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4 Hydroxycyclophosphamide

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Jos H. Beijnen – 1st expert on this subject based on the ideXlab platform

  • Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4Hydroxycyclophosphamide.
    Pharmacogenetics and Genomics, 2008
    Co-Authors: Corine Ekhart, Valerie D. Doodeman, Sjoerd Rodenhuis, Paul H.m. Smits, Jos H. Beijnen, Alwin D. R. Huitema

    Abstract:

    PURPOSE: The anticancer agent, cyclophosphamide, is metabolized by cytochrome P450 (CYP), glutathione S-transferase (GST) and aldehyde dehydrogenase (ALDH) enzymes. Polymorphisms of these enzymes may affect the pharmacokinetics of cyclophosphamide and thereby its toxicity and efficacy. The purpose of this study was to evaluate the effects of known allelic variants in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes on the pharmacokinetics of the anticancer agent, cyclophosphamide, and its active metabolite 4Hydroxycyclophosphamide. EXPERIMENTAL DESIGN: A cohort of 124 Caucasian patients received a high-dose chemotherapy combination consisting of cyclophosphamide (4-6 g/m2), thiotepa (320-480 mg/m2) and carboplatin (area under the curve 13-20 mg x min/ml) as intravenous infusions over 4 consecutive days. Genomic DNA was analysed using PCR and sequencing. Liquid chromatography-tandem mass spectrometry was used to measure plasma concentrations of cyclophosphamide and 4Hydroxycyclophosphamide. The relationship between allelic variants and the elimination pharmacokinetic parameters noninducible cyclophosphamide clearance (CL(nonind)), inducible cyclophosphamide clearance (CL(ind)) and elimination rate constant of 4Hydroxycyclophosphamide (k(4OHCP)) were evaluated using nonlinear mixed effects modelling. RESULTS: The interindividual variability in the noninducible cyclophosphamide clearance, inducible cyclophosphamide clearance and 4Hydroxycyclophosphamide clearance was 23, 27 and 31%, respectively. No effect of the allelic variants investigated on the clearance of cyclophosphamide or 4Hydroxycyclophosphamide could be demonstrated. CONCLUSION: This study indicates that the presently evaluated variant alleles in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes do not explain the interindividual variability in cyclophosphamide and 4Hydroxycyclophosphamide pharmacokinetics and are, probably, not the cause of the observed variability in toxicity

  • Carbamazepine induces bioactivation of cyclophosphamide and thiotepa.
    Cancer Chemotherapy and Pharmacology, 2008
    Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. Huitema

    Abstract:

    We report a patient with metastatic breast cancer who received three cycles of high-dose chemotherapy with cyclophosphamide [1,000 mg/(m2 day)], thiotepa (80 mg/(m2 day) and carboplatin (dose calculated based on modified Calvert formula with 3.25 mg min/ml as daily target AUC) over 4 days, followed by peripheral blood progenitor cell support. During the first two cycles the patient concomitantly used carbamazepine for the treatment of epilepsy. Due to severe nausea and vomiting the patient was unable to ingest carbamazepine; therefore, this was discontinued after the second cycle. Blood samples were drawn on 2 days (day 1 and 2, 3 or 4) of each cycle and plasma levels of cyclophosphamide, its active metabolite 4Hydroxycyclophosphamide, thiotepa, its main, active metabolite tepa and carboplatin were determined. Exposure to 4Hydroxycyclophosphamide and tepa on day 1 was increased in the presence of carbamazepine (58 and 75%, respectively), while exposure to cyclophosphamide and thiotepa was reduced (40 and 43%, respectively). Since increased exposure to the active metabolites is associated with an increased risk of toxicity, it is important to be aware of this drug–drug interaction.

  • Altered cyclophosphamide and thiotepa pharmacokinetics in a patient with moderate renal insufficiency.
    Cancer Chemotherapy and Pharmacology, 2008
    Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, Jos H. Beijnen, J. Martijn Kerst, Alwin D. R. Huitema

    Abstract:

    Purpose We report a patient with renal insuYciency (creatinine clearance, CLcr = 38 mL/min) who received high-dose chemotherapy with cyclophosphamide (1,500 mg/m 2 day i1 ), thiotepa (120 mg/m 2 day i1 ) and carboplatin (AUC = 5 mg min/mL day i1 ) for four consecutive days. Methods Blood samples were collected on day 1 and 3 and plasma levels of cyclophosphamide, its active metabolite 4Hydroxycyclophosphamide, thiotepa, its main metabolite tepa and carboplatin were determined. Results Pharmacokinetic analyses indicated that the elimination of cyclophosphamide, thiotepa, carboplatin, but especially tepa was strongly reduced in this patient, resulting in increased exposures to these compounds of 67, 43, 30 and 157%, respectively, compared to a reference population (n = 24) receiving similar doses. Exposure to 4Hydroxycyclophosphamide increased 11%. Conclusion These results suggest that it may not be necessary to alter the dose of cyclophosphamide in patients with moderate renal impairment. However, because high exposures to thiotepa and tepa have been correlated with increased toxicity, caution should be applied when administering thiotepa to patients with renal insuYciency.

