The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform
Jos H. Beijnen - One of the best experts on this subject based on the ideXlab platform.
-
Evaluation of the autoinduction of Ifosfamide metabolism by a population pharmacokinetic approach using NONMEM.
British Journal of Clinical Pharmacology, 2001Co-Authors: Thomas Kerbusch, Alwin D. R. Huitema, Jan Ouwerkerk, H. J. Keizer, Ron A. A. Mathôt, Jan H.m. Schellens, Jos H. BeijnenAbstract:Aims This study investigated the population pharmacokinetics of Ifosfamide in 15 patients treated for soft tissue sarcoma with 9 or 12 g m−2 Ifosfamide by means of a 72 h continuous i.v. infusion. Methods A model was developed using nonlinear mixed effects modelling (NONMEM) to describe the nonlinear pharmacokinetics of Ifosfamide by linking the Ifosfamide plasma concentrations to the extent of the autoinduction. Results The proposed model revealed the effect of autoinduction on the disposition of Ifosfamide. The initial clearance, volume of distribution, rate constant for enzyme degradation, induction half-life of the enzyme and the Ifosfamide concentration at 50% of the maximum inhibition of enzyme degradation were estimated at 2.94 ± 0.27 l h−1, 43.5 ± 2.9 l, 0.0546 ± 0.0078 h−1, 12.7 h and 30.7 ± 4.8 µm, respectively. Interindividual variabilities of initial clearance, volume of distribution, rate constant for enzyme degradation were 24.5, 23.4 and 22.7%, respectively. Proportional and additive variability not explained by the model were 13.6% and 0.0763 µm, respectively. Conclusions The absence of a lag time for the autoinduction of Ifosfamide metabolism could be the result of an immediate inhibition of the enzymatic degradation of CYP3A4 by Ifosfamide. By application of the autoinduction model individual pharmacokinetic profiles of patients were described with adequate precision. This model may therefore be used in the future development of a model to individualize dose selection in patients.
-
Population Pharmacokinetics of Ifosfamide and its Dechloroethylated and Hydroxylated Metabolites in Children with Malignant Disease
Clinical Pharmacokinetics, 2001Co-Authors: Thomas Kerbusch, Ron A. A. Mathôt, Jan Kraker, Jos H. BeijnenAbstract:Objective To assess the feasibility of a sparse sampling approach for the determination of the population pharmacokinetics of Ifosfamide, 2- and 3-dechloro-ethyl-Ifosfamide and 4-hydroxy-Ifosfamide in children treated with single-agent Ifosfamide against various malignant tumours. Design Pharmacokinetic assessment followed by model fitting. Patients The analysis included 32 patients aged between 1 and 18 years receiving a total of 45 courses of Ifosfamide 1.2, 2 or 3 g/m^2 in 1 or 3 hours on 1, 2 or 3 days. Methods A total of 133 blood samples (median of 3 per patient) were collected. Plasma concentrations of Ifosfamide and its dechloroethylated metabolites were determined by gas chromatography. Plasma concentrations of 4-hydroxy- Ifosfamide were measured by high-performance liquid chromatography. The models were fitted to the data using a nonlinear mixed effects model as implemented in the NONMEM program. A cross-validation was performed. Results Population values (mean ± standard error) for the initial clearance and volume of distribution of Ifosfamide were estimated at 2.36 ± 0.33 L/h/m^2 and 20.6 ± 1.6 L/m^2 with an interindividual variability of 43 and 32%, respectively. The enzyme induction constant was estimated at 0.0493 ± 0.0104 L/h^2/m^2. The ratio of the fraction of Ifosfamide metabolised to each metabolite to the volume of distribution of that metabolite, and the elimination rate constant, of 2- and 3-dechloroethyl-Ifosfamide and 4-hydroxy-Ifosfamide were 0.0976 ± 0.0556, 0.0328 ± 0.0102 and 0.0230 ± 0.0083 m^2/L and 3.64 ± 2.04, 0.445 ± 0.174 and 7.67 ± 2.87 h^−1, respectively. Interindividual variability of the first parameter was 23, 34 and 53%, respectively. Cross-validation indicated no bias and minor imprecision (12.5 ± 5.1%) for 4-hydroxy-Ifosfamide only. Conclusions We have developed and validated a model to estimate Ifosfamide and metabolite concentrations in a paediatric population by using sparse sampling.
-
Influence of dose and infusion duration on pharmacokinetics of Ifosfamide and metabolites.
