Busulphan Pharmacokinetics Research Articles

Vitamin D levels and busulphan kinetics in patients undergoing hematopoietic stem cell transplantation, a multicenter study.

Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P < 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.

Comparison of Two Busulphan-Based Conditioning Regimens Outcomes for Children and Young Adults with Acute Myeloid Leukemia in a Silgle Center in Brazil

Introduction: As well as best allogeneic donor choice is imperative to bone marrow transplant (BMT), best conditioning regimen is one of the major cornerstones of the treatment success. Although high-dose busulfan have been employed along with cyclophoshamide (BuCy) for more than two decades as one of the best options for allogeneic BMT in acute myeloid leukemia patients (AML), we were unable to attain the best published outcomes in our center, which led us to pursue new treatment strategies, including alternative conditioning regimens. We chose to use a combination of Busulfan and Melphalan (BuMel) together with Busulfan plasma concentration monitoring.Objective: to compare outcomes of children and young adults who underwent allogeneic BMT for AML using two different myeloablative conditioning regimens without radiotherapy.Methods: retrospective analysis of data.Results: from September, 1999, to July, 2016, 40 patients (30 male), median age 4,6 yo (1,2 to 20,7) underwent allogeneic BMT at Instituto de Oncologia Pediatrica (GRAACC - IOP - UNIFESP). Third-four patients had matched related donors. Median follow-up was 472 days. BuCy (oral busulfan 16 mg/kg or intravenous equivalente dose and cyclophosphamide 200 mg/kg) was the conditioning regimen for 15 patients, and BuMel (oral busulfan 16 mg/kg or intravenous equivalent dose and melphalan 140 mg/m2) for the other 25. Graft versus host disease (GVHD) prophylaxis included rabbit antithymocyte globulin for six matched unrelated transplants. Half of the patients were in first, 19 in second and one in third remission. Bone marrow stem cells were used in the majority of the procedures (38). Only two out of 15 patients who received BuCy as conditioning regimen are alive (OS 13%), versus 15 of the 25 who were transplanted using BuMel (OS 60%). Leukemia relapse was cause of death in 70% for BuCy, followed by transplant-related mortality (TRM) in 23% and GVHD in 7% of the cases. In BuMel group, main cause of death was GVHD (50%), followed by leukemia relapse (20%), TRM (20%) and one disseminated fusariosis. Busulphan pharmacokinetics was available for 18 procedures (17 BuMel and one BuCy). Death rate for those patients was 44%, against 68% for those who had not their busulphan plasmatic levels monitored. However, BuCy was the chosen conditioning regimen for 14 of the 22 patients in the latter group.Conclusion: in view of the unsatisfactory results obtained with BuCy for allogeneic BMT in AML patients in our center urgent measures were required. The choice of a different conditioning regimen as well as busulphan pharmacokinetics monitoring from May, 2012 on, have led us to attain overall survival rates comparable to Center for International Blood and Marrow Transplant Research (CIBMTR) data. Longer follow up will be required to confirm our current data DisclosuresNo relevant conflicts of interest to declare.

Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients

To examine inter- and intrapatient variability in the pharmacokinetics of intravenous (i.v.) busulphan given as a single daily dose to children with malignant (n = 19) and nonmalignant (n = 21) disease. Busulphan (120 mg m(-2), 130 mg m(-2) or 3.2 mg kg(-1)) was administered over median 2.1 h. Blood samples (4-10) were collected after the first dose, busulphan concentrations were measured and pharmacokinetic parameters, including clearance (CL) and area under the concentration-time curve (AUC), were determined using the Kinetica software (Innaphase). Interpatient variability was assessed as percent coefficient of variation (% CV). Intrapatient variability was assessed by calculating percent differences between observed full dose AUC and AUC predicted from an initial 65 mg m(-2) dose in 13 children who had busulphan pharmacokinetic monitoring. Clearance of i.v. busulphan in 40 children was 4.78 +/- 2.93 l h(-1) (% CV 61%), 0.23 +/- 0.08 l h(-1) kg(-1) (% CV 35%) and 5.79 +/- 1.59 l h(-1) m(-2) (% CV 27%). Age correlated significantly (p < 0.001) with CL (l h(-1)) and CL (l h(-1) kg(-1)), but not with CL (l h(-1) m(-2)). AUC normalized to the 130 mg m(-2) dose ranged from 14.1 to 56.3 mg l(-1) x h (% CV 37%) and also did not correlate with age. Interpatient variability in CL (l h(-1) m(-2)) was highest in six children with immune deficiencies (60%) and lowest in seven children with solid tumours (14%). Intrapatient variability was <13% for nine (of 13) children, but between 20 and 44% for four children. There is considerable inter- and intrapatient variability in i.v. busulphan CL (l h(-1) m(-2)) and exposure that is unrelated to age, especially in children with immune deficiencies. These results suggest that monitoring of i.v. busulphan pharmacokinetics is required.

Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients.

The aims of the present study were (1) to investigate and quantify the pharmacokinetics, including inter-occasion variability and covariate relationships, of busulphan in BMT patients and (2) to develop a user-friendly initial dosing and therapeutic drug monitoring (TDM) strategy for the treatment of those patients with busulphan. The pharmacokinetics of busulphan was studied in 64 adults and 12 children who received busulphan (1 mg/kg) four times daily for 4 days. A one-compartment model with first order absorption and a lag time was sufficient in describing the concentration-time profile. Oral clearance (CL/F) was found to be correlated to weight (+1.2%/kg), ALT (-13%/microcat/l) and concomitant phenytoin treatment (+21%). CL/F and the volume of distribution (V/F) were estimated to 9.23 l/h and 39.3 l, respectively, in a typical individual. Inter-occasion variability (9.4%) in CL/F was estimated to be less than inter-individual variability (28%), a prerequisite for the value of TDM. Bayesian CL/F estimates based on three samples were in good accordance with those based on all samples. The final population model was implemented into the program Excel. The resulting flexible and easy to use dosing program might be used for both initial and, requiring only three plasma samples, maintenance dose individualization of busulphan therapy.

Busulphan is active against neuroblastoma and medulloblastoma xenografts in athymic mice at clinically achievable plasma drug concentrations.

High-dose busulphan-containing chemotherapy regimens have shown high response rates in children with relapsed or refractory neuroblastoma, Ewing's sarcoma and medulloblastoma. However, the anti-tumour activity of busulfan as a single agent remains to be defined, and this was evaluated in athymic mice bearing advanced stage subcutaneous paediatric solid tumour xenografts. Because busulphan is highly insoluble in water, the use of several vehicles for enteral and parenteral administration was first investigated in terms of pharmacokinetics and toxicity. The highest bioavailability was obtained with busulphan in DMSO administered i.p. When busulphan was suspended in carboxymethylcellulose and given orally or i.p., the bioavailability was poor. Then, in the therapeutic experiments, busulphan in DMSO was administered i.p. on days 0 and 4. At the maximum tolerated total dose (50 mg kg−1), busulphan induced a significant tumour growth delay, ranging from 12 to 34 days in the three neuroblastomas evaluated and in one out of three medulloblastomas. At a dose level above the maximum tolerated dose, busulphan induced complete and partial tumour regressions. Busulphan was inactive in a peripheral primitive neuroectodermal tumour (PNET) xenograft. When busulphan pharmacokinetics in mice and humans were considered, the estimated systemic exposure at the therapeutically active dose in mice (113 μg h ml−1) was close to the mean total systemic exposure in children receiving high-dose busulphan (102.4 μg h ml−1). In conclusion, busulphan displayed a significant anti-tumour activity in neuroblastoma and medulloblastoma xenografts at plasma drug concentrations which can be achieved clinically in children receiving high-dose busulphan-containing regimens. 1999 Cancer Research Campaign

Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics

The pharmacokinetics of high-dose busulphan was studied in 17 patients during conditioning prior to bone marrow transplantation using deuterium-labeled busulphan (d8-BU). About 50% of busulphan doses 1 and 16 was replaced with d8-BU. Patients were treated with phenytoin or diazepam as prophylactic anticonvulsant therapy. Patients who received phenytoin demonstrated significantly higher clearance (mean +/- SD, 3.32 +/- 0.99 ml min-1 kg-1), a lower area under the concentration-time curve (AUC, 5,412 +/- 1,534 ng h ml-1; corrected for dose/kilogram) and a shorter elimination half-life (3.03 +/- 0.57 h) for the last dose of d8-BU (dose 16) as compared with the first dose (2.80 +/- 0.78 ml min-1 kg-1, 6,475 +/- 2,223 ng h ml-1 and 3.94 +/- 1.10 h, respectively). No difference in the above mentioned pharmacokinetic parameters was seen in patients treated with diazepam. Moreover, a continuous decrease in the steady-state level of busulphan was observed in four of seven patients in the phenytoin-treated group, whereas in the diazepam group, such a decrease was seen in only one of eight patients. We conclude that phenytoin used as prophylactic anticonvulsant therapy alters busulphan pharmacokinetics and, most probably, its pharmacodynamics. For adequate prophylactic therapy, anticonvulsants with fewer enzyme-inductive properties than phenytoin should be used.