Alwin D. R. Huitema – 2nd expert on this subject based on the ideXlab platform

  • Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4Hydroxycyclophosphamide.
    Pharmacogenetics and Genomics, 2008
    Co-Authors: Corine Ekhart, Valerie D. Doodeman, Sjoerd Rodenhuis, Paul H.m. Smits, Jos H. Beijnen, Alwin D. R. Huitema

    Abstract:

    PURPOSE: The anticancer agent, cyclophosphamide, is metabolized by cytochrome P450 (CYP), glutathione S-transferase (GST) and aldehyde dehydrogenase (ALDH) enzymes. Polymorphisms of these enzymes may affect the pharmacokinetics of cyclophosphamide and thereby its toxicity and efficacy. The purpose of this study was to evaluate the effects of known allelic variants in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes on the pharmacokinetics of the anticancer agent, cyclophosphamide, and its active metabolite 4Hydroxycyclophosphamide. EXPERIMENTAL DESIGN: A cohort of 124 Caucasian patients received a high-dose chemotherapy combination consisting of cyclophosphamide (4-6 g/m2), thiotepa (320-480 mg/m2) and carboplatin (area under the curve 13-20 mg x min/ml) as intravenous infusions over 4 consecutive days. Genomic DNA was analysed using PCR and sequencing. Liquid chromatography-tandem mass spectrometry was used to measure plasma concentrations of cyclophosphamide and 4Hydroxycyclophosphamide. The relationship between allelic variants and the elimination pharmacokinetic parameters noninducible cyclophosphamide clearance (CL(nonind)), inducible cyclophosphamide clearance (CL(ind)) and elimination rate constant of 4Hydroxycyclophosphamide (k(4OHCP)) were evaluated using nonlinear mixed effects modelling. RESULTS: The interindividual variability in the noninducible cyclophosphamide clearance, inducible cyclophosphamide clearance and 4Hydroxycyclophosphamide clearance was 23, 27 and 31%, respectively. No effect of the allelic variants investigated on the clearance of cyclophosphamide or 4Hydroxycyclophosphamide could be demonstrated. CONCLUSION: This study indicates that the presently evaluated variant alleles in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes do not explain the interindividual variability in cyclophosphamide and 4Hydroxycyclophosphamide pharmacokinetics and are, probably, not the cause of the observed variability in toxicity

  • Carbamazepine induces bioactivation of cyclophosphamide and thiotepa.
    Cancer Chemotherapy and Pharmacology, 2008
    Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. Huitema

    Abstract:

    We report a patient with metastatic breast cancer who received three cycles of high-dose chemotherapy with cyclophosphamide [1,000 mg/(m2 day)], thiotepa (80 mg/(m2 day) and carboplatin (dose calculated based on modified Calvert formula with 3.25 mg min/ml as daily target AUC) over 4 days, followed by peripheral blood progenitor cell support. During the first two cycles the patient concomitantly used carbamazepine for the treatment of epilepsy. Due to severe nausea and vomiting the patient was unable to ingest carbamazepine; therefore, this was discontinued after the second cycle. Blood samples were drawn on 2 days (day 1 and 2, 3 or 4) of each cycle and plasma levels of cyclophosphamide, its active metabolite 4Hydroxycyclophosphamide, thiotepa, its main, active metabolite tepa and carboplatin were determined. Exposure to 4Hydroxycyclophosphamide and tepa on day 1 was increased in the presence of carbamazepine (58 and 75%, respectively), while exposure to cyclophosphamide and thiotepa was reduced (40 and 43%, respectively). Since increased exposure to the active metabolites is associated with an increased risk of toxicity, it is important to be aware of this drug–drug interaction.

