The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform
Jos H. Beijnen - One of the best experts 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 4-Hydroxycyclophosphamide.
Pharmacogenetics and Genomics, 2008Co-Authors: Corine Ekhart, Valerie D. Doodeman, Sjoerd Rodenhuis, Paul H.m. Smits, Jos H. Beijnen, Alwin D. R. HuitemaAbstract: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 4-Hydroxycyclophosphamide. 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 4-Hydroxycyclophosphamide. 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 4-Hydroxycyclophosphamide (k(4OHCP)) were evaluated using nonlinear mixed effects modelling. RESULTS: The interindividual variability in the noninducible cyclophosphamide clearance, inducible cyclophosphamide clearance and 4-Hydroxycyclophosphamide clearance was 23, 27 and 31%, respectively. No effect of the allelic variants investigated on the clearance of cyclophosphamide or 4-Hydroxycyclophosphamide 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 4-Hydroxycyclophosphamide pharmacokinetics and are, probably, not the cause of the observed variability in toxicity
-
Carbamazepine induces bioactivation of cyclophosphamide and thiotepa.
Cancer Chemotherapy and Pharmacology, 2008Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. HuitemaAbstract: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 4-Hydroxycyclophosphamide, thiotepa, its main, active metabolite tepa and carboplatin were determined. Exposure to 4-Hydroxycyclophosphamide 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, 2008Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, Jos H. Beijnen, J. Martijn Kerst, Alwin D. R. HuitemaAbstract: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 4-Hydroxycyclophosphamide, 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 4-Hydroxycyclophosphamide 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.
-
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, 2007Co-Authors: Corine Ekhart, Jos H. Beijnen, S Rodenhuis, A Gebretensae, Hilde Rosing, Alwin D. R. HuitemaAbstract: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 4-Hydroxycyclophosphamide 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 4-Hydroxycyclophosphamide 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 4-Hydroxycyclophosphamide. 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.
-
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, 2005Co-Authors: Milly E De Jonge, Alwin D. R. Huitema, S Rodenhuis, Jos H. BeijnenAbstract:Abstract:The anticancer prodrug cyclophosphamide (CP) is activated by the formation of 4-Hydroxycyclophosphamide (4OHCP), which decomposes into phosphoramide mustard (PM). This activation pathway is inhibited by thiotepa. CP is inactivated by formation of 2-dechloroethylcyclophosphamide (2DCECP). Th
Alwin D. R. Huitema - One of the best experts 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 4-Hydroxycyclophosphamide.
Pharmacogenetics and Genomics, 2008Co-Authors: Corine Ekhart, Valerie D. Doodeman, Sjoerd Rodenhuis, Paul H.m. Smits, Jos H. Beijnen, Alwin D. R. HuitemaAbstract: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 4-Hydroxycyclophosphamide. 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 4-Hydroxycyclophosphamide. 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 4-Hydroxycyclophosphamide (k(4OHCP)) were evaluated using nonlinear mixed effects modelling. RESULTS: The interindividual variability in the noninducible cyclophosphamide clearance, inducible cyclophosphamide clearance and 4-Hydroxycyclophosphamide clearance was 23, 27 and 31%, respectively. No effect of the allelic variants investigated on the clearance of cyclophosphamide or 4-Hydroxycyclophosphamide 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 4-Hydroxycyclophosphamide pharmacokinetics and are, probably, not the cause of the observed variability in toxicity
-
Carbamazepine induces bioactivation of cyclophosphamide and thiotepa.
Cancer Chemotherapy and Pharmacology, 2008Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. HuitemaAbstract: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 4-Hydroxycyclophosphamide, thiotepa, its main, active metabolite tepa and carboplatin were determined. Exposure to 4-Hydroxycyclophosphamide 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, 2008Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, Jos H. Beijnen, J. Martijn Kerst, Alwin D. R. HuitemaAbstract: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 4-Hydroxycyclophosphamide, 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 4-Hydroxycyclophosphamide 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.
