Systematic Review of Salivary Versus Blood Concentrations of Antituberculosis Drugs and Their Potential for Salivary Therapeutic Drug Monitoring

Abstract

Background: Therapeutic drug monitoring is useful in the treatment of tuberculosis to assure adequate exposure, minimize antibiotic resistance, and reduce toxicity. Salivary therapeutic drug monitoring could reduce the risks, burden, and costs of blood-based therapeutic drug monitoring. This systematic review compared human pharmacokinetics of antituberculosis drugs in saliva and blood to determine if salivary therapeutic drug monitoring could be a promising alternative.

Methods: On December 2, 2016, PubMed and the Institute for Scientific Information Web of Knowledge were searched for pharmacokinetic studies reporting human salivary and blood concentrations of antituberculosis drugs. Data on study population, study design, analytical method, salivary Cmax, salivary area under the time-concentration curve, plasma/serum Cmax, plasma/serum area under the time-concentration curve, and saliva-plasma or saliva-serum ratio were extracted. All included articles were assessed for risk of bias.

Results: In total, 42 studies were included in this systematic review. For the majority of antituberculosis drugs, including the first-line drugs ethambutol and pyrazinamide, no pharmacokinetic studies in saliva were found. For amikacin, pharmacokinetic studies without saliva-plasma or saliva-serum ratios were found.

Conclusions: For gatifloxacin and linezolid, salivary therapeutic drug monitoring is likely possible due to a narrow range of saliva-plasma and saliva-serum ratios. For isoniazid, rifampicin, moxifloxacin, ofloxacin, and clarithromycin, salivary therapeutic drug monitoring might be possible; however, a large variability in saliva-plasma and saliva-serum ratios was observed. Unfortunately, salivary therapeutic drug monitoring is probably not possible for doripenem and amoxicillin/clavulanate, as a result of very low salivary drug concentrations.

FIGURE 1.

Results of searches and study selection. Using the search terms, 162 records were found, 71 of which were assessed as relevant. After full-text assessment, 30 articles were excluded. A total of 42 articles were included in this systematic review.

FIGURE 2.

Saliva–plasma or saliva–serum ratio of anti-TB drugs. The weighted mean () and range of saliva–plasma or saliva–serum ratio are displayed per drug. Mean (range) of doripenem: 0.04 (0.01–0.07); amoxicillin: 0.43 (0.34–0.55); linezolid: 0.98 (0.95–1.03); gatifloxacin: 0.91 (0.81–1.00); clarithromycin: 0.62 (0.25–1.30); ofloxacin: 0.90 (0.29–1.25); moxifloxacin: 0.75 (0.31–1.03); rifampicin: 0.19 (0.00–0.67); and isoniazid: 0.84 (0.14–1.38). For doripenem, amoxicillin, and linezolid, only 1 study with a saliva–plasma or saliva– serum ratio was included. For the other drugs, the numbers of included studies were as follows: gatifloxacin (n = 2), clarithromycin (n = 6), ofloxacin (n = 9), moxifloxacin (n = 5), rifampicin (n = 6), and isoniazid (n = 3).

FIGURE 3.

Saliva–plasma or saliva–serum ratios of anti-TB drugs. Top left: isoniazid; top right: rifampicin; middle left: moxifloxacin; middle right: ofloxacin; bottom left: clarithromycin; and bottom right: gatifloxacin. As per drug, the saliva–plasma or saliva–serum ratios of the included articles are displayed as weighted mean () with range. In addition, the overall mean (♦) and range were determined for each drug. All numerical values of mean and range are presented to the right of the graphs.

FIGURE 4.

Ideal study design for pharmacokinetic studies comparing anti-TB drug concentrations in saliva and plasma or serum. LLOQ, lower limit of quantification; N, number.