Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa

Abstract

Effective treatment of tuberculosis during pregnancy is essential for preventing maternal and fetal mortality, but little is known about the effects of pregnancy on the disposition of antituberculosis drugs. We explored the effects of pregnancy on the pharmacokinetics of rifampin, the key sterilizing drug in tuberculosis treatment, in Tshepiso, a prospective cohort study involving pregnant HIV-infected women with or without tuberculosis in Soweto, South Africa. Participants receiving standard first-line tuberculosis treatment underwent sparse sampling for rifampin at 37 weeks' gestation or delivery and then postpartum. Cord blood was collected when possible. A population pharmacokinetic model was developed to investigate the effects of pregnancy on rifampin pharmacokinetics. Among the 48 participants, median age and weight were 28 years and 67 kg, respectively. A one-compartment model with first-order elimination, transit compartment absorption, and allometric scaling described the data well. Pregnancy reduced rifampin clearance by 14%. The median (interquartile range) model-estimated rifampin area under the concentration-time curve over 24 h (AUC0-24) during pregnancy or intrapartum was 40.8 h · mg/liter (27.1 to 54.2 h · mg/liter) compared to 37.4 h · mg/liter (26.8 to 50.3 h · mg/liter) postpartum. The maximum concentrations were similar during pregnancy and postpartum. Rifampin was detectable in 36% (8/22) of cord blood samples, and 88% (42/48) of the women had successful treatment outcomes. There was one case of perinatal tuberculosis. In conclusion, rifampin clearance is modestly reduced during the last trimester of pregnancy. Exposures are only slightly increased, so dose adjustment during pregnancy is not needed. Rifampin was detected in cord blood samples when delivery occurred soon after dosing. The consequences of exposure to this potent inducer of metabolizing enzymes among HIV-exposed infants are unclear.

FIG 1

Structural model. Rifampin is assumed to go through a series of transit compartments before it appears at the absorption site, from which it is absorbed into the central compartment with a first-order absorption rate (k_a). It is then eliminated from the central compartment with first-order kinetics. The transit compartments do not represent the physical compartments of the digestive system, but they are simply a mathematical expedient to flexibly describe drug absorption. Their number and the transit time through them are estimated from the data.

FIG 2

Visual predictive check. Prediction-corrected visual predictive check of the final model, stratified by pregnancy status (data during pregnancy on the left and postpartum on the right). The upper panels refer to the concentrations above the limit of quantification (LLOQ): the solid and dashed lines are the 5th, 50th, and 95th percentiles of the observations, while the shaded areas represent the 95% model-predicted confidence intervals for the same percentiles. The lower panels show the proportion of data below the limit of quantification (BLQ): the solid line is the proportion observed, while the shaded area is the 95% confidence interval for the proportion predicted by the model. An appropriate model is expected to have the most percentiles observed within the simulated confidence intervals. It is important to note that both observations and model predictions in this chart are rescaled due to the prediction-correction; they can thus be used to diagnose the model, but they are not on the same scale as the original data.

FIG 3

Cord blood concentrations. Rifampin cord blood concentration versus time after the mother's rifampin dose intake. The black dots are the rifampin concentrations observed in cord blood, while the solid and dashed lines represent the model-simulated 5th, 50th, and 95th percentiles of rifampin concentration in this cohort of pregnant women. The shaded areas are the 95% confidence intervals of the same percentiles. BLQ concentrations are shown in the graph as LLOQ/2.