-
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, 2007Co-Authors: Corine Ekhart, Jos H. Beijnen, S Rodenhuis, A Gebretensae, Hilde Rosing, Alwin D. R. HuitemaAbstract: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 4-Hydroxycyclophosphamide 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 4-Hydroxycyclophosphamide 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 4-Hydroxycyclophosphamide. 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.
-
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, 2005Co-Authors: Milly E De Jonge, Alwin D. R. Huitema, S Rodenhuis, Jos H. BeijnenAbstract:Abstract:The anticancer prodrug cyclophosphamide (CP) is activated by the formation of 4-Hydroxycyclophosphamide (4OHCP), which decomposes into phosphoramide mustard (PM). This activation pathway is inhibited by thiotepa. CP is inactivated by formation of 2-dechloroethylcyclophosphamide (2DCECP). Th
S Rodenhuis - One of the best experts 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, 2007Co-Authors: Corine Ekhart, Jos H. Beijnen, S Rodenhuis, A Gebretensae, Hilde Rosing, Alwin D. R. HuitemaAbstract: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 4-Hydroxycyclophosphamide 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 4-Hydroxycyclophosphamide 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 4-Hydroxycyclophosphamide. 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, 2006Co-Authors: M E De Jonge, A D R Huitema, J H Beijnen, S RodenhuisAbstract: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 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 =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, 2005Co-Authors: Milly E De Jonge, Alwin D. R. Huitema, S Rodenhuis, Jos H. BeijnenAbstract:Abstract:The anticancer prodrug cyclophosphamide (CP) is activated by the formation of 4-Hydroxycyclophosphamide (4OHCP), which decomposes into phosphoramide mustard (PM). This activation pathway is inhibited by thiotepa. CP is inactivated by formation of 2-dechloroethylcyclophosphamide (2DCECP). Th
-
simultaneous quantification of cyclophosphamide 4 Hydroxycyclophosphamide n n n triethylenethiophosphoramide thiotepa and n n n triethylenephosphoramide tepa in human plasma by high performance liquid chromatography coupled with electrospray ionizati
Journal of Mass Spectrometry, 2004Co-Authors: Milly E De Jonge, Jos H. Beijnen, Alwin D. R. Huitema, S Rodenhuis, Hilde Rosing, Michel J.x. HillebrandAbstract:The alkylating agents cyclophosphamide (CP) and N, N′, N″-triethylenethiophosphoramide (thiotepa) are often co-administered in high-dose chemotherapy regimens. Since these regimens can be complicated by the occurrence of severe and sometimes life-threatening toxicities, pharmacokinetically guided administration of these compounds, to reduce variability in exposure, may lead to improved tolerability. For rapid dose adaptations during a chemotherapy course, we have developed and validated an assay, using liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS), for the routine quantification of CP, thiotepa and their respective active metabolites 4-Hydroxycyclophosphamide (4OHCP) and N, N′, N″-triethylenephosphoramide (tepa) in plasma. Because of the instability of 4OHCP in plasma, the compound is derivatized with semicarbazide (SCZ) immediately after sample collection and quantified as 4OHCP-SCZ. Sample pretreatment consisted of protein precipitation with a mixture of methanol and acetronitrile using 100 µl of plasma. Chromatographic separation was performed on an Zorbax Extend C18 column (150 × 2.1 mm i.d., particle size 5 µm), with a quick gradient using 1 mM ammonia solution and acetonitrile, at a flow-rate of 0.4 ml min−1. The analytical run time was 10 min. The triple quadrupole mass spectrometer was operating in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges 200–40 000 ng ml−1 for CP, 50–5000 ng ml−1 for 4OHCP-SCZ and 5–2500 ng ml−1 for thiotepa and tepa, using 100 µl of human plasma. These dynamic concentration ranges proved to be relevant in daily practice. Hexamethylphosphoramide was used as an internal standard. The coefficients of variation were <12% for both intra-day and inter-day precisions for each compound. Mean accuracies were also between the designated limits (±15%). This robust and rapid LC/MS/MS assay is now successfully applied for routine therapeutic drug monitoring of CP, thiotepa and their metabolites in our hospital. Copyright © 2004 John Wiley & Sons, Ltd.
