Cyclophosphamide Metabolism in Children with Non-Hodgkin’s Lymphoma

Yule, S. M.; Price, L.; McMahon, Alex D.; Pearson, Andrew D.J.; Boddy, Alan V.

doi:10.1158/1078-0432.ccr-0844-03

Cited by 48 publications

(51 citation statements)

References 19 publications

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“…The only significant correlation was found between AUCHD and AUC for IFO itself, and then only for those patients where IFO was administered as fractionated infusions over 3 days. This is in contrast to previous reports on cyclophosphamide, where either antitumour effect or toxicity has been found to be inversely related to plasma AUC for the parent drug (or positively correlated to clearance) (Ayash et al, 1992;Yule et al, 2004). This discrepancy in the data for these two related drugs, which are thought to share a common mechanism of action, may relate to the differing contributions of activating and inactivating pathways of metabolism (Boddy and Yule, 2000).…”

Section: Discussioncontrasting

confidence: 95%

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

et al. 2005

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The degree of damage to DNA following ifosfamide (IFO) treatment may be linked to the therapeutic efficacy. The pharmacokinetics and metabolism of IFO were studied in 19 paediatric patients, mostly with rhabdomyosarcoma or Ewings sarcoma. Ifosfamide was dosed either as a continuous infusion or as fractionated doses over 2 or 3 days. Samples of peripheral blood lymphocytes were obtained during and up to 96 h after treatment, and again prior to the next cycle of chemotherapy. DNA damage was measured using the alkaline COMET assay, and quantified as the percentage of highly damaged cells per sample. Samples were also taken for the determination of IFO and metabolites. Pharmacokinetics and metabolism of IFO were comparable with previous studies. Elevations in DNA damage could be determined in all patients after IFO administration. The degree of damage increased to a peak at 72 h, but had returned to pretreatment values prior to the next dose of chemotherapy. There was a good correlation between area under the curve of IFO and the cumulative percentage of cells with DNA damage (r 2 ¼ 0.554, P ¼ 0.004), but only in those patients receiving fractionated dosing. The latter patients had more DNA damage (mean7s.d., 27367597) than those patients in whom IFO was administered by continuous infusion (14537730). The COMET assay can be used to quantify DNA damage following IFO therapy. Fractionated dosing causes a greater degree of DNA damage, which may suggest a greater degree of efficacy, with a good correlation between pharmacokinetic and pharmacodynamic data.

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Section: Discussioncontrasting

confidence: 95%

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

et al. 2005

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“…The use of a low K m P450 enzyme, such as P450 2B11, could be particularly useful for GDEPT applications in certain patient populations, such as children with B-cell non-Hodgkin's lymphoma, where inadequate (hepatic) conversion of cyclophosphamide to active metabolites is associated with an increased risk of disease recurrence (49). Consequently, for patients with low rates of cyclophosphamide clearance and for individuals who produce significant quantities of inactive cyclophosphamide metabolites (49), P450 gene therapy may well prove to be clinically beneficial.…”

Section: Discussionmentioning

confidence: 99%

Enhanced antitumor activity of P450 prodrug-based gene therapy using the low Km cyclophosphamide 4-hydroxylase P450 2B11

Jounaïdi

Chen

Veal

et al. 2006

Molecular Cancer Therapeutics

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Gene therapy using the prodrug-activating enzyme P450 2B6 has shown substantial promise in preclinical and initial clinical studies with the P450 prodrugs cyclophosphamide and ifosfamide. We sought to optimize this therapy using the canine P450 enzyme 2B11, which activates cyclophosphamide and ifosfamide with K m of 80 to 160 Mmol/L, f10-to 20-fold lower than the K m of P450 2B6. Retrovirus encoding a P450 2B11-internal ribosome entry signal-P450 reductase expression cassette induced marked cyclophosphamide and ifosfamide cytotoxicity toward 9L gliosarcoma cells and exhibited an impressive bystander killing effect at micromolar prodrug concentrations, where P450 2B6 displayed low activity. Adeno-2B11, a replication-defective, E1/E3 region-deleted adenovirus engineered to coexpress P450 2B11 and P450 reductase, dramatically increased tumor cell-catalyzed cyclophosphamide 4-hydroxylation and cytotoxicity compared with Adeno-2B6 and effected strong bystander killing at low (20 Mmol/L) cyclophosphamide concentrations. Further increases in cyclophosphamide cytotoxicity were obtained in several human cancer cell lines, including a 4-hydroperoxycyclophosphamide-resistant MCF-7 breast cancer cell line, when Adeno-2B11 was combined with Onyx-017, an E1b-55-kDa gene-deleted, tumor cellreplicating adenovirus that coamplifies and facilitates tumor cell spread of Adeno-2B11. To evaluate the therapeutic effect of P450 2B11 expression in vivo, 9L gliosarcoma cells transduced with P450-expressing retrovirus were grown as solid s.c. tumors in immunodeficient mice. Cyclophosphamide treatment on a metronomic, 6-day repeating schedule led to full regression of 9L/2B11 tumors but not P450-deficient control tumors, resulting in a tumor-free period lasting up to f100 days. 9L/2B6 tumors regressed more slowly and exhibited a tumor-free period of only 21 to 39 days. Thus, P450 genedirected enzyme prodrug therapy can be greatly improved by using the low K m P450 enzyme 2B11, which catalyzes intratumoral activation of cyclophosphamide and ifosfamide at pharmacologically relevant drug concentrations.