  • Altered cyclophosphamide and thiotepa pharmacokinetics in a patient with moderate renal insufficiency.
    Cancer Chemotherapy and Pharmacology, 2008
    Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, Jos H. Beijnen, J. Martijn Kerst, Alwin D. R. Huitema

    Abstract:

    Purpose We report a patient with renal insuYciency (creatinine clearance, CLcr = 38 mL/min) who received high-dose chemotherapy with cyclophosphamide (1,500 mg/m 2 day i1 ), thiotepa (120 mg/m 2 day i1 ) and carboplatin (AUC = 5 mg min/mL day i1 ) for four consecutive days. Methods Blood samples were collected on day 1 and 3 and plasma levels of cyclophosphamide, its active metabolite 4Hydroxycyclophosphamide, thiotepa, its main metabolite tepa and carboplatin were determined. Results Pharmacokinetic analyses indicated that the elimination of cyclophosphamide, thiotepa, carboplatin, but especially tepa was strongly reduced in this patient, resulting in increased exposures to these compounds of 67, 43, 30 and 157%, respectively, compared to a reference population (n = 24) receiving similar doses. Exposure to 4Hydroxycyclophosphamide increased 11%. Conclusion These results suggest that it may not be necessary to alter the dose of cyclophosphamide in patients with moderate renal impairment. However, because high exposures to thiotepa and tepa have been correlated with increased toxicity, caution should be applied when administering thiotepa to patients with renal insuYciency.

S Rodenhuis – 3rd expert on this subject based on the ideXlab platform

  • simultaneous quantification of cyclophosphamide and its active metabolite 4 Hydroxycyclophosphamide in human plasma by high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry lc ms ms
    Journal of Chromatography B, 2007
    Co-Authors: Corine Ekhart, Jos H. Beijnen, S Rodenhuis, A Gebretensae, Hilde Rosing, Alwin D. R. Huitema

    Abstract:

    Abstract Cyclophosphamide is a cytotoxic prodrug with a very narrow therapeutic index. To study the clinical pharmacology of cyclophosphamide in a large cohort of patients a previously published method for the simultaneous quantitative determination of cyclophosphamide and 4Hydroxycyclophosphamide in human plasma using liquid chromatography tandem mass spectrometry (LC–MS/MS) was optimized. Addition of an isotopically labelled internal standard and adaptation of the gradient resulted in a fast, robust and sensitive assay. Because 4Hydroxycyclophosphamide is not stable in plasma, the compound is derivatized with semicarbazide immediately after sample collection. Sample preparation was carried out by protein precipitation with methanol–acetonitrile (1:1, v/v), containing isotopically labelled cyclophosphamide and hexamethylphosphoramide as internal standards. The LC separation was performed on a Zorbax Extend C18 column (150 mm × 2.1 mm ID, particle size 5 μm) with 1 mM ammonium hydroxide in water–acetonitrile (90:10, v/v) as the starting gradient, at a flow-rate of 0.40 mL/min with a total run time of 6 min. The lower limit of quantification (LLQ, using a 100 μL sample volume) was 200 ng/mL and the linear dynamic range extended to 40,000 ng/mL for cyclophosphamide and 50–5000 ng/mL for 4Hydroxycyclophosphamide. Accuracies as well as precisions were lower than 20% at the LLQ concentration and lower than 15% for all other concentrations. This method has been successfully applied in our institute to support ongoing studies into the pharmacokinetics and pharmacogenetics of cyclophosphamide.

  • High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy
    British Journal of Cancer, 2006
    Co-Authors: M E De Jonge, A D R Huitema, J H Beijnen, S Rodenhuis

    Abstract:

    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^−2 day^−1), thiotepa (80 or 120 mg m^−2 day^−1) and carboplatin (265–400 mg m^−2 day^−1) (CTC) for 4 consecutive days. The area under the plasma concentration–time curves (AUCs) were calculated for cyclophosphamide and its activated metabolites 4Hydroxycyclophosphamide 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 4Hydroxycyclophosphamide ( P =0.003) but not of phosphoramide mustard ( P =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.

  • population pharmacokinetics of cyclophosphamide and its metabolites 4 Hydroxycyclophosphamide 2 dechloroethylcyclophosphamide and phosphoramide mustard in a high dose combination with thiotepa and carboplatin
    Therapeutic Drug Monitoring, 2005
    Co-Authors: Milly E De Jonge, Alwin D. R. Huitema, S Rodenhuis, Jos H. Beijnen

    Abstract:

    Abstract:The anticancer prodrug cyclophosphamide (CP) is activated by the formation of 4Hydroxycyclophosphamide (4OHCP), which decomposes into phosphoramide mustard (PM). This activation pathway is inhibited by thiotepa. CP is inactivated by formation of 2-dechloroethylcyclophosphamide (2DCECP). Th