Abstract
Background: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. Methods: A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and Cmax/MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. Results: Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (p < 0.0001). Clearance and volume of distribution were 93% (p < 0.0001) and 53% (p = 0.002) lower in ICU patients, respectively. Conclusions: ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures.
Highlights
Tuberculosis (TB) is a leading cause of infectious-diseases related deaths worldwide [1].It is estimated that 3–16% of TB patients will require admission to an intensive care unit (ICU) due to acute respiratory failure, acute respiratory distress syndrome and/or multiorgan failure [2,3,4]
The aim of this study was to compare the pharmacokinetics of ethambutol of patients with TB admitted to the intensive care units (ICU) to outpatients, where both patient groups are administered their treatment using an fixed-dose combination (FDC) tablet
Understanding the role of the pharmacokinetics of ethambutol in ICU patients remains an important issue, and low serum concentrations can be associated with a worse likelihood of survival [5,23,47]
Summary
It is estimated that 3–16% of TB patients will require admission to an intensive care unit (ICU) due to acute respiratory failure, acute respiratory distress syndrome and/or multiorgan failure [2,3,4]. Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (p < 0.0001).
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