Individual dose adjustment of endovenous busulfan during conditioning of hematopoietic cell transplantation (HCT) reduces the toxicity and improves the therapeutic outcomes of this drug. Busulfan therapeutic monitoring demands multiple blood collections for measurement of its plasmatic concentration, which can provoke discomfort to the patients. This agent is found in the saliva during the conditioning, but its salivary pharmacokinetics is unknown. The first aim of this study was to compare the busulfan concentration in saliva and plasma during the HCT conditioning, analyzing the viability for future busulfan therapeutic monitoring using saliva. The second aim was to propose an oral cryotherapy protocol for reducing the toxicity in the oral cavity, based on the salivary busulfan concentration curve. We collected saliva and blood from 20 patients undergoing allogeneic HCT each hour after endovenous infusion, totalizing nine collections of each fluid. Busulfan was measured in saliva and plasma using a previous standardized and validated ultra high-performance liquid chromatography method. We found a significant high correlation between plasmatic and salivary busulfan concentrations (r=0.92, CI – 0.89-0.93, p<0.001). The drug peak in the both fluids was at 180min, decreasing to the half of the peak concentration at 300 min; however, after 480min, time of the last collection, there was no return to zero values. Considering the similarities between the concentrations values found in plasma and saliva, the oral mucosa is exposed to a double source of toxicity. For an efficient oral cryotherapy protocol, the procedure should initiate after 30min of the busulfan infusion and extent at least 360 min. In conclusion, the saliva is a good alternative matrix for busulfan therapeutic monitoring. The agreement between the salivary and plasmatic concentration curves encourage an adoption of oral cryotherapy for minimize the toxic effects of busulfan in the oral cavity.

09 / CORRELATION OF SALIVARY AND PLASMA BUSULFAN CONCENTRATIONS: IMPLICATIONS FOR THERAPEUTIC MONITORING AND ORAL CRYOTHERAPY PROTOCOLS