-
high performance liquid chromatographic determination of the stabilized cyclophosphamide metabolite 4 Hydroxycyclophosphamide in plasma and red blood cells
Journal of Liquid Chromatography & Related Technologies, 2000Co-Authors: A D R Huitema, S Rodenhuis, M M Tibben, Thomas Kerbusch, J Kettenes J Van Den Bosch, Jos H. BeijnenAbstract:A reversed-phase high performance liquid chromatographic (HPLC) method for the determination of the activated cyclophosphamide (CP) metabolite 4-Hydroxycyclophosphamide (4-OHCP) in human plasma and red blood cells is described. 4-OHCP is very unstable in biological matrices. Therefore, it was treated, immediately after sampling, with semicarbazide to form a stable semicarbazone derivative, which was identified with electron spray mass spectrometry. The derivative was analysed with HPLC with ultraviolet (UV) detection at 230 nm. Sample pre-treatment consisted of a liquid-liquid extraction with ethyl acetate, the chromatography system was a 25 cm C8 column (particle size 5 μm) with a mobile phase of acetonitrile-0.025 M potassium phosphate buffer (15:85 v/v) pH 6.0. After assay optimisation, the method was validated and stability studies were carried out. The method proved linear in clinically relevant concentrations (50-5000 ng/mL). The lower limit of quantitation was 50 ng/mL. Accuracy and precision were ...
Milly E De Jonge - One of the best experts on this subject based on the ideXlab platform.
-
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, 2005Co-Authors: Milly E De Jonge, Alwin D. R. Huitema, S Rodenhuis, Jos H. BeijnenAbstract:Abstract:The anticancer prodrug cyclophosphamide (CP) is activated by the formation of 4-Hydroxycyclophosphamide (4OHCP), which decomposes into phosphoramide mustard (PM). This activation pathway is inhibited by thiotepa. CP is inactivated by formation of 2-dechloroethylcyclophosphamide (2DCECP). Th
-
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, 2005Co-Authors: Milly E De Jonge, Sjoerd Rodenhuis, Alwin D. R. Huitema, Jos H. BeijnenAbstract:The anticancer prodrug cyclophosphamide (CP) is activated by the formation of 4-Hydroxycyclophosphamide (4OHCP), which decomposes into phosphoramide mustard (PM). This activation pathway is inhibited by thiotepa. CP is inactivated by formation of 2-dechloroethylcyclophosphamide (2DCECP). The aim of this study was to develop a population pharmacokinetic model describing the complex pharmacokinetics of CP, 4OHCP, 2DCECP, and PM when CP is administered in a high-dose combination with thiotepa and carboplatin. Patients received a combination of CP (1000-1500 mg/m/d), carboplatin (265-400 mg/m/d), and thiotepa (80-120 mg/m/d) administered in short infusions over 4 days. Twenty blood samples were collected per patient per course. Concentrations of CP, 4OHCP, 2DCECP, PM, thiotepa, and tepa were determined in plasma. Using NONMEM, an integrated population pharmacokinetic model was used to describe the pharmacokinetics of CP, 4OHCP, 2DCECP, and PM, including the already described processes of autoinduction of CP and the interaction with thiotepa. Data were available on 35 patients (70 courses). The pharmacokinetics of CP were described with a 2-compartment model, and those of 4OHCP, 2DCECP, and PM with 1-compartment models. Before onset of autoinduction, it was assumed that CP is eliminated through a noninducible pathway accounting for 20% of total CP clearance, whereas 2 inducible pathways resulted in formation of 4OHCP (75%) and 2DCECP (5%). It was assumed that 4OHCP was fully converted to PM. Induction of CP metabolism was mediated by 2 hypothetical amounts of enzyme whose quantities increased in time in the presence of CP (kenz=0.0223 and 0.0198 hours). Induction resulted in an increased formation of 4OHCP (approximately 50%), PM (approximately 50%), and 2DCECP (approximately 35%) during the 4-day course, and concomitant decreased exposure to CP (approximately 50%). The formation of 2DCECP was not inhibited by thiotepa. Apparent volumes of distribution of CP, PM, and 2DCECP could be estimated being 43.7, 55.5, and 18.5 L, respectively. Exposure to metabolites varied up to 9-fold. The complex population pharmacokinetics of CP, 4OHCP, 2DCECP, and PM in combination with thiotepa and carboplatin has been established and may form the basis for further treatment optimization with this combination
-