Drug metabolism and disposition: the biological fate of chemicals, 2001Co-Authors: Thomas Kerbusch, H. J. Keizer, Ron A. A. Mathôt, Jan H.m. Schellens, G. P. Kaijser, Jos H. BeijnenAbstract:The anticancer drug Ifosfamide is a prodrug requiring activation through 4-hydroxyIfosfamide to ifosforamide mustard, to exert cytotoxicity. Deactivation of Ifosfamide leads to 2- and 3-dechloroethylIfosfamide and the release of potentially neurotoxic chloracetaldehyde. The aim of this study was to quantify and to compare the pharmacokinetics of Ifosfamide, 2- and 3-dechloroethylIfosfamide, 4-hydroxyIfosfamide, and ifosforamide mustard in short (1-4 h), medium (24-72 h), and long infusion durations (96-240 h) of Ifosfamide. An integrated population pharmacokinetic model was used to describe the autoinducible pharmacokinetics of Ifosfamide and its four metabolites in 56 patients. The rate by which autoinduction of the metabolism of Ifosfamide developed was found to be significantly dependent on the infusion schedule. The rate was 52% lower with long infusion durations compared with short infusion durations. This difference was, however, comparable with its interindividual variability (22%) and was, therefore, considered to be of minor clinical importance. Autoinduction caused a less than proportional increase in the area under the Ifosfamide plasma concentration-time curve (AUC) and more than proportional increase in metabolite exposure with increasing Ifosfamide dose. During long infusion durations dose-corrected exposures (AUC/D) were significantly decreased for Ifosfamide and increased for 3-dechloroethylIfosfamide compared with short infusion durations. No differences in dose-normalized exposure to Ifosfamide and metabolites were observed between short and medium infusion durations. This study demonstrates that the duration of Ifosfamide infusion influences the exposure to the parent and its metabolite 3-dechloroethylIfosfamide. The observed dose and infusion duration dependence should be taken into account when modeling Ifosfamide metabolism.
-
Clinical Pharmacokinetics and Pharmacodynamics of Ifosfamide and its Metabolites
Clinical Pharmacokinetics, 2001Co-Authors: Thomas Kerbusch, Jan H.m. Schellens, Jan Kraker, H. Jan Keizer, John W. G. Putten, Harry J. M. Groen, Rob L. H. Jansen, Jos H. BeijnenAbstract:This review discusses several issues in the clinical pharmacology of the antitumour agent Ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of Ifosfamide has been elucidated. Identification of specific isoenzymes responsible for Ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether Ifosfamide is specifically transported by erythrocytes and which activated Ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of Ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality of the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of Ifosfamide. Correlations between the new insights into Ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of Ifosfamide treatment.
-
Pharmacokinetics of Ifosfamide and some metabolites in children.
Anticancer research, 1998Co-Authors: G. P. Kaijser, Auke Bult, Willy J. M. Underberg, J. De Kraker, Jos H. BeijnenAbstract:The pharmacokinetics of Ifosfamide and some metabolites in children was investigated. The patients received various doses of Ifosfamide, mostly by continuous infusion, over several days. The penetration of Ifosfamide and its metabolites into the cerebrospinal fluid was also studied in four cases. Ifosfamide and 4-hydroxyIfosfamide pass the blood-brain barrier, reaching cerebrospinal fluid concentrations that are almost as high as plasma concentrations.
G. T. Budd - One of the best experts on this subject based on the ideXlab platform.
-
Ifosfamide in the treatment of soft tissue sarcomas.
Seminars in Oncology, 1996Co-Authors: E. F. Connelly, G. T. BuddAbstract:Ifosfamide is one of the three most active agents in the treatment of soft tissue sarcomas. Ifosfamide-induced urothelial toxicity has been adequately controlled with the use of hydration and the uroprotective agent mesna. This is a review of pilot and phase I and II studies of Ifosfamide as a single agent and randomized trials of combination chemotherapy regimens incorporating Ifosfamide in the treatment of soft tissue sarcomas. Issues of schedule and dose of Ifosfamide will be addressed as well.
Bernd Ratzewiss - One of the best experts on this subject based on the ideXlab platform.
