Evaluation of Saliva as a Potential Alternative Sampling Matrix for Therapeutic Drug Monitoring of Levofloxacin in Patients with Multidrug-Resistant Tuberculosis

Abstract

Saliva may be a useful alternative matrix for monitoring levofloxacin concentrations in multidrug-resistant tuberculosis (MDR-TB) patients. The objectives of this study were (i) to evaluate the correlation between plasma and salivary levofloxacin (Lfx) concentrations in MDR-TB patients and (ii) to gauge the possibility of using saliva as an alternative sampling matrix for therapeutic drug monitoring of Lfx in areas where TB is endemic. This was a prospective pharmacokinetic study that enrolled MDR-TB patients receiving levofloxacin (750- to 1,000-mg once-daily dosing) under standardized treatment regimen in Nepal. Paired blood and saliva samples were collected at steady state. Lfx concentrations were quantified using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental kinetics. Lfx drug exposures were evaluated in 23 MDR-TB patients. During the first month, the median (interquartile range [IQR]) areas under the concentration-time curve from 0 to 24 h (AUC0-24) were 67.09 (53.93 to 98.37) mg ⋅ h/liter in saliva and 99.91 (76.80 to 129.70) mg ⋅ h/liter in plasma, and the saliva plasma (S/P) ratio was 0.69 (0.53 to 0.99). Similarly, during the second month, the median (IQR) AUC0-24 were 75.63 (61.45 to 125.5) mg ⋅ h/liter in saliva and 102.7 (84.46 to 131.9) mg ⋅ h/liter in plasma, with an S/P ratio of 0.73 (0.66 to 1.18). Furthermore, large inter- and intraindividual variabilities in Lfx concentrations were observed. This study could not demonstrate a strong correlation between plasma and saliva Lfx levels. Despite a good Lfx penetration in saliva, the variability in individual saliva-to-plasma ratios limits the use of saliva as a valid substitute for plasma. Nevertheless, saliva could be useful in semiquantitatively predicting Lfx plasma levels. (This study has been registered at ClinicalTrials.gov under identifier NCT03000517.).

Keywords: levofloxacin; pharmacokinetics; plasma; saliva; tuberculosis.

Copyright © 2019 American Society for Microbiology.

Figures

FIG 1

Lfx plasma and saliva concentration-time curves (means ± the standard errors of the mean).

FIG 2

Passing-Bablok regression analysis of mean Lfx concentrations (at 0, 1, 2, 4, and 8 h) in plasma and saliva for 2 months. The bold solid line represents the Passing-Bablok fitted line, whereas the solid lighter line is the line of identity. The dashed lines indicate the 95% CI, r is the Spearman’s rank correlation, and N is the number of paired mean plasma and saliva concentrations.

FIG 3

Lfx saliva-plasma ratios at different time points (0, 1, 2, 4, and 8 h) and salivary pH values at the first (I) and second (II) months of treatment.

FIG 4

Lfx Cmin in saliva to predict plasma AUC0–24. The vertical line at 2 mg/liter is the Cmin cutoff.