BUSULFAN KINETICS AND LIMITED SAMPLING MODEL IN CHILDREN WITH LEUKEMIA AND INHERITED DISORDERS

Busulphan pharmacokinetics were investigated in 20 children, who under went bone marrow transplantation for either leukemia or inherited diso rders, Busulphan (1.90-6.02 mg/kg/day) was administered orally as a si ngle dose or twice daily, Busulphan kinetics were found to be linear w ithin the studied range, Children with inherited disorders eliminated busulphan significantly faster after the first and the last dose with half-lives (t(1/2)) of 1.93 and 1.71 h, respectively compared to child ren with leukemia (3.16 and 2.70 h, respectively), The area under plas ma concentration curves (AUCs, corrected for mg/kg) as an expression f or the systemic exposure of busulphan were significantly higher in chi ldren with leukemia, 22.4 and 19.04 mu mol/l.h (5527 and 4690 ng.h.ml( -1)) after the first and the last dose, respectively, compared to 11.2 and 8.2 mu mol/l.h (2768 and 2029 ng.h.ml(-1)) found in children with inherited disorders, The present results confirm those reported by ot hers, ie busulphan pharmacokinetics can be influenced by the underlyin g disease and its status, Our population pharmacokinetic analysis show ed a negative correlation between the weight corrected clearance and t he age in both groups of children, However, clearance was about 42% hi gher in children with inherited disorders compared to those with leuke mia, To estimate AUC for the first dose, we evaluated a limited sampli ng model based on three concentrations (1, 3 and 6 h), A high correlat ion (r = 0.998, P < 0.0001, n = 40) between the estimated and the dete rmined AUC was found, The present model is reliable and adequate for s tudying more patients, with a long-term follow-up combined with drug m onitoring in correlation with drug efficacy and toxicity to define the optimal busulphan dosage required.