-
measurement of 4 hydroxylation of Ifosfamide in human liver microsomes using the estimation of free and protein bound acrolein and codetermination of keto and carboxyIfosfamide
Journal of Cancer Research and Clinical Oncology, 2002Co-Authors: Rainer Preiss, Florian Geissler, Hartmut Pahlig, Frank Baumann, Henning Hanschmann, Renate Schmidt, Johann Hauss, Bernd RatzewissAbstract:Abstract Purpose. The aim of the present study was to determine the turnover (4-hydroxylation and N-dechloroethylation) of Ifosfamide in a total of 25 human liver microsomal preparations in which the codetermination of keto- and carboxyIfosfamide as well as the calculation of free and protein-bound acrolein was carried out for the first time. Methods. The 4-hydroxylation of Ifosfamide was estimated by using acrolein (free and protein-bound) and a newly developed procedure involving the codetermination of keto- and carboxyIfosfamide (LC/MS). The Ifosfamide N-dechloroethylation was determined as the sum of 2- and 3-dechloroethylIfosfamide (LC/MS). Results. Using the usual estimation of liberated free acrolein in 25 human liver microsomal preparations, the 4-hydroxylation of Ifosfamide amounted to 0.28±0.16 nmol/min · nmolP450. However, after calculating the 4-hydroxylation as the sum of free and protein-bound acrolein and keto- and carboxyIfosfamide, a ninefold higher activity (2.40±0.73 nmol/min · nmolP450) was found. The percentage of the inactive metabolites keto- (25/25) and carboxyIfosfamide (5/25) in the 4-hydroxylation amounted to only 0.79–5.25% (mean 2.90%). The Ifosfamide N-dechloroethylation (mean 0.21±0.11 nmol/min · nmolP450) determined as the sum of 2- and 3-dechloroethylIfosfamide was estimated as 8.3±4.3% of the total Ifosfamide turnover. The application of the relative substrate-activity factor (RSF)-approach and the calculation of the contribution of various isoforms in the Ifosfamide 4-hydroxylation yielded the following results: CYP 3A4: 58±31%, CYP 2A6: 25±15%, and CYP 2C9: 5±2% of the total measured 4-hydroxylation. A correlation between 4-hydroxylation and the N-dechloroethylation rates of Ifosfamide and the activities of isoenzymes indicates the involvement of both CYP 3A4 (P=0.026) and CYP 2C9 (P=0.012) in the 4-hydroxylation reaction and of CYP 3A4 (P<0.01) in the N-dechloroethylation reaction. Conclusions. The estimation of protein-bound acrolein should be included in the calculation of the Ifosfamide 4-hydroxylation besides liberated free acrolein. Because of the small amounts of the inactive metabolites keto- and carboxyIfosfamide, the exclusive determination of acrolein only (free and protein-bound) seems to suffice for the calculation of total Ifosfamide hydroxylation. Using this method the hepatic in vitro turnover of Ifosfamide was estimated as 92% for 4-hydroxylation (CYP 3A4 and CYP 2A6 mediated) and 8% for N-dechloroethylation (CYP 3A4 mediated), and in this way, a relative overestimation of the N-dechloroethylation of Ifosfamide on the whole metabolism is avoided.
-
Measurement of 4-hydroxylation of Ifosfamide in human liver microsomes using the estimation of free and protein-bound acrolein and codetermination of keto- and carboxyIfosfamide
Journal of Cancer Research and Clinical Oncology, 2002Co-Authors: Rainer Preiss, Florian Geissler, Hartmut Pahlig, Frank Baumann, Henning Hanschmann, Renate Schmidt, Johann Hauss, Bernd RatzewissAbstract:Abstract Purpose. The aim of the present study was to determine the turnover (4-hydroxylation and N-dechloroethylation) of Ifosfamide in a total of 25 human liver microsomal preparations in which the codetermination of keto- and carboxyIfosfamide as well as the calculation of free and protein-bound acrolein was carried out for the first time. Methods. The 4-hydroxylation of Ifosfamide was estimated by using acrolein (free and protein-bound) and a newly developed procedure involving the codetermination of keto- and carboxyIfosfamide (LC/MS). The Ifosfamide N-dechloroethylation was determined as the sum of 2- and 3-dechloroethylIfosfamide (LC/MS). Results. Using the usual estimation of liberated free acrolein in 25 human liver microsomal preparations, the 4-hydroxylation of Ifosfamide amounted to 0.28±0.16 nmol/min · nmolP450. However, after calculating the 4-hydroxylation as the sum of free and protein-bound acrolein and keto- and carboxyIfosfamide, a ninefold higher activity (2.40±0.73 nmol/min · nmolP450) was found. The percentage of the inactive metabolites keto- (25/25) and carboxyIfosfamide (5/25) in the 4-hydroxylation amounted to only 0.79–5.25% (mean 2.90%). The Ifosfamide N-dechloroethylation (mean 0.21±0.11 nmol/min · nmolP450) determined as the sum of 2- and 3-dechloroethylIfosfamide was estimated as 8.3±4.3% of the total Ifosfamide turnover. The application of the relative substrate-activity factor (RSF)-approach and the calculation of the contribution of various isoforms in the Ifosfamide 4-hydroxylation yielded the following results: CYP 3A4: 58±31%, CYP 2A6: 25±15%, and CYP 2C9: 5±2% of the total measured 4-hydroxylation. A correlation between 4-hydroxylation and the N-dechloroethylation rates of Ifosfamide and the activities of isoenzymes indicates the involvement of both CYP 3A4 (P=0.026) and CYP 2C9 (P=0.012) in the 4-hydroxylation reaction and of CYP 3A4 (P
Thomas Kerbusch - One of the best experts on this subject based on the ideXlab platform.
