Cyclophosphamide metabolism in children with Fanconi’s anaemia

Yule, S. M.; Price, L.; Cole, Michael; Pearson, Andrew D.J.; Boddy, Alan V.

doi:10.1038/sj.bmt.1701868

Cited by 27 publications

(27 citation statements)

References 24 publications

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“…41 --43 CY Cl (L/h/m 2 ) was significantly lower in our patient population compared with three studies in the pediatric population treated with myeloablative doses of CY (Table 3). CY CL has been shown to be reduced in patients with hepatic dysfunction 44 and also in patients with Fanconi anemia 45 receiving lower than the myeloablative dose of CY. It is possible that the influence of age on CY CL in thalassemia and Fanconi anemia is masked by other factors including the disease itself.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Balasubramanian

Desire

Panetta

et al. 2012

Bone Marrow Transplant

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“…It is a prodrug requiring metabolic transformation to generate active alkylating species (9,10). The initial activation is mediated by hepatic cytochrome P-450 enzymes and is the major pathway of elimination of the parent drug (11).…”

Section: Introductionmentioning

confidence: 99%

“…Cyclophosph- amide pharmacokinetics was assumed to follow a single compartment open model with first order elimination. Although a two-compartment model has been reported previously for cyclophosphamide, a one-compartment model has been found to be adequate in pediatric studies (10). Estimates of pharmacokinetic parameters were obtained by a maximum-likelihood method using ADAPT II (16).…”

Section: Introductionmentioning

confidence: 99%

Cyclophosphamide Metabolism in Children with Non-Hodgkin’s Lymphoma

Yule

Price

McMahon

et al. 2004

Clinical Cancer Research

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Purpose: The purpose of our study was to determine whether variation in cyclophosphamide metabolism influences the incidence of recurrence among children receiving chemotherapy for B-cell non-Hodgkin's lymphoma.Experimental Design: The pharmacokinetics and metabolism of cyclophosphamide were studied during a single course of treatment in 36 children receiving a uniform chemotherapy regimen for B-cell non-Hodgkin's lymphoma and were analyzed in terms of disease recurrence and hematological toxicity.Results: At a median follow-up of 43 months (range, 17-98 months), six children had developed recurrent disease, giving an overall disease-free survival of 83%. The median clearance of cyclophosphamide in patients who remain free of B-cell non-Hodgkin's lymphoma was 3.7 liter/ h/m 2 (range, 2.3-5.0 liter/h/m 2 ), compared with 2.2 (range, 1.5-2.5 liter/h/m 2 ) in those with disease recurrence. Likelihood of recurrence was higher in patients with low clearance (<3.5 liter/h/m 2 ) of cyclophosphamide (P < 0.01) and positively related to detection of the inactive metabolites carboxyphosphamide and dechloroethylcyclophosphamide in plasma (P ‫؍‬ 0.01). There was no correlation between cyclophosphamide metabolism and hematological toxicity.Conclusions: Inadequate clearance of cyclophosphamide to active metabolites is associated with increased risk of recurrence of B-cell non-Hodgkin's lymphoma in children. Modified chemotherapy strategies should be considered in patients who exhibit low rates of clearance of the parent drug and/or extensive production of inactive metabolites.

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“…A high degree of interpatient variability has been reported in the pharmacokinetics and systemic exposure of CPA in children and adults with cancer (Moore et al, 1988;Yule et al, 1996;Ren et al, 1998;Yule et al, 1999a). This variability could partially reflect differences in the expression of individual P450 isozymes.…”

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confidence: 99%

The Effect of Cyclophosphamide with and without Dexamethasone on Cytochrome P450 3A4 and 2B6 in Human Hepatocytes

Lindley

Hamilton²,

Faucette

et al. 2002

Drug Metab Dispos

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ABSTRACT:The purpose of this study was to characterize the concentrationresponse effects of cyclophosphamide (CPA) with and without dexamethasone (DEX; 10 M) on the expression of CYP3A4 and CYP2B6 in cultured human hepatocytes at concentrations representative of standard-and high-dose CPA therapy (25 to 750 M). CPA produced concentration-dependent increases in CYP3A4 and CYP2B6 activity and immunoreactive protein that peaked at 250 and 125 M, respectively, and declined thereafter. The inductive effect of CPA alone and in combination with DEX was greater in magnitude for CYP2B6 compared with CYP3A4. To further examine the inductive effect of CPA on CYP3A4, CPA (250 M) and DEX (10 M) alone and in combination were examined in 10 hepatocyte preparations. The combination of CPA and DEX yielded higher rates of 6␤-hydroxytestosterone formation than either agent alone. However, the effect was less than additive in human hepatocyte cultures with relatively high baseline CYP3A4 activity and additive or synergistic in human hepatocyte cultures with relatively low baseline CYP3A4 activity. Induction index was highly correlated with CYP3A4 baseline activity for both CPA (r 2 ‫؍‬ 0.75) and CPA plus DEX (r 2 ‫؍‬ 0.85). To investigate the potential mechanism for CPA-induced increases in CYP3A4 activity, the ability of CPA alone and in combination with DEX to activate pregnane X receptor (PXR) was explored using transient transfection assays. CPA produced a dose-dependent increase in PXR activation that was maximal at the highest CPA concentration studied (500 M). The addition of DEX to CPA resulted in a minor increase in PXR activation compared with CPA alone. These results indicate that CPA alone and in combination with DEX differentially induces the expression of CYP3A4 and 2B in a concentration-dependent manner, which may be mediated partially through activation of PXR. The impact of these effects on the efficacy and toxicity of CPA therapy warrants further investigation.

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Cyclophosphamide metabolism in children with Fanconi’s anaemia

Cited by 27 publications

References 24 publications

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Cyclophosphamide Metabolism in Children with Non-Hodgkin’s Lymphoma

The Effect of Cyclophosphamide with and without Dexamethasone on Cytochrome P450 3A4 and 2B6 in Human Hepatocytes

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