Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction

Abstract

Rifampin is a key sterilizing drug in the treatment of tuberculosis (TB). It induces its own metabolism, but neither the onset nor the extent of autoinduction has been adequately described. Currently, the World Health Organization recommends a rifampin dose of 8 to 12 mg/kg of body weight, which is believed to be suboptimal, and higher doses may potentially improve treatment outcomes. However, a nonlinear increase in exposure may be observed because of saturation of hepatic extraction and hence this should be taken into consideration when a dose increase is implemented. Intensive pharmacokinetic (PK) data from 61 HIV-TB-coinfected patients in South Africa were collected at four visits, on days 1, 8, 15, and 29, after initiation of treatment. Data were analyzed by population nonlinear mixed-effects modeling. Rifampin PKs were best described by using a transit compartment absorption and a well-stirred liver model with saturation of hepatic extraction, including a first-pass effect. Autoinduction was characterized by using an exponential-maturation model: hepatic clearance almost doubled from the baseline to steady state, with a half-life of around 4.5 days. The model predicts that increases in the dose of rifampin result in more-than-linear drug exposure increases as measured by the 24-h area under the concentration-time curve. Simulations with doses of up to 35 mg/kg produced results closely in line with those of clinical trials.

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Figures

FIG 1

Schematic diagram of the final model. V is the volume of the observation/central compartment, and NN is number of absorption transit compartments.

FIG 2

Prediction-corrected VPC stratified by day after treatment initiation. Open circles are the observed concentrations. The middle continuous line is the 50th percentile of the observed data, and the upper and lower dashed lines are the 95th and 5th percentiles of the observed data, respectively. The shaded regions represent the 95% prediction intervals of the 5th, 50th, and 95th percentiles.

FIG 3

(a) Change in the AUC0–24 from the first day of treatment to day 29 for a typical male patient (median weight of 55 kg and height of 1.65 m) daily administered 600 mg and larger doses of up to 2,100 mg (3.5 times larger). (b) Simulated concentration-time profile on day 29 after TB treatment initiation for a typical male patient.

FIG 4

Distribution of exposures (AUC0–24) at steady state (day 29) based on the currently recommended doses. The simulated exposures are shown in box plots with the individual values observed in the present study superimposed in closed circles.

FIG 5

Probabilities of target (steady-state AUC0–24/MIC ratio of 271) attainment over a range of MICs (plotted on a log2 scale) with different doses in milligrams per kilogram of body weight.

FIG 6

Comparison of simulated exposure (Cmax and AUC0–24, median and 90% range) on day 14 after TB treatment initiation and exposure (Cmax and AUC0–24, geometric mean and range) obtained from reference .