Population Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Pregnant South African Women with Tuberculosis and HIV

Abstract

Tuberculosis is an important cause of maternal morbidity, but little is known about the effects of pregnancy on antituberculosis drug concentrations. We developed population pharmacokinetic models to describe drug dispositions of isoniazid, pyrazinamide, and ethambutol in pregnant women with tuberculosis and HIV. HIV-positive pregnant women with tuberculosis receiving standard first-line tuberculosis treatment and participating in Tshepiso, a prospective cohort study in Soweto, South Africa, underwent sparse pharmacokinetic sampling at >36 weeks of gestation and 7 weeks postpartum. The effects of pregnancy on the pharmacokinetics of isoniazid, pyrazinamide, and ethambutol were investigated via population pharmacokinetic modeling. Isoniazid, pyrazinamide, and ethambutol concentrations were available for 29, 18, and 18 women, respectively. Their median weight was 66 kg while pregnant and 64 kg postpartum. No significant differences were observed in drug clearance, volume of distribution, or bioavailability during and after pregnancy. The model-estimated isoniazid, pyrazinamide, and ethambutol area under the concentration-time curve from 0 to 24 h (AUC_0-24) medians were, respectively, 6.88, 419, and 16.5 mg · h/liter during pregnancy versus 5.01, 407, and 19.0 mg · h/liter postpartum. The model-estimated maximum concentration (C_max) medians for isoniazid, pyrazinamide, and ethambutol were, respectively, 1.39, 35.9, and 1.82 mg/liter during pregnancy versus 1.43, 34.5, and 2.11 mg/liter postpartum. A posteriori power calculations determined that our analysis was powered 91.8%, 59.2%, and 90.1% at a P of <0.01 to detect a 40% decrease in the AUCs of isoniazid, pyrazinamide, and ethambutol, respectively. Pregnancy does not appear to cause relevant changes in the exposure to isoniazid, pyrazinamide, and ethambutol. Additional studies of antituberculosis drugs in pregnancy are needed.

Keywords: NAT2; NONMEM; modeling; pharmacometrics; pregnancy; simulation.

FIG 1

Structural model for isoniazid, pyrazinamide, and ethambutol. The dose of each drug is assumed to go through a series of transit compartments (Trans Cmpts) before being absorbed into the central compartment. It is then eliminated from the central compartment with first-order kinetics. An asterisk (*) indicates the peripheral compartment, which applies only to isoniazid and ethambutol. NN, number of transit compartments; V₁, central volume of distribution; Vp, peripheral volume of distribution; Q, intercompartmental clearance; CL, central clearance.

FIG 2

Box and whisker plots showing the AUC_0–24 and C_max values for the three drugs stratified by pre- and postpartum conditions. The dots represent individual values. Whiskers show the 2.5th and 97.5th percentiles.

FIG 3

Visual predictive check (VPC) for isoniazid, pyrazinamide, and ethambutol concentration versus time (time since the dose), stratified by pregnancy. The circles represent the original data, the dashed and solid lines are the 5th, 50th, and 95th percentiles of the original data, and the shaded areas are the corresponding 95% confidence intervals for the same percentiles, as predicted by the model. An appropriate model is expected to have most observed percentiles within the simulated confidence intervals.