Population Pharmacokinetic Study of a Test Dose Busulfan Patients Undergoing Hematopoietic Stem Cell Transplantation

Introduction:Busulfan (bu) is one of the most used chemotherapy in conditioning regimens for patients submitted to hematopoietic cell transplantation (HCT). As Bu pharmacokinetic (PK) is widely variable, dose adjustment according to patient PK has been shown to minimize toxicities improving clinical outcome. Usually, PK is calculated from blood samples collected after the first Bu dose, guiding adjustment of following doses. Although this method has shown to be reliable, it can be difficult to perform PK in an optimal time frame. Therefore, using a test dose before HCT can optimize this method, potentially given more accurate dose adjustment. Bu test dose has been used with Bu iv formulation, but little is known with oral Bu. In countries like Brazil where oral Bu is still been used because of cost issues an optimal drug administration should be developed. Objectives: To validate the use of oral Bu test dose by comparing PK from dose test and first conditioning regimen dose. Methods: 19 patientes were enrolled. Median age was 28 year  (range, 4-56). 4 (21%) patients received autologous HCT while 19 (79%) allogeneic grafts from MRD or MUD donors. As conditioning regimens, 1 patient recieved Bu(16)/Flu(160), 9 Bu(16)/Cy(120), 3 Bu(16)Mel(140), 2 Bu(12)/Cy(120)/Mel(140) and 4 Bu(12)/Cy(120)/Etoposide(1200). After oral test dose (1mg/kg) 72 hours before conditioning regimen, blood samples were collected at 8 time points. Samples were also collected after the first Bu dose (1mg/kg) during conditioning regimen. Bu concentrations were measured by HPLC. PK parameters were estimated by using nonlinear mixed effects model computer program. No Bu dose adjustment was performed based on test dose. Results: PK parameters were comparable between test dose and first conditioning dose: median Bu Clearance (microMol/min) was 10115,9 (range: 333,43-18270,4) and 11866,1 (range: 4520,3-15589,2) respectively (p=0,738); median concentration steady state (mcg/L) was 0,80 (range: 0,55-1,59) and 0,76 (range: 0,59-1,23) respectively (p=0,672); half life (hours) was 2,85 (range: 1,65-5,61) and 2,65 (range: 1,71-6,09) respectively (p=0,172). Area under the curve (AUC) (mcgMol.min) was also comparable showing a median of 1174 (range: 799-2328) and 1110 (range: 857-1795) respectively (p=0,679). Toxicities was comparable to literature data: 14 (88%) and 5 (12%) patients developed grades 1 to 3 and grade 4 mucositis respectively; 2 (10%) patients developed sinuisodal obstruction syndrome (SOS) both received Bu/Cy/Etoposide protocol. All patients achieved full donor chimerism. Incidence of grade II-IV acute and extensive chronic GVHD was 55% and 31% respectively.  With a median follow-up of 82 days (range: 18-321) 17 patients were alive. Conclusions: A population PK model for oral Bu could be developed, showing efficacy and safety of oral Bu test dose.