Simultaneous quantification of cyclophosphamide, 4-Hydroxycyclophosphamide, N,N',N"-triethylenethiophosphoramide (thiotepa) and N,N',N"-triethylenephosphoramide (tepa) in human plasma by high-performance liquid chromatography coupled with electrospra
Journal of Mass Spectrometry, 2004Co-Authors: Milly E De Jonge, Sjoerd Rodenhuis, Alwin D. R. Huitema, Hilde Rosing, Michel J.x. Hillebrand, Jos H. BeijnenAbstract:The alkylating agents cyclophosphamide (CP) and N, N', N"-triethylenethiophosphoramide (thiotepa) are often co-administered in high-dose chemotherapy regimens. Since these regimens can be complicated by the occurrence of severe and sometimes life-threatening toxicities, pharmacokinetically guided administration of these compounds, to reduce variability in exposure, may lead to improved tolerability. For rapid dose adaptations during a chemotherapy course, we have developed and validated an assay, using liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS), for the routine quantification of CP, thiotepa and their respective active metabolites 4-Hydroxycyclophosphamide (4OHCP) and N, N', N"-triethylenephosphoramide (tepa) in plasma. Because of the instability of 4OHCP in plasma, the compound is derivatized with semicarbazide (SCZ) immediately after sample collection and quantified as 4OHCP-SCZ. Sample pretreatment consisted of protein precipitation with a mixture of methanol and acetronitrile using 100 microl of plasma. Chromatographic separation was performed on an Zorbax Extend C18 column (150 x 2.1 mm i.d., particle size 5 microm), with a quick gradient using 1 mM ammonia solution and acetonitrile, at a flow-rate of 0.4 ml min(-1). The analytical run time was 10 min. The triple quadrupole mass spectrometer was operating in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges 200-40,000 ng ml(-1) for CP, 50-5000 ng ml(-1) for 4OHCP-SCZ and 5-2500 ng ml(-1) for thiotepa and tepa, using 100 microl of human plasma. These dynamic concentration ranges proved to be relevant in daily practice. Hexamethylphosphoramide was used as an internal standard. The coefficients of variation were
-
simultaneous quantification of cyclophosphamide 4 Hydroxycyclophosphamide n n n triethylenethiophosphoramide thiotepa and n n n triethylenephosphoramide tepa in human plasma by high performance liquid chromatography coupled with electrospray ionizati
Journal of Mass Spectrometry, 2004Co-Authors: Milly E De Jonge, Jos H. Beijnen, Alwin D. R. Huitema, S Rodenhuis, Hilde Rosing, Michel J.x. HillebrandAbstract:The alkylating agents cyclophosphamide (CP) and N, N′, N″-triethylenethiophosphoramide (thiotepa) are often co-administered in high-dose chemotherapy regimens. Since these regimens can be complicated by the occurrence of severe and sometimes life-threatening toxicities, pharmacokinetically guided administration of these compounds, to reduce variability in exposure, may lead to improved tolerability. For rapid dose adaptations during a chemotherapy course, we have developed and validated an assay, using liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS), for the routine quantification of CP, thiotepa and their respective active metabolites 4-Hydroxycyclophosphamide (4OHCP) and N, N′, N″-triethylenephosphoramide (tepa) in plasma. Because of the instability of 4OHCP in plasma, the compound is derivatized with semicarbazide (SCZ) immediately after sample collection and quantified as 4OHCP-SCZ. Sample pretreatment consisted of protein precipitation with a mixture of methanol and acetronitrile using 100 µl of plasma. Chromatographic separation was performed on an Zorbax Extend C18 column (150 × 2.1 mm i.d., particle size 5 µm), with a quick gradient using 1 mM ammonia solution and acetonitrile, at a flow-rate of 0.4 ml min−1. The analytical run time was 10 min. The triple quadrupole mass spectrometer was operating in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges 200–40 000 ng ml−1 for CP, 50–5000 ng ml−1 for 4OHCP-SCZ and 5–2500 ng ml−1 for thiotepa and tepa, using 100 µl of human plasma. These dynamic concentration ranges proved to be relevant in daily practice. Hexamethylphosphoramide was used as an internal standard. The coefficients of variation were <12% for both intra-day and inter-day precisions for each compound. Mean accuracies were also between the designated limits (±15%). This robust and rapid LC/MS/MS assay is now successfully applied for routine therapeutic drug monitoring of CP, thiotepa and their metabolites in our hospital. Copyright © 2004 John Wiley & Sons, Ltd.
