Background: Busulfan (Bu), an alkylating agent commonly used in chemotherapy and transplantation, exhibits high intraindividual pharmacokinetic variability and possible time-dependent variations in clearance, which complicate therapeutic drug monitoring. Numerous analytical methods have been developed to reduce analysis time and facilitate timely decision-making regarding treatment changes; however, the validation procedures rarely involve analysis of potentially interfering excipients. Macrogol 400 (PEG 400) should be considered as a possible interfering agent in the detection of plasma Bu levels, especially as an ionization suppressor.
Methods: Six intravenous formulations of Bu were compared with identify at least 1 common excipient (PEG 400). During the 176 therapeutic drug monitoring analyses of Bu, one of the PEG 400 specific mass-to-charge ratio transitions was determined using an instrumental method. After coelution with Bu and its internal standard (Bu-d8) was confirmed, all analyses were repeated using a different experimental setup free of ion suppression induced by PEG. The concentration-time profile of PEG 400 was also analyzed.
Results: The area under the curve obtained from the 2 data sets was compared and analyzed using Lin concordance correlation coefficient and Bland-Altman plot analysis. The results from the 2 analytical methods were comparable: PEG 400 negatively affected the Bu-d8 coefficient of variation but not the Bu/Bu-d8 ratio.
Conclusions: The possible interference of PEG 400 should be thoroughly investigated, especially with respect to analytical methods that cannot be supported by correction of the stable isotopically labeled internal standard analog.
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