Abstract

Ertapenem is a broad-spectrum carbapenem antibiotic whose activity against Mycobacterium tuberculosis is being explored. Carbapenems have antibacterial activity when the plasma concentration exceeds the MIC at least 40% of the time (40% T-MIC). To assess the 40% T-MIC in multidrug-resistant tuberculosis (MDR-TB) patients, a limited sampling strategy was developed using a population pharmacokinetic model based on data for healthy volunteers. A two-compartment population pharmacokinetic model was developed with data for 42 healthy volunteers using an iterative two-stage Bayesian method. External validation was performed by Bayesian fitting of the model developed with data for volunteers to the data for individual MDR-TB patients (in which the fitted values of the area under the concentration-time curve from 0 to 24 h [ AUC(0-24), fit values] were used) using the population model developed for volunteers as a prior. A Monte Carlo simulation (n = 1,000) was used to evaluate limited sampling strategies. Additionally, the 40% T-MIC with the free fraction (f 40% T-MIC) of ertapenem in MDR-TB patients was estimated with the population pharmacokinetic model. The population pharmacokinetic model that was developed was shown to overestimate the area under the concentration-time curve from 0 to 24 h (AUC(0 -24)) in MDR-TB patients by 6.8% (range, -17.2 to 30.7%). The best-performing limited sampling strategy, which had a time restriction of 0 to 6 h, was found to be sampling at 1 and 5 h (r(2) = 0.78, mean prediction error = - 0.33%, root mean square error = 5.5%). Drug exposure was overestimated by a mean percentage of 4.2% (range, -15.2 to 23.6%). When a free fraction of 5% was considered and the MIC was set at 0.5 mg/liter, the minimum f 40% T-MIC would have been exceeded in 9 out of 12 patients. A population pharmacokinetic model and limited sampling strategy, developed using data from healthy volunteers, were shown to be adequate to predict ertapenem exposure in MDR-TB patients.

Original languageEnglish
Article numberUNSP e01783-16
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number4
DOIs
Publication statusPublished - Apr-2017

Keywords

  • ertapenem
  • tuberculosis
  • pharmacokinetics
  • pharmacokinetic model
  • limited sampling
  • multidrug resistance
  • CRITICALLY-ILL PATIENTS
  • MYCOBACTERIUM-TUBERCULOSIS
  • CARBAPENEMS
  • HEMODIALYSIS
  • PERFORMANCE
  • DIALYSIS
  • OBESE

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