Evaluation of initial and steady-state gatifloxacin pharmacokinetics and dose in pulmonary tuberculosis patients by using monte carlo simulations

Abstract

A 4-month regimen of gatifloxacin with rifampin, isoniazid, and pyrazinamide is being evaluated for the treatment of tuberculosis in a phase 3 randomized controlled trial (OFLOTUB). A prior single-dose study found that gatifloxacin exposure increased by 14% in the combination. The aims of the study are to evaluate the initial and steady-state pharmacokinetics of gatifloxacin when daily doses are given to patients with newly diagnosed drug-sensitive pulmonary tuberculosis as part of a combination regimen and to evaluate the gatifloxacin dose with respect to the probability of attaining a pharmacokinetic/pharmacodynamic target. We describe the population pharmacokinetics of gatifloxacin from the first dose to a median of 28 days in 169 adults enrolled in the OFLOTUB trial in Benin, Guinea, Senegal, and South Africa. The probability of achieving a ratio of ≥125 for the area under the concentration time curve to infinity (AUC0-∞) for the free fraction of gatifloxacin over the MIC (fAUC/MIC) was investigated using Monte Carlo simulations. The median AUC0-∞ of 41.2 μg · h/ml decreased on average by 14.3% (90% confidence interval [CI], -90.5% to +61.5%) following multiple 400-mg daily doses. At steady state, 90% of patients achieved an fAUC/MIC of ≥125 only when the MIC was <0.125 μg/ml. We conclude that systemic exposure to gatifloxacin declines with repeated daily 400-mg doses when used together with rifampin, isoniazid, and pyrazinamide, thus compensating for any initial increase in gatifloxacin levels due to a drug interaction. (The OFLOTUB study has been registered at ClinicalTrials.gov under registration no. NCT00216385.).

Fig 1

Visual predictive check (VPC) of the final gatifloxacin pharmacokinetic model stratified by occasion, i.e., first dose (a) and steady-state (day 28) (b). The solid line and the two dashed lines are the median and 5th and 95th percentiles, respectively, of the observed gatifloxacin concentrations in plasma. Shaded areas are the 90% prediction intervals for the median and 5th and 95th percentiles of simulated data. The open circles are observed concentrations.

Fig 2

Box plot of gatifloxacin area under the concentration-time curve from 0 h to infinity (AUC_0–∞) at first dose and at steady state (day 28) based on 10,000 virtual patients and Monte Carlo simulations of 400 mg gatifloxacin daily together with rifampin, isoniazid, and pyrazinamide. In this population, the median gatifloxacin AUC_0–∞ of 41.2 μg · h/ml (5th and 95th percentiles, 17.9 and 93.8) after the first dose was reduced on an individual level by 14.3% (5th and 95th percentiles, −90.4 and 61.5) to 35.4 μg · h/ml (5th and 95th percentiles, 15.2 and 80.4) at steady state (day 28).

Fig 3

The probability of target attainment (PTA) versus Mycobacterium tuberculosis (MTB) MIC following daily administration of 400 mg (dashed line), 600 mg (solid line), and 800 mg (long dash-dot-dot line) gatifloxacin together with rifampin, isoniazid, and pyrazinamide based on 10,000 virtual patients and Monte Carlo simulations. The PTA was defined as the probability of achieving the target PK/PD index ratio of the area under the unbound concentration versus time curve from 0 h to infinity at steady state (fAUC) divided by MIC (fAUC/MIC) of ≥125 (a correlate of maximal bactericidal effect and reduced probability of resistance (10, 40). The dashed horizontal line indicates the reference line of 90% PTA. The solid drop lines with crosses (×) represent the frequency distribution for MIC of gatifloxacin (y axis on the right) obtained from 243 clinical isolates of M. tuberculosis (37).

Fig 4

Median (solid thick line) total probability function, irrespective of the target, as a function of the Mycobacterium tuberculosis (MTB) MIC, with the 80th (solid lines) and 90th (dashed lines) percentiles following daily administration of 400 (a), 600 (b), and 800 (c) mg of gatifloxacin together with rifampin, isoniazid, and pyrazinamide. The lower boundary in the 80th percentile of the total probability function is equivalent to 90% PTA. The dashed horizontal line indicates the reference line (fAUC/MIC = 125).