The application of pharmacokinetics for Busulfan dose adjustment in hematopoietic stem cell transplantation (HSTC) in Thai children

[Speaker] Nuttawut Jenjirattithigarn:1
[Co-author] Santirat Prommas:1, Sassawat Lertrit-Anan:2, Chonlaphat Sukasem:1
1:Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 2:Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

Background: Busulfan (Bu) is an immunosuppressive agent commonly used for hematopoietic stem cell transplantation (HSTC) in children and adults. As usual immunosuppressive agent, the dose-related effects was observed both toxicity and failure of graft transplants. The regimen for Bu was suggested as single dose for 4 days, the dose adjustment must be available directly before the next dose was prepared. In order to make precise and accurate adjustment the pharmacokinetics of Bu must be elucidated. The plasma concentration for therapeutic monitoring was based on the total exposure or area under the curve (AUC). The effective AUC for once daily regimen was suggested 3,600 to 6,000 uMxmin

Methods: The pharmacokinetics study was performed with Bu IV infusion for 180 min (130 mg/m2/day) on 25 HSTC children. Heparinized blood samples were collected for 0.5 mL before infusion and 0, 15, 30, 60, 120, 180 and 300 min after the end of infusion. The extraction was performed with solid phase extraction (SPE) (C18) before analyze with LC. The dose adjustment was calculated from New dose (mg/kg) = Target AUC (uMxmin) x Clearance (L/min/kg) x 0.246.

Results: Mean total AUC of Bu was 4,851 +/- 847 uMxmin while mean Cmax was 4.07 +/- 0.67 ug/mL. The mean elimination half life was 2.19 +/- 0.58 hr with total body clearance of 81.99 +/- 30.29 mL/min. The primary pharmacokinetic parameters were in agreement with the previous report. The application for dose adjustment was shown that 16 of 25 (64.0%) cases need to adjust the dose to achieve the target AUC and 5 cases (55.6%) need twice adjustment for desire AUC.

Conclusion: This study was the first study in Thailand that applied the pharmacokinetics for Bu dose adjustment on routine basis. Even IV Bu was introduced but the fluctuation still high more than a half of all cases still need adjustment which suggests the initial conventional regimen (130 mg/m2/day) might not sufficient to reach the target AUC. Moreover, the current calculation for new dose still insufficient with 55.6% needed to repeat twice. The population pharmacokinetics might be the key for multifactor analysis and more precise calculation.

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