-
Evaluation of the autoinduction of Ifosfamide metabolism by a population pharmacokinetic approach using NONMEM.
British Journal of Clinical Pharmacology, 2001Co-Authors: Thomas Kerbusch, Alwin D. R. Huitema, Jan Ouwerkerk, H. J. Keizer, Ron A. A. Mathôt, Jan H.m. Schellens, Jos H. BeijnenAbstract:Aims This study investigated the population pharmacokinetics of Ifosfamide in 15 patients treated for soft tissue sarcoma with 9 or 12 g m−2 Ifosfamide by means of a 72 h continuous i.v. infusion. Methods A model was developed using nonlinear mixed effects modelling (NONMEM) to describe the nonlinear pharmacokinetics of Ifosfamide by linking the Ifosfamide plasma concentrations to the extent of the autoinduction. Results The proposed model revealed the effect of autoinduction on the disposition of Ifosfamide. The initial clearance, volume of distribution, rate constant for enzyme degradation, induction half-life of the enzyme and the Ifosfamide concentration at 50% of the maximum inhibition of enzyme degradation were estimated at 2.94 ± 0.27 l h−1, 43.5 ± 2.9 l, 0.0546 ± 0.0078 h−1, 12.7 h and 30.7 ± 4.8 µm, respectively. Interindividual variabilities of initial clearance, volume of distribution, rate constant for enzyme degradation were 24.5, 23.4 and 22.7%, respectively. Proportional and additive variability not explained by the model were 13.6% and 0.0763 µm, respectively. Conclusions The absence of a lag time for the autoinduction of Ifosfamide metabolism could be the result of an immediate inhibition of the enzymatic degradation of CYP3A4 by Ifosfamide. By application of the autoinduction model individual pharmacokinetic profiles of patients were described with adequate precision. This model may therefore be used in the future development of a model to individualize dose selection in patients.
-
Population Pharmacokinetics of Ifosfamide and its Dechloroethylated and Hydroxylated Metabolites in Children with Malignant Disease
Clinical Pharmacokinetics, 2001Co-Authors: Thomas Kerbusch, Ron A. A. Mathôt, Jan Kraker, Jos H. BeijnenAbstract:Objective To assess the feasibility of a sparse sampling approach for the determination of the population pharmacokinetics of Ifosfamide, 2- and 3-dechloro-ethyl-Ifosfamide and 4-hydroxy-Ifosfamide in children treated with single-agent Ifosfamide against various malignant tumours. Design Pharmacokinetic assessment followed by model fitting. Patients The analysis included 32 patients aged between 1 and 18 years receiving a total of 45 courses of Ifosfamide 1.2, 2 or 3 g/m^2 in 1 or 3 hours on 1, 2 or 3 days. Methods A total of 133 blood samples (median of 3 per patient) were collected. Plasma concentrations of Ifosfamide and its dechloroethylated metabolites were determined by gas chromatography. Plasma concentrations of 4-hydroxy- Ifosfamide were measured by high-performance liquid chromatography. The models were fitted to the data using a nonlinear mixed effects model as implemented in the NONMEM program. A cross-validation was performed. Results Population values (mean ± standard error) for the initial clearance and volume of distribution of Ifosfamide were estimated at 2.36 ± 0.33 L/h/m^2 and 20.6 ± 1.6 L/m^2 with an interindividual variability of 43 and 32%, respectively. The enzyme induction constant was estimated at 0.0493 ± 0.0104 L/h^2/m^2. The ratio of the fraction of Ifosfamide metabolised to each metabolite to the volume of distribution of that metabolite, and the elimination rate constant, of 2- and 3-dechloroethyl-Ifosfamide and 4-hydroxy-Ifosfamide were 0.0976 ± 0.0556, 0.0328 ± 0.0102 and 0.0230 ± 0.0083 m^2/L and 3.64 ± 2.04, 0.445 ± 0.174 and 7.67 ± 2.87 h^−1, respectively. Interindividual variability of the first parameter was 23, 34 and 53%, respectively. Cross-validation indicated no bias and minor imprecision (12.5 ± 5.1%) for 4-hydroxy-Ifosfamide only. Conclusions We have developed and validated a model to estimate Ifosfamide and metabolite concentrations in a paediatric population by using sparse sampling.