-
Extremely high exposures in an obese patient receiving high-dose cyclophosphamide, thiotepa and carboplatin.
Cancer Chemotherapy and Pharmacology, 2002Co-Authors: Milly E De Jonge, Jos H. Beijnen, Ron A. A. Mathot, Sjoerd RodenhuisAbstract:An obese 53-year-old woman (height 167 cm, weight 130 kg) with metastatic breast cancer received high-dose chemotherapy comprising cyclophosphamide, thiotepa and carboplatin (CTC). The cyclophosphamide (1 g/m2 per day) and thiotepa (80 mg/m2 per day) doses were based on body surface area (BSA) calculated using total body weight (TBW). The daily carboplatin dose was calculated based on the Calvert formula, using a target area under the plasma concentration-time curve (AUC) value of 3.25 mg·min/ml and applying the Cockcroft-Gault equation to estimate the glomerular filtration rate. The patient received the three agents as short infusions over four consecutive days. For therapeutic drug monitoring (TDM), blood samples were collected on day 1. Thiotepa and its main metabolite tepa, ultrafilterable platinum, cyclophosphamide and its activated metabolite 4-Hydroxycyclophosphamide were determined. Individual pharmacokinetics were assessed using Bayesian analysis. Exposure to the individual compounds was determined by calculating the AUC. Exposures to 4-Hydroxycyclophosphamide, the combination of thiotepa/tepa and carboplatin were 94%, 117% and 71% higher than the median respective exposures in a non-obese population of patients (n=24) receiving similar doses. Because high AUCs of 4-Hydroxycyclophosphamide, thiotepa/tepa and carboplatin correlate with increased toxicity, the treatment risk in this obese patient was significantly increased. Therefore doses were adapted on the 3rd day of the course. It is concluded that cyclophosphamide and thiotepa in obese patients should not be dosed on the basis of BSA incorporating TBW since the patient will be overexposed. Moreover, applying the Cockcroft-Gault equation to obese patients leads to an overprediction of creatinine clearance and, when used in the Calvert equation, consequently to a carboplatin dose that is too high. Obese patients represent a unique group of patients in which TDM is extremely valuable in optimizing dosing, particularly in high-dose chemotherapy.
Hilde Rosing - One of the best experts 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, 2007Co-Authors: Corine Ekhart, Jos H. Beijnen, S Rodenhuis, A Gebretensae, Hilde Rosing, Alwin D. R. HuitemaAbstract: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 4-Hydroxycyclophosphamide 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 4-Hydroxycyclophosphamide 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 4-Hydroxycyclophosphamide. 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.
