Pharmacokinetics and tolerability of intravenous busulfan in hematopoietic stem cell transplantation.
ABSTRACT Intravenous (IV) busulfan has been developed to overcome variable absorption of oral busulfan and tested in several trials. We tested its pharmacological properties and tolerability in 16 Korean stem cell transplantation (SCT) patients. IV busulfan was administered at 0.8 mg/kg every six h for a total of 16 doses (days -7 to -4), which was followed by cyclophosphamide administration at 60 mg/kg every 24 h for two d (days -3 and -2). The median AUC(inf) values (at the first dose) and AUC(ss) (at the steady state) were 1060.4 microM.min (range: 511.1-1812.7) and 1092.5 microM.min (range: 539.7-1560.8) respectively. All patients had an AUC(inf) of <1500 microM.min at the first dose, and 13 of the 16 (81.3%) maintained AUC(ss) levels between 800 and 1500 microM.min. Thirteen of 16 patients showed successful engraftments but four patients (25%) developed hepatic VOD (two of which were fatal), three of whom had advanced disease at the time of SCT. Overall, pharmacokinetics of IV busulfan in our SCT patients appeared comparable with those observed in other study. However, hepatic VOD was a major morbidity in patients with advanced disease.
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ABSTRACT: The influence of busulfan (BU) plasma concentration on outcome of transplantation from HLA identical family members for the treatment of chronic myelogenous leukemia (CML) was examined in 45 patients transplanted in chronic phase (CP) (n = 39) or accelerated phase (AP) (n = 6). All patients received the same regimen of BU, 16 mg/kg orally and cyclophosphamide (CY), 120 mg/kg intravenously. Plasma concentrations of BU at steady state (C(SS)BU) during the dosing interval were measured for each patient. The mean C(SS)BU was 917 ng/mL (range, 642 to 1,749; median, 917; standard deviation, 213). Of patients with C(SS)BU below the median, seven (five of 18 in CP and two of four in AP) developed persistent cytogenetic relapse and three of these patients died. There were no relapses in patients with C(SS)BU above the median. The difference in the cumulative incidence of relapse between the two groups was statistically significant (P = .0003). C(SS)BU was the only statistically significant determinant of relapse in univariable or multivariable analysis. The 3-year survival estimates were 0.82 and 0.64 for patients with C(SS)BU above and below the median (P = .33). There was no statistically significant association of C(SS)BU with survival or nonrelapse mortality, although the power to detect a difference in survival between 0.82 and 0.64 was only 0.24, similarly C(SS)BU above the median was not associated with an increased risk of severe regimen-related toxicity. We conclude that low BU plasma levels are associated with an increased risk of relapse.Blood 05/1997; 89(8):3055-60. · 9.06 Impact Factor
Article: Busulfan bioavailability.[show abstract] [hide abstract]
ABSTRACT: Busulfan is widely used as a component of the myeloablative therapy in bone marrow transplantation. Recent studies have shown that the drug disposition is altered in children and is associated with less therapeutic effectiveness, lower toxicities, and higher rates of engraftment failure. We have evaluated the bioavailability of the drug in two groups of patients: eight children between 1.5 and 6 years of age and eight older children and adults between 13 and 60 years. Oral bioavailability showed a large interindividual variation. In children, the bioavailability ranged from 0.22 to 1.20, and for adults, it was within the range 0.47 to 1.03. The elimination half-life after intravenous administration in children (2.46 +/- 0.27 hours; mean +/- SD) did not differ from that obtained for adults (2.61 +/- 0.62 hours). However, busulfan clearance normalized to body weight was significantly higher in children (3.62 +/- 0.78 mL.min-1.kg-1) than that in adults (2.49 +/- 0.52 mL.min-1.kg-1). Also, the distribution volume normalized for body weight was significantly higher in children (0.74 +/- 0.10 L.kg-1) compared with 0.56 +/- 0.10 L. kg-1 in adults. The difference in clearance between children and adults was not statistically significant when normalized to body surface area, which most probably shows that busulfan dosage should be calculated on the basis of surface area rather than body weight. However, to avoid drug-related toxicities, drug monitoring and an individual dose adjustment should be considered because of the variability in busulfan bioavailability.Blood 11/1994; 84(7):2144-50. · 9.06 Impact Factor
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ABSTRACT: Busulfan pharmacokinetics, specifically area under the concentration curve (AUC), have been correlated with the occurrence of veno-occlusive disease (VOD) following BMT. To evaluate the risk of VOD, we studied 66 patients who received pharmacotherapeutically monitored busulfan regimens in combination with CY, etoposide (VP16) and/or Ara-C in preparation for BMT. These patients received a total of 16 doses of busulfan dosed as 1 mg/kg/dose q 6 h beginning at 09.00 (n = 39), 18.00 (n = 2), 21.00 (n = 1) or 24.00 (n = 24) h. With the first dose, blood samples were obtained at baseline, every 15-30 min for 2 h, then every 1-2 h for 4 h. Blood was analyzed for busulfan concentration by high performance liquid chromatography and AUC calculated by the trapezoidal rule. Seventeen patients (25.8%) were not evaluable for AUC calculation due to slow absorption and/or elimination: 13 of 27 (48.1%) received the first dose between 18.00-24.00 vs four of 39 (10.2%) patients who received the first dose at 09.00 (P < 0.001). Eighteen of 51 (35.3%) evaluable patients had an AUC > 1500 mumol x min/l; 10 of whom received doses reduced proportionally to achieve an AUC = 1200 mumol x min/l starting with the 10th to 15th dose. Six of 18 (33.3%) patients with an initial AUC > 1500 mumol x min/l developed VOD vs one of 33 (3.0%) patients with an initial AUC < 1500 mumol x min/l (relative risk = 11.1; P = 0.0056). Other pharmacokinetic parameters, age, gender, type of BMT, previous therapy or pre-transplant liver function tests were not predictive of VOD. A higher incidence of VOD occurred in patients receiving BUCY (4 of 10) compared to those receiving BUCYAra-C (1 of 18) or BUCYVP16 (7 of 38), which could not be attributed to increased busulfan exposure in the BUCY patients. Routine pharmacotherapeutic monitoring of busulfan is recommended with further study to evaluate the impact of earlier and greater overall dose reduction in patients with high initial busulfan exposures.Bone Marrow Transplantation 03/1996; 17(2):225-30. · 3.54 Impact Factor