The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity

Hassan, Moustapha; Ljungman, Per; Ringdén, Olle; Hassan, Zuzana; Öberg, Gunnar; Nilsson, Christína; Békássy, Albert N.; Bielenstein, Margareta; Abdel‐Rehim, Mohamed; Georén, Susanna Kumlien; Astner, L

doi:10.1038/sj.bmt.1702377

Cited by 136 publications

(110 citation statements)

References 35 publications

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“…Compared with previous reports from patients receiving BU/CYconditioning regimen, 17,19,20 there was significantly decreased formation of HCY and increased AUC of CY in this study resulting in lower AUC HCY/CY ratio (Table 4). This difference in PK parameters could be age related because all the previous studies were from adult patients, whereas patients in this study are all under 15 years.…”

Section: Discussioncontrasting

confidence: 51%

“…As it has been shown that the PK of HCY is formation-rate limited, a better measure of exposure to this metabolite was suggested to be the ratio of AUC-HCY/ AUC-CY. 20 This is henceforth called AUC 4HCY/CY ratio in this article.…”

Section: Cy and Hcy Pk Analysismentioning

confidence: 99%

“…As HCY is an unstable compound and requires immediate derivatization to a more stable derivative, a 500-mL volume of plasma was added to 1 ml of ice-cold acetonitrile, vortexed and centrifuged at 3000 r.p.m. for 3 min at 4 1C and the supernatant was separated as reported previously 20 and stored at À80 1C until analysis.…”

Section: Pharmacogenetic Analysismentioning

confidence: 99%

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Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Balasubramanian

Desire

Panetta

et al. 2012

Bone Marrow Transplant

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CY in combination with BU is a widely used conditioning regimen for haematopoietic SCT (HSCT). The aim of this study was to evaluate the pharmacokinetics (PK) of CY and its major metabolite 4-hydroxyCY (HCY) in patients with thalassemia undergoing HSCT. A total of 55 patients received BU (16 mg/kg) followed by CY (160 --200 mg/kg) both over 4 days before HSCT. A population PK model was developed to describe the disposition of CY and HCY and the inter-individual (IIV) and inter-occasion variability (IOV). The model was also used to determine the effects covariates including: demographics, Lucarelli classification and polymorphisms in enzymes involved in the metabolism or biotransformation of CY had on CY and HCY disposition. Overall, 17 --114% IIV and 12 --103% IOV in CY and HCY PK parameters were observed. Body weight and age were the main covariates, which explained the largest portion of the IIV. In addition, CYP2C9*2 explained a significant portion of the IIV in the clearance (Po0.002) and thus the area under the concentration curve (Po0.05) of CY. This covariate model may be used to design and plan targeted dose therapy in this group of pediatric patients, if clinical outcome association with CY PK are proved and target range established.Bone Marrow Transplantation (2012) 47, 1178 --1185; doi:10.1038/bmt.2011.254; published online 9 January 2012Keywords: CY; pharmacokinetics; thalassemia, HSCT INTRODUCTION CY in combination with BU has been a commonly used conditioning regimen in HSCT for malignant and non-malignant diseases. 1 --3 Even though advances in transplantation practices including reducing the intensity of the conditioning regimen have improved the outcome of HSCT in recent years, 4,5 doselimiting toxicities such as sinusoidal obstruction syndrome (SOS) and hemorrhagic cystitis 6,7 remain as the major problems associated with BU-CY-based myeloablative-conditioning regimen. We and others have previously shown that BU pharmacokinetics (PK) influences toxicity and outcome associated with HSCT in patients with thalassemia major treated with BU/CY conditioning. 8 --10 The PK and pharmacodynamics of CY in pediatric patients receiving myeloablative doses of CY are limited and to the best of our knowledge, there is no report on CY PK in pediatric patients undergoing HSCT with myeloablative BU/CY-conditioning regimen. A recent study on the PK of CY and its metabolites in pediatric patients receiving high-dose myeloablative therapy 11 showed very little inter-patient variation in CY elimination, which is largely accounted for by body surface area, suggesting that high-dose chemotherapy resulted in minimal differences in CY PK as compared with more conventional dosage regimens. A population PK model was developed for the first time in children with neuroblastoma, 12 which showed substantial inter-patient variability in the PK of CY and its metabolites. Neither of these two studies described any pharmacodynamics associations. Several studies in adult patients have shown association between the incidence of SO...