-
Influence of dose and infusion duration on pharmacokinetics of Ifosfamide and metabolites.
Drug metabolism and disposition: the biological fate of chemicals, 2001Co-Authors: Thomas Kerbusch, H. J. Keizer, Ron A. A. Mathôt, Jan H.m. Schellens, G. P. Kaijser, Jos H. BeijnenAbstract:The anticancer drug Ifosfamide is a prodrug requiring activation through 4-hydroxyIfosfamide to ifosforamide mustard, to exert cytotoxicity. Deactivation of Ifosfamide leads to 2- and 3-dechloroethylIfosfamide and the release of potentially neurotoxic chloracetaldehyde. The aim of this study was to quantify and to compare the pharmacokinetics of Ifosfamide, 2- and 3-dechloroethylIfosfamide, 4-hydroxyIfosfamide, and ifosforamide mustard in short (1-4 h), medium (24-72 h), and long infusion durations (96-240 h) of Ifosfamide. An integrated population pharmacokinetic model was used to describe the autoinducible pharmacokinetics of Ifosfamide and its four metabolites in 56 patients. The rate by which autoinduction of the metabolism of Ifosfamide developed was found to be significantly dependent on the infusion schedule. The rate was 52% lower with long infusion durations compared with short infusion durations. This difference was, however, comparable with its interindividual variability (22%) and was, therefore, considered to be of minor clinical importance. Autoinduction caused a less than proportional increase in the area under the Ifosfamide plasma concentration-time curve (AUC) and more than proportional increase in metabolite exposure with increasing Ifosfamide dose. During long infusion durations dose-corrected exposures (AUC/D) were significantly decreased for Ifosfamide and increased for 3-dechloroethylIfosfamide compared with short infusion durations. No differences in dose-normalized exposure to Ifosfamide and metabolites were observed between short and medium infusion durations. This study demonstrates that the duration of Ifosfamide infusion influences the exposure to the parent and its metabolite 3-dechloroethylIfosfamide. The observed dose and infusion duration dependence should be taken into account when modeling Ifosfamide metabolism.
-
Clinical Pharmacokinetics and Pharmacodynamics of Ifosfamide and its Metabolites
Clinical Pharmacokinetics, 2001Co-Authors: Thomas Kerbusch, Jan H.m. Schellens, Jan Kraker, H. Jan Keizer, John W. G. Putten, Harry J. M. Groen, Rob L. H. Jansen, Jos H. BeijnenAbstract:This review discusses several issues in the clinical pharmacology of the antitumour agent Ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of Ifosfamide has been elucidated. Identification of specific isoenzymes responsible for Ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether Ifosfamide is specifically transported by erythrocytes and which activated Ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of Ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality of the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of Ifosfamide. Correlations between the new insights into Ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of Ifosfamide treatment.
E. F. Connelly - One of the best experts on this subject based on the ideXlab platform.
-
Ifosfamide in the treatment of soft tissue sarcomas.
Seminars in Oncology, 1996Co-Authors: E. F. Connelly, G. T. BuddAbstract:Ifosfamide is one of the three most active agents in the treatment of soft tissue sarcomas. Ifosfamide-induced urothelial toxicity has been adequately controlled with the use of hydration and the uroprotective agent mesna. This is a review of pilot and phase I and II studies of Ifosfamide as a single agent and randomized trials of combination chemotherapy regimens incorporating Ifosfamide in the treatment of soft tissue sarcomas. Issues of schedule and dose of Ifosfamide will be addressed as well.
