Japanese Journal of Clinical Oncology Advance Access originally published online on June 23, 2005
Japanese Journal of Clinical Oncology 2005 35(7):400-403; doi:10.1093/jjco/hyi110
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© 2005 Foundation for Promotion of Cancer Research
An Evaluation of Busulfan Pharmacokinetics in Patients Undergoing Hematopoietic Stem Cell Transplantation
1 First Department of Internal Medicine and 2 Department of Pharmacology, Fukuoka University Hospital, 3 Faculty of Pharmaceutical Sciences, Fukuoka University and 4 Department of Hematology, Hara Sanshin Hospital, Fukuoka, Japan
For reprints and all correspondence: Yasushi Takamatsu, First Department of Internal Medicine, Fukuoka University School of Medicine, Nanakuma 7-45-1, Jonan-ku, Fukuoka 814-0180, Japan. E-mail: yasushi{at}fukuoka-u.ac.jp
Received March 15, 2005; accepted May 15, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Busulfan (BU) pharmacokinetics (PK) are shown to be highly variable and thus their evaluation is critical for the success of hematopoietic stem cell transplantation (HST) in Caucasians. However, there are no data available for Japanese patients.
Methods: BU PK were evaluated in seven Japanese adult patients who underwent allogeneic HST. Four patients received 16 doses of 1 mg/kg of oral BU every 6 h for over 4 days followed by 120 mg/kg of intravenous cyclophosphamide, while three patients were given eight doses of 1 mg/kg of oral BU over 2 days in addition to 180 mg/kg of intravenous fludarabine with or without 2 Gy of total body irradiation. Blood samples were collected for PK analysis after the sixth dose of BU was administered.
Results: The average plasma BU concentrations at steady state (Css) ranged from 745 to 2422 ng/ml. Four of seven patients had BU Css >1000 ng/ml, the previously defined concentration associated with an increased risk of regimen-related toxicity (RRT). Indeed, one of them developed hepatic veno-occlusive disease. On the other hand, no severe toxicity greater than grade II except stomatitis was observed in the remaining patients whose Css were <1000 ng/ml.
Conclusion: A possible increased risk of RRT associated with high plasma BU concentrations should be kept in mind after oral administration of BU. A prospective trial of adjusting BU doses depending on the BU PK is warranted for Japanese patients.
Key Words: busulfan • pharmacokinetics • regimen-related toxicity • veno-occlusive disease
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Total body irradiation (TBI) in combination with cyclophosphamide (CY) is the standard myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (HST). Busulfan (BU) was introduced as an alternative to TBI, and cumulative data indicate that the therapeutic efficacy of a preparative regimen with BU and CY is equivalent to TBI and CY in patients with chronic myeloid leukemia (CML) (1). However, veno-occlusive disease (VOD) of the liver seems to be experienced more in BU-treated patients (2).
The standard dose of BU is 1 mg/kg body weight administered orally every 6 h. As for alkylating agents in general, the therapeutic effect of BU is closely correlated with the area under the plasma concentration–time curve (AUC) or the average plasma concentrations at steady state (Css) (3). It is demonstrated that AUC or Css varies widely from one patient to another after oral BU, and excessively high BU concentrations are associated with an increase in hepatic VOD (4,5), while lower levels are related to a high relapse rate in patients with CML (6) and graft rejection in children (7,8). Monitoring of BU concentrations and the dose adjustment according to the BU levels is shown to reduce the risk of severe toxicity in patients with myelodysplastic syndrome (MDS) and CML (9,10).
BU, which causes DNA damage and induces cells to undergo cell cycle arrest, is metabolized mainly in the liver through conjugation with glutathione by glutathione S-transferase (GST). High hepatic GST activity correlates with high BU clearance and low plasma BU concentrations (11), indicating that conjugation with glutathione is an effective mechanism to detoxify BU metabolically. A recent study has shown that the polymorphisms of GST genes are associated with the risk of developing hepatic VOD in patients undergoing HST (12). Ethnic variation is also demonstrated in relation to a gene deletion polymorphism of GST (13), suggesting that BU metabolism is influenced by race. The pharmacokinetics (PK) of BU have been extensively investigated in Caucasians and few studies have focused on Asian people (14).
We have recently developed a high-performance liquid chromatographic method to determine BU concentrations (15). By using this method, we undertook the BU PK study in seven Japanese adult patients who received oral BU for allogeneic HST.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENTS AND TREATMENT
We prospectively evaluated BU PK in seven Japanese adult patients who underwent allogeneic HST for hematological malignancies. Four patients received 16 doses of BU at 1 mg/kg every 6 h over 4 days followed by 120 mg/kg of CY, while three patients received BU as a part of a reduced-intensity preparative regimen which was given in eight doses over 2 days in addition to 180 mg/kg of fludarabine (FLU) with or without 2 Gy of TBI. Prophylaxis against graft-versus-host disease (GVHD) consisted of a combination of cyclosporin and methotrexate in five patients who were transplanted with either bone marrow (BM) cells or peripheral blood stem cells (PBSCs) from their human leukocyte antigen (HLA)-matched siblings, while cyclosporin and mycophenolate mofetil were given in two patients undergoing unrelated cord blood (CB) cell transplantation. Sodium valproate was given to all patients as prophylaxis against BU-related seizures, and fluconazole, ciprofloxacin and aciclovir were administered as prophylaxis against fungal, bacterial and herpes infection, respectively. Patients' characteristics are shown in Table 1. All patients provided an informed consent to participate in this study.
