, rifampin, isoniazid, and ethambutol in fixed-dose combination tablets according to WHO guidelines and underwent intensive PK sampling on days 1, 8, 15, and 29. The data were interpreted using nonlinear mixed-effects modeling. PK profiles were best described using a one-compartment model with first-order elimination. Allometric scaling was applied to disposition parameters using fat-free mass. Clearance increased by 14% from the 1st day to the 29th day of treatment. More than 50% of patients with weight less than 55 kg achieved lower pyrazinamide exposures at steady state than the targeted area under the concentration-time curve from 0 to 24 h of 363 mg · h/liter. Among patients with drug-susceptible TB, adding 400 mg to the dose for those weighing 30 to 54 kg improved exposure. Average pyrazinamide exposure in different weight bands among patients with MDR-TB could be matched by administering 1,500 mg, 1,750 mg, and 2,000 mg to patients in the 33- to 50-kg, 51- to 70-kg, and greater than 70-kg weight bands, respectively.

Keywords: AUC; HIV/TB coinfection; NONMEM; fat-free mass; population pharmacokinetics; weight band dosing.

FIG 1

Visual predictive check. Open circles are the observed concentrations. The middle continuous line is the 50th percentile of the observed data, and upper and lower dashed lines are the 97.5th and 2.5th percentiles of the observed data, respectively. The shaded regions represent the 95th prediction interval of the 2.5th, 50th, and 97.5th percentiles.

FIG 2

Box plots of simulated AUC_0–24 for currently recommended doses for drug-susceptible TB (14) and 3 alternative dosing strategies, stratified by weight band. Dots are the observed AUC_0–24 on day 29 of treatment. The dashed line represents an AUC_0–24 of 363 mg · h/liter. The dosing strategies used for the 30- to 37-, 38- to 54-, 55- to 70-, and >70-kg weight bands are 800 mg, 1,200 mg, 1,600 mg, and 2,000 mg for current doses. For alternative dosing strategy 1, patients weighing 30 to 37 kg receive 1,200 mg, while the doses for patients in the other weight bands are unchanged. For alternative 2, 1,200-mg and 1,600-mg doses are administered to patients weighing 30 to 37 kg and 38 to 54 kg, respectively, while other patients' dosing is unchanged. For alternative 3 dosing, 1,600 mg is administered to patients weighing 30 to 54 kg and dosing for other patients is unchanged.

FIG 3

(a) Predicted concentrations for a typical male patient weighing 34 kg, receiving 800 mg (solid line) and 1,200 mg (dashed line). (b) Predicted concentrations for a typical male patient weighing 46 kg, receiving 1,200 mg (solid line) and 1,600 mg (dashed line).

FIG 4

Box plots of simulated AUC_0–24 achieved during treatment of MDR-TB using the model without the increase in clearance over time, stratified by weight band and dose administered. Single-dose tablets of pyrazinamide were used in the simulations, with each tablet containing either 400 mg, 500 mg, or 700 mg. The minimum and maximum values of the box plots are the 2.5th and 97.5th percentiles, and the horizontal tick mark on each box plot shows the 10th percentile. The dashed line represents the AUC_0–24 of 363 mg · h/liter.