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 (AUC 0 -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) AUC 0 -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.)

From Therapeutic Drug Monitoring to Model‐Informed Precision Dosing for Antibiotics

“…Saliva has been introduced as a patient‐friendly alternative matrix to determine drug concentrations 32 . Depending on the interpatient and intrapatient variability in the saliva/plasma ratio, saliva monitoring can be applied as semiquantitative (screening) or quantitative assays 33 . When using saliva sampling, salivary flow, pH, and protein binding can cause variability and must be considered 33 …”

Diagnostic and medical needs for therapeutic drug monitoring of antibiotics

“…The development of such miniaturized and potentially automatable methods can better position TDM in routine microbiology laboratories, particularly if they are shown to be cost-effective. The assaying of body fluids that can be obtained non-invasively may make TDM more feasible [57]. The major current need are large-scale clinical validation studies for these new technologies.…”

Therapeutic drug monitoring using saliva as matrix: an opportunity for linezolid, but challenge for moxifloxacin

“…[10] Salivary pH values were determined by two independent observers using pH indicator strips with pH range 4.0-7.0 and 2.0-9.0 (Merck KGaA, Darmstadt, Germany), because it could influence drug penetration into saliva. [9] Recovery of both sampling methods was determined similarly to Ghimire et al [11], except that moxifloxacin was tested at 1 and 3 mg/L and linezolid at 2 and 20 mg/L. Recovery was comparable for low and high concentrations.…”