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“…Increased CEPM systemic exposure, as measured by its AUC, has been associated with an increased risk of sinusoidal obstruction syndrome and increased mortality in patients undergoing cyclophosphamide/total body irradiation conditioning for hematopoietic cell transplant (2). In addition, a pharmacodynamic relationship has been found between cyclophosphamide and its metabolites and the risk of recurrence in children receiving 300 to 1,000 mg/m 2 cyclophosphamide for treatment of B-cell non-Hodgkin's lymphoma (6). A higher recurrence rate was found in children with low cyclophosphamide clearance (i.e., <3.5 L/hÁm 2 ) and detectable plasma concentrations of two cyclophosphamide metabolites, CEPM and dechlorocyclophosphamide.…”

mentioning

confidence: 99%

Real-time Dose Adjustment of Cyclophosphamide in a Preparative Regimen for Hematopoietic Cell Transplant: A Bayesian Pharmacokinetic Approach

Salinger

Ren

Shen

et al. 2006

Clinical Cancer Research

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Purpose: Dose-related toxicity of cyclophosphamide may be reduced and therapeutic efficacy may be improved by pharmacokinetic sampling and dose adjustment to achieve a target area under the curve (AUC) for two of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM). To facilitate real-time dose adjustment, we developed open-source code within the statistical software R that incorporates individual data into a population pharmacokinetic model. Experimental Design: Dosage prediction performance was compared to that obtained with nonlinear mixed-effects modeling using NONMEM in 20 cancer patients receiving cyclophosphamide. Bayesian estimation of individual pharmacokinetic parameters was accomplished from limited (i.e., five samples over 0-16 hours) sampling of plasma HCY and CEPM after the initial cyclophosphamide dose. Conditional on individual pharmacokinetics, simulations of the AUC of both HCY and CEPM were provided for a range of second doses (i.e., 0-100 mg/kg cyclophosphamide). Results:The results compared favorably with NONMEM and returned accurate predictions for AUCs of HCYand CEPM with comparable mean absolute prediction error and root mean square prediction error. With our method, the mean absolute prediction error and root mean square prediction error of AUC CEPM were 11.0% and 12.8% and AUC HCY were 31.7% and 44.8%, respectively. Conclusions: We developed dose adjustment software that potentially can be used to adjust cyclophosphamide dosing in a clinical setting, thus expanding the opportunity for pharmacokinetic individualization of cyclophosphamide. The software is simple to use (requiring no programming experience), reads individual patient data directly from an Excel spreadsheet, and runs in less than 5 minutes on a desktop PC.The alkylating agent cyclophosphamide is used for treating a wide range of malignancies in both pediatric and adult patients and as part of myeloablative conditioning regimens before hematopoietic cell transplant. Cyclophosphamide dosing based on body weight (mg/kg) or body surface area (mg/m 2 ) results in highly variable area under the concentration-time curve (AUC) of the parent drug between patients and an even greater variability in the AUC of its metabolites (1, 2).Cyclophosphamide is a prodrug with complex metabolic features that include autoinduction and inhibition of its metabolism. Approximately 10% to 30% of a cyclophosphamide dose is excreted unchanged in the urine, whereas 5% of a dose is inactivated to dechloroethylcyclophosphamide. The remaining 65% to 85% of a dose is activated by several cytochrome P450 enzymes to hydroxycyclophosphamide (HCY); this oxidative pathway is autoinducible. HCY or its tautomer aldophosphamide is metabolized via at least five separate pathways, the most relevant of which to this work is its conversion to carboxyethylphosphoramide mustard (CEPM) by aldehyde dehydrogenase 1A1 (3 -5). Increased CEPM systemic exposure, as measured by its AUC, has been associated with an increased risk o...

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Cyclophosphamide Metabolism in Children with Non-Hodgkin’s Lymphoma

Cited by 48 publications

References 19 publications

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

Enhanced antitumor activity of P450 prodrug-based gene therapy using the low Km cyclophosphamide 4-hydroxylase P450 2B11

Real-time Dose Adjustment of Cyclophosphamide in a Preparative Regimen for Hematopoietic Cell Transplant: A Bayesian Pharmacokinetic Approach

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