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PK STUDIES
Blood samples were collected for analysis in heparinized tubes at 30, 60, 120, 240 and 360 min after the sixth dose of BU was taken orally. They were stored on ice until the plasma was separated and the separated plasma was frozen at –20°C until analysis. BU concentrations were measured by a high-performance liquid chromatographic method as previously described (15). Population parameter and variance values published by Sandstrom were used (16). Individual PK parameters of BU were calculated with a one-compartment model by using a Bayesian modeling program. BU Css was determined by the ratio of BU AUC over the dosing interval to the time between doses.
REGIMEN-RELATED TOXICITY (RRT)
RRT was scored using the criteria described by Bearman et al. (17). The overall grade was calculated from the maximum toxicity grade for the bladder, renal, pulmonary, hepatic, central nervous system, mucosal and gastrointestinal organ systems which the patients experienced during the first 28 post-transplant days. The diagnosis of VOD was made clinically based on the standard criteria of a bilirubin >2 mg/dl and at least two of the following signs or symptoms: hepatomegaly with right upper quadrant pain, ascites or weight gain >5% from the baseline (18).
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RESULTS |
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BUSULFAN PK
Table 1 presents the PK data of BU. The median clearance (CL/F) was 0.15 l/h/kg (0.07–0.21 l/h/kg), the median volume of distribution (Vd/F) 0.64 l/kg (range 0.48–0.81 l/kg), the median elimination half-life (t1/2) 3.2 h (range 2.1–6.0 h) and the median absorption rate constant (ka) 2.56/h (range 0.54–3.39/h). The average plasma concentrations of BU Css ranged from 745 to 2422 ng/ml (median 1146 ng/ml).
ENGRAFTMENT
All seven patients achieved engraftment. Neutrophil recovery to >0.5 x 109/l and platelet recovery to 50 x 109/l occurred on days 11–28 (median 13 days) and on days 13–75 (median 14 days), respectively.
RRT
Previous studies indicate that BU Css of >1000 ng/ml is associated with an increased risk of developing hepatic VOD (4,5). Four of seven patients were treated with 16 mg/kg of BU and 120 mg/kg of CY. One of them developed hepatic VOD. This was a 21-year-old female patient (UPN 3) with acute myeloid leukemia (AML) in second remission. She underwent allogeneic HST from her HLA-matched brother. Hematological recovery was quite rapid; neutrophil counts reached >0.5 x 109/l on day 11 and platelet counts >50 x 109/l on day 13. However, serum levels of total bilirubin rose to 9.6 mg/dl on day 20 with no significant increase in liver transaminase and alkaline phosphatase levels. Hepatomegaly and ascites became apparent in a few days. She fulfilled the clinical criteria of hepatic VOD. She became anuric, with serum creatinine levels up to 4.6 mg/dl, requiring hemodialysis on day 23. Her BU Css came back to 1676 ng/ml. Fortunately, her liver and renal function returned to normal and the ascites disappeared within 3 weeks. She has been alive in remission for 21 months. There were three remaining patients who also received BU and CY. No grade II–III toxicity except stomatitis was experienced in these patients whose BU Css were 745, 827 and 861 ng/ml, respectively.
Three patients received a reduced-intensity conditioning regimen consisting of a total of 8 mg/kg of BU. They had BU Css of 1745, 2422 and 1146 ng/ml, respectively. They were all higher than 1000 ng/ml, but no grade II–III RRT was observed.
CLINICAL OUTCOME OF THE HST
There were two patients who ended up with recurrence of the underlying disease or fatal complication. A 60-year-old female (UPN 2) with malignant lymphoma in third remission received allogeneic HST following a BU and CY conditioning regimen, but had recurrence of the disease after 2 months. Another patient was a 65-year-old female (UPN 6) with AML in second relapse, who underwent unrelated umbilical cord transplantation following a reduced-intensity conditioning, and died of Aspergillus pneumonia at 4 months after HST. The remaining five patients have been alive in remission for 13–27 months (median 19 months) after HST.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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This study represents the first PK data of oral BU for Japanese adult patients. A BU Css level below 600 ng/ml is shown to correlate with the increased risk of graft rejection (7). It was fortunate that all patients achieved BU Css of higher than 600 ng/ml, and therefore, the influence of low BU concentrations on the risk of poor engraftment was not evaluable from our small study.
More than half (four out of seven) of the patients had BU Css higher than 1000 ng/ml and, one of them developed hepatic VOD. On the other hand, no severe toxicity greater than grade II except stomatitis was observed in the other three patients whose Css were below 1000 ng/ml. The number of patients evaluated in the present study was too small to draw a definitive conclusion. However, an increased risk of RRT associated with high plasma BU concentrations was suggested in Japanese adults after the oral administration of BU in combination with CY.
In contrast, three patients receiving BU as a reduced-intensity conditioning had high BU Css, but no severe RRT was observed. In these cases, the total dose of BU was half of that given in the BU–CY regimen. This may suggest that not only BU Css but also the total dose is important to predict adverse events of BU. A prospective trial monitoring BU concentrations and adjusting BU doses depending on the PK is warranted for Japanese patients who are planning to undergo HST especially when a high and full dose BU-containing conditioning regimen is used.
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Acknowledgments |
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We thank Atsuko Shono and Noriko Ikoma for valuable assistance in conducting the present study. This study was supported in part by a grant for Scientific Research (No. 15591030) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by a grant for cancer research from Fukuoka Cancer Society, Fukuoka, Japan.
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References |
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