Cyclophosphamide pharmacokinetics in children

Yule, S. M.; Boddy, Alan V.; Cole, Michael; Price, L.; Wyllie, Ruth; Tasso, M.; Pearson, Andrew D.J.; Idle, J R

doi:10.1111/j.1365-2125.1996.tb00153.x

Cited by 75 publications

(63 citation statements)

References 34 publications

(23 reference statements)

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“…Variability in extent of CYP3A4 induction was primarily the result of baseline differences in CYP3A4 activity rather than to differences in maximum CYP3A4 activity achieved, as was previously described by McCune et al (2000). 2 ), whereas Ͼ250 M are observed in cancer patients receiving CPA as myeloablative therapy (Moore et al, 1988;Slattery et al, 1996;Yule et al, 1996;Ren et al, 1998;Busse et al, 1999;Yule et al, 1999b). Rifampin (10 M) was used as a positive control in all hepatocyte preparations.…”

Section: Resultsmentioning

confidence: 86%

“…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%

“…Other sources of variation include concomitant treatment with P450 inhibitors (Yule et al, 1999b) or prior treatment with P450 inducers including dexamethasone (Yule et al, 1996) and anticonvulsants (Slattery et al, 1996). CPA itself has been shown to induce its own metabolism manifested by an increase in clearance following repeated administration of high doses at 24-h intervals (Chen et al, 1995;Slattery et al, 1996;Busse et al, 1997).…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 86%

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confidence: 99%

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confidence: 99%

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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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“…21,43,53 Variability in CY PK has been explained by population PK models in various disease conditions 12,31 but no such data exist in patients with thalassemia major. In this study, this variation was explained by body weight and CYP2C9*2 polymorphisms.…”

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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“…A high degree of interpatient variation in the pharmacokinetic parameters of CPA and its active 4-hydroxylated metabolite (4-OH-CPA) has been observed. 25,26 Such variation may have implications on the outcome of therapy with CPA that is a substrate of CYP2B6. Additionally, the CYP2C9, CYP2C19, CYP3A4, and CYP2A6 have also been identified as enzymes involved in the formation of 4-OH-CPA.…”

Section: Introductionmentioning

confidence: 99%

Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation

et al. 2003

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The role of polymorphic CYP2B6 in cyclophosphamide (CPA) bioactivation was investigated in human liver microsomes. A total of 67 human liver specimens were first genotyped with respect to the CYP2B6*5 and CYP2B6*6 variant alleles. CYP2B6 apoprotein levels in 55 liver microsomal preparations were assessed by immunoblotting. 4-Hydroxy-CPA and hydroxy-bupropion were quantified by using HPLC and LC-MS, respectively. 7-Ethoxy-4-trifluoromethyl coumarin O-deethylase activity was measured fluorometrically. The frequencies of CYP2B6*5 and CYP2B6*6 mutant alleles were 9.0 and 16.4%, respectively. CYP2B6 protein expression was detected in 80% of the samples, with a large variation (0.003-2.234, arbitrary units). There was a high correlation between CYP2B6 apoprotein content and CPA 4-hydroxylation (n ¼ 55, r ¼ 0.81, Po0.0001). When based on the CYP2B6 apoprotein levels, the *6 carriers had significantly higher CPA 4-hydroxylation (Po0.05). CPA 4-hydroxylation also correlated significantly with other CYP2B6-specific reactions (n ¼ 20, Po0.0001). V max and K m for CPA 4-hydroxylation in recombinant CYP2B6 enzyme were 338 nmol/min/nmol enzyme and 1.4 mM, respectively. CYP2B6 showed much higher in vitro intrinsic clearance than previously observed in recombinant CYP2C19 and CYP2C9 variants in yeast expression system. Our results demonstrate that the polymorphic CYP2B6 is a major enzyme in the bioactivation of CPA. Moreover, we identified a strong impact of CYP2B6*6 on CPA 4-hydroxylation.

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Cyclophosphamide pharmacokinetics in children

Cited by 75 publications

References 34 publications

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

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

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation

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