Is Salivary Busulfan the Cause of Oral Mucositis and the Changes in Salivary Antioxidant Enzymes After Hematopoietic Cell Transplantation?

Abstract

Background: To determine whether the busulfan (Bu) present in saliva during hematopoietic cell transplantation (HCT) conditioning correlates with oral mucositis and the changes in salivary antioxidant enzymes. Methods: Bu levels in the plasma and saliva of 19 patients who received HCTs were quantified. Salivary flow and salivary superoxide dismutase and catalase activities were measured during HCT. For the toxicity analysis of salivary Bu, an in vitro assay was conducted by exposing human keratinocytes to artificial saliva containing Bu. Results: Plasma and salivary Bu concentrations were very similar (rho = 0.92, P < 0.001). Salivary Bu concentration correlated with the degree of oral mucositis severity (rho = 0.391, P = 0.029) and was inversely proportional to salivary superoxide dismutase and catalase activities (rho = −0.458, P = 0.036; rho = −0.424, P = 0.043, respectively). Cells exposed to Bu-containing saliva had fewer viable cells (P < 0.01) and more apoptotic cells (P = 0.001) than those exposed to non–Bu-containing saliva. Conclusions: Bu found in saliva during HCT conditioning was correlated with severe oral mucositis and the reduction in salivary antioxidative activity. Furthermore, Bu can be toxic to keratinocytes.

Limited Sampling Strategies for Estimating Busulfan Area Under the Concentration–Time Curve: Based on Peak and Trough Concentrations in Saliva

“…Due to faster drug metabolization and rapid distribution, children displayed a higher clearance than adults, which led to lower busulfan AUC 0-∞,p in pediatric patients. Using a target AUC 0-∞,p range of 900-1500 μmol • min/L at each dose (European Medicines Agency recommendation), 23 patients (62.2%) could achieve the therapeutic window, which was consistent with the results (40%-60%) of Rhee et al, 29 but lower than those (78% and 76%) reported by Michel et al 30 Several investigators [16][17][18] have demonstrated the feasibility and accuracy of saliva TDM in busulfan. There was a significant correlation between busulfan concentration in the plasma and saliva (r = 0.87, p < .01), which is similar to the previous research by Rauh et al 16 (r = 0.96), de Paula Eduardo et al 18 (r = 0.92), and Bezinelli et al 17 (r = 0.97).…”

“…Using a target AUC 0-∞,p range of 900-1500 μmol • min/L at each dose (European Medicines Agency recommendation), 23 patients (62.2%) could achieve the therapeutic window, which was consistent with the results (40%-60%) of Rhee et al, 29 but lower than those (78% and 76%) reported by Michel et al 30 Several investigators [16][17][18] have demonstrated the feasibility and accuracy of saliva TDM in busulfan. There was a significant correlation between busulfan concentration in the plasma and saliva (r = 0.87, p < .01), which is similar to the previous research by Rauh et al 16 (r = 0.96), de Paula Eduardo et al 18 (r = 0.92), and Bezinelli et al 17 (r = 0.97). The busulfan saliva concentrations were lower than plasma concentrations (C max,p = 1.19 ± 0.25 μg/mL, C max,s = 1.07 ± 0.22 μg/mL), with the S/P ratio close to 0.89.…”

“…15 Previous studies have shown that it is feasible to use saliva as the matrix of TDM for busulfan; salivary busulfan levels are well correlated with plasma busulfan levels. [16][17][18] Despite the good correlation, LSS models proposed for the TDM of busulfan are mostly based on plasma samples rather than salivary samples. [19][20][21][22] Therefore, this study aimed to investigate the plasma and saliva PK of intravenous busulfan.…”

“…Moreover, there are no contraindications for saliva collection except for inflammation or pathological changes of oral mucosa 15 . Previous studies have shown that it is feasible to use saliva as the matrix of TDM for busulfan; salivary busulfan levels are well correlated with plasma busulfan levels 16‐18 . Despite the good correlation, LSS models proposed for the TDM of busulfan are mostly based on plasma samples rather than salivary samples 19‐22 …”

Dried Plasma Spots and Oral Fluid as Alternative Matrices for Therapeutic Drug Monitoring of Busulfan: Analytical Method Development and Clinical Evaluation

“…However, a correlation between BU concentrations in oral fluid and the occurrence of severe mucositis has been reported, and this could represent a useful application of oral fluid analysis. 27 In our study, all enrolled patients presented oral mucositis (71.4% grade 2 and 27.6% grade 3); however, the small number of observations does not allow any conclusions to be made in terms of the relationship with BU concentrations in oral fluid.…”