-
Simultaneous quantification of cyclophosphamide, 4-Hydroxycyclophosphamide, N,N',N"-triethylenethiophosphoramide (thiotepa) and N,N',N"-triethylenephosphoramide (tepa) in human plasma by high-performance liquid chromatography coupled with electrospra
Journal of Mass Spectrometry, 2004Co-Authors: Milly E De Jonge, Sjoerd Rodenhuis, Alwin D. R. Huitema, Hilde Rosing, Michel J.x. Hillebrand, Jos H. BeijnenAbstract:The alkylating agents cyclophosphamide (CP) and N, N', N"-triethylenethiophosphoramide (thiotepa) are often co-administered in high-dose chemotherapy regimens. Since these regimens can be complicated by the occurrence of severe and sometimes life-threatening toxicities, pharmacokinetically guided administration of these compounds, to reduce variability in exposure, may lead to improved tolerability. For rapid dose adaptations during a chemotherapy course, we have developed and validated an assay, using liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS), for the routine quantification of CP, thiotepa and their respective active metabolites 4-Hydroxycyclophosphamide (4OHCP) and N, N', N"-triethylenephosphoramide (tepa) in plasma. Because of the instability of 4OHCP in plasma, the compound is derivatized with semicarbazide (SCZ) immediately after sample collection and quantified as 4OHCP-SCZ. Sample pretreatment consisted of protein precipitation with a mixture of methanol and acetronitrile using 100 microl of plasma. Chromatographic separation was performed on an Zorbax Extend C18 column (150 x 2.1 mm i.d., particle size 5 microm), with a quick gradient using 1 mM ammonia solution and acetonitrile, at a flow-rate of 0.4 ml min(-1). The analytical run time was 10 min. The triple quadrupole mass spectrometer was operating in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges 200-40,000 ng ml(-1) for CP, 50-5000 ng ml(-1) for 4OHCP-SCZ and 5-2500 ng ml(-1) for thiotepa and tepa, using 100 microl of human plasma. These dynamic concentration ranges proved to be relevant in daily practice. Hexamethylphosphoramide was used as an internal standard. The coefficients of variation were
-
simultaneous quantification of cyclophosphamide 4 Hydroxycyclophosphamide n n n triethylenethiophosphoramide thiotepa and n n n triethylenephosphoramide tepa in human plasma by high performance liquid chromatography coupled with electrospray ionizati
Journal of Mass Spectrometry, 2004Co-Authors: Milly E De Jonge, Jos H. Beijnen, Alwin D. R. Huitema, S Rodenhuis, Hilde Rosing, Michel J.x. HillebrandAbstract:The alkylating agents cyclophosphamide (CP) and N, N′, N″-triethylenethiophosphoramide (thiotepa) are often co-administered in high-dose chemotherapy regimens. Since these regimens can be complicated by the occurrence of severe and sometimes life-threatening toxicities, pharmacokinetically guided administration of these compounds, to reduce variability in exposure, may lead to improved tolerability. For rapid dose adaptations during a chemotherapy course, we have developed and validated an assay, using liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS), for the routine quantification of CP, thiotepa and their respective active metabolites 4-Hydroxycyclophosphamide (4OHCP) and N, N′, N″-triethylenephosphoramide (tepa) in plasma. Because of the instability of 4OHCP in plasma, the compound is derivatized with semicarbazide (SCZ) immediately after sample collection and quantified as 4OHCP-SCZ. Sample pretreatment consisted of protein precipitation with a mixture of methanol and acetronitrile using 100 µl of plasma. Chromatographic separation was performed on an Zorbax Extend C18 column (150 × 2.1 mm i.d., particle size 5 µm), with a quick gradient using 1 mM ammonia solution and acetonitrile, at a flow-rate of 0.4 ml min−1. The analytical run time was 10 min. The triple quadrupole mass spectrometer was operating in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges 200–40 000 ng ml−1 for CP, 50–5000 ng ml−1 for 4OHCP-SCZ and 5–2500 ng ml−1 for thiotepa and tepa, using 100 µl of human plasma. These dynamic concentration ranges proved to be relevant in daily practice. Hexamethylphosphoramide was used as an internal standard. The coefficients of variation were <12% for both intra-day and inter-day precisions for each compound. Mean accuracies were also between the designated limits (±15%). This robust and rapid LC/MS/MS assay is now successfully applied for routine therapeutic drug monitoring of CP, thiotepa and their metabolites in our hospital. Copyright © 2004 John Wiley & Sons, Ltd.