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Section: Discussioncontrasting

confidence: 51%

Section: Cy and Hcy Pk Analysismentioning

confidence: 99%

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Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Balasubramanian

Desire

Panetta

et al. 2012

Bone Marrow Transplant

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“…Inhibition of hepatic glutathione-S-transferase by acrolein (Scott and Kirsch, 1988), as well as direct glutathione depletion (DeLeve, 1996), may cause acrolein accumulation in the liver after administration of high doses of cyclophosphamide. High-dose busulphan may also cause a depletion of glutathione and glutathione-S-transferase levels (Hassan et al, 2000). Therefore, the combination cyclophosphamide/busulphan, regularly used in the bone marrow transplantation setting, is often complicated by hepatic toxicity (Nevill et al, 1991;McDonald et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy

et al. 2006

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We investigated whether the occurrence of veno-occlusive disease of the liver (VOD) may be associated with individual variations in the pharmacokinetics of high-dose cyclophosphamide. Patients received single or multiple courses of cyclophosphamide (1000 or 1500 mg m À2 day À1 ), thiotepa (80 or 120 mg m À2 day À1 ) and carboplatin (265 -400 mg m À2 day À1 ) (CTC) for 4 consecutive days. The area under the plasma concentration -time curves (AUCs) were calculated for cyclophosphamide and its activated metabolites 4-hydroxycyclophosphamide and phosphoramide mustard based on multiple blood samples. Possible relationships between the AUCs and the occurrence of VOD were studied. A total of 59 patients (115 courses) were included. Four patients experienced VOD after a second CTC course. The first-course AUC of 4-hydroxycyclophosphamide (P ¼ 0.003) but not of phosphoramide mustard (P ¼ 0.101) appeared to be predictive of the occurrence of VOD after multiple courses. High exposures to bioactivated cyclophosphamide may lead to increased organ toxicity.

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“…Applying BU before CY enhances hepatic conversion to the active drug and increases toxicity. 24 Therefore, the application of CY should be delayed for at least 24 h after BU.…”

Section: Discussionmentioning

confidence: 99%

Allo-SCT using BU, CY and melphalan for children with AML in second CR

Beier

Albert

Bader

et al. 2012

Bone Marrow Transplant

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Based on the results from the AML-BFM 98 trial, hematopoietic SCT (HSCT) is recommended for children with AML in second CR only. Here, we retrospectively analyze interphase data of children who underwent HSCT after myeloablative conditioning with BU, CY, and melphalan (BuCyMel) for AML in second remission (CR2) between 1998 and 2009. Out of 152 children, transplant data were available on 109 individuals. Sixty out of 109 children (55%) received BuCyMel. Median age at HSCT was 12.2 years (range 3.0; 18.3). GVHD prophylaxis mostly consisted of CsA and short term MTX with or without antithymocyte globulin. Matched-sibling donors were used for 6/60 analyzed recipients, the remainder either received grafts from matched unrelated (30/60) or mismatched donors. OS after 5 years was 62% (s.e. 6%), relapse incidence 35% (18/60 children) and treatment-related mortality accounted for 12% (7/60) of fatal events. In conclusion, even taking into account possible selection bias in this retrospective analysis, HSCT in CR2 using BuCyMel resulted in a respectable OS. Based on this data the prospective, controlled and centrally monitored AML SCT-BFM 2007 trial has started to recruit patients in January 2010 aiming to generate valid outcome data for further strategy decisions.

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The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity

Cited by 136 publications

References 35 publications

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy

Allo-SCT using BU, CY and melphalan for children with AML in second CR

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