Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy
Abstract Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin c...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Agoram, Balaji [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2006 |
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| Schlagwörter: |
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| Anmerkung: |
© American Association of Pharmaceutical Scientists 2006 |
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| Übergeordnetes Werk: |
Enthalten in: AAPS PharmSci - Arlington, Va. : Soc., 1999, 8(2006), 3 vom: 01. Sept., Seite E552-E563 |
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| Übergeordnetes Werk: |
volume:8 ; year:2006 ; number:3 ; day:01 ; month:09 ; pages:E552-E563 |
| Links: |
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| DOI / URN: |
10.1208/aapsj080364 |
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SPR024668044 |
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| 520 | |a Abstract Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (SC) doses of 2.25 μg/kg every week and SC doses of 6.75 μg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after SC doses of 0.5 μg/kg every week to 15 μg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important. | ||
| 650 | 4 | |a population PkPd modeling |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a darbepoetin alfa |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a covariate analysis |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Heatherington, Anne C. |4 aut | |
| 700 | 1 | |a Gastonguay, Marc R. |4 aut | |
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10.1208/aapsj080364 doi (DE-627)SPR024668044 (SPR)aapsj080364-e DE-627 ger DE-627 rakwb eng Agoram, Balaji verfasserin aut Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy 2006 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © American Association of Pharmaceutical Scientists 2006 Abstract Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (SC) doses of 2.25 μg/kg every week and SC doses of 6.75 μg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after SC doses of 0.5 μg/kg every week to 15 μg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important. population PkPd modeling (dpeaa)DE-He213 darbepoetin alfa (dpeaa)DE-He213 covariate analysis (dpeaa)DE-He213 Heatherington, Anne C. aut Gastonguay, Marc R. aut Enthalten in AAPS PharmSci Arlington, Va. : Soc., 1999 8(2006), 3 vom: 01. Sept., Seite E552-E563 (DE-627)328321060 (DE-600)2045715-7 1522-1059 nnns volume:8 year:2006 number:3 day:01 month:09 pages:E552-E563 https://dx.doi.org/10.1208/aapsj080364 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_206 GBV_ILN_224 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 AR 8 2006 3 01 09 E552-E563 |
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10.1208/aapsj080364 doi (DE-627)SPR024668044 (SPR)aapsj080364-e DE-627 ger DE-627 rakwb eng Agoram, Balaji verfasserin aut Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy 2006 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © American Association of Pharmaceutical Scientists 2006 Abstract Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (SC) doses of 2.25 μg/kg every week and SC doses of 6.75 μg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after SC doses of 0.5 μg/kg every week to 15 μg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important. population PkPd modeling (dpeaa)DE-He213 darbepoetin alfa (dpeaa)DE-He213 covariate analysis (dpeaa)DE-He213 Heatherington, Anne C. aut Gastonguay, Marc R. aut Enthalten in AAPS PharmSci Arlington, Va. : Soc., 1999 8(2006), 3 vom: 01. Sept., Seite E552-E563 (DE-627)328321060 (DE-600)2045715-7 1522-1059 nnns volume:8 year:2006 number:3 day:01 month:09 pages:E552-E563 https://dx.doi.org/10.1208/aapsj080364 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_206 GBV_ILN_224 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 AR 8 2006 3 01 09 E552-E563 |
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10.1208/aapsj080364 doi (DE-627)SPR024668044 (SPR)aapsj080364-e DE-627 ger DE-627 rakwb eng Agoram, Balaji verfasserin aut Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy 2006 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © American Association of Pharmaceutical Scientists 2006 Abstract Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (SC) doses of 2.25 μg/kg every week and SC doses of 6.75 μg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after SC doses of 0.5 μg/kg every week to 15 μg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important. population PkPd modeling (dpeaa)DE-He213 darbepoetin alfa (dpeaa)DE-He213 covariate analysis (dpeaa)DE-He213 Heatherington, Anne C. aut Gastonguay, Marc R. aut Enthalten in AAPS PharmSci Arlington, Va. : Soc., 1999 8(2006), 3 vom: 01. Sept., Seite E552-E563 (DE-627)328321060 (DE-600)2045715-7 1522-1059 nnns volume:8 year:2006 number:3 day:01 month:09 pages:E552-E563 https://dx.doi.org/10.1208/aapsj080364 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_206 GBV_ILN_224 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 AR 8 2006 3 01 09 E552-E563 |
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10.1208/aapsj080364 doi (DE-627)SPR024668044 (SPR)aapsj080364-e DE-627 ger DE-627 rakwb eng Agoram, Balaji verfasserin aut Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy 2006 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © American Association of Pharmaceutical Scientists 2006 Abstract Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (SC) doses of 2.25 μg/kg every week and SC doses of 6.75 μg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after SC doses of 0.5 μg/kg every week to 15 μg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important. population PkPd modeling (dpeaa)DE-He213 darbepoetin alfa (dpeaa)DE-He213 covariate analysis (dpeaa)DE-He213 Heatherington, Anne C. aut Gastonguay, Marc R. aut Enthalten in AAPS PharmSci Arlington, Va. : Soc., 1999 8(2006), 3 vom: 01. Sept., Seite E552-E563 (DE-627)328321060 (DE-600)2045715-7 1522-1059 nnns volume:8 year:2006 number:3 day:01 month:09 pages:E552-E563 https://dx.doi.org/10.1208/aapsj080364 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_206 GBV_ILN_224 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 AR 8 2006 3 01 09 E552-E563 |
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10.1208/aapsj080364 doi (DE-627)SPR024668044 (SPR)aapsj080364-e DE-627 ger DE-627 rakwb eng Agoram, Balaji verfasserin aut Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy 2006 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © American Association of Pharmaceutical Scientists 2006 Abstract Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (SC) doses of 2.25 μg/kg every week and SC doses of 6.75 μg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after SC doses of 0.5 μg/kg every week to 15 μg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important. population PkPd modeling (dpeaa)DE-He213 darbepoetin alfa (dpeaa)DE-He213 covariate analysis (dpeaa)DE-He213 Heatherington, Anne C. aut Gastonguay, Marc R. aut Enthalten in AAPS PharmSci Arlington, Va. : Soc., 1999 8(2006), 3 vom: 01. Sept., Seite E552-E563 (DE-627)328321060 (DE-600)2045715-7 1522-1059 nnns volume:8 year:2006 number:3 day:01 month:09 pages:E552-E563 https://dx.doi.org/10.1208/aapsj080364 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_206 GBV_ILN_224 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 AR 8 2006 3 01 09 E552-E563 |
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development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy |
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Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy |
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Abstract Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (SC) doses of 2.25 μg/kg every week and SC doses of 6.75 μg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after SC doses of 0.5 μg/kg every week to 15 μg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important. © American Association of Pharmaceutical Scientists 2006 |
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Abstract Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (SC) doses of 2.25 μg/kg every week and SC doses of 6.75 μg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after SC doses of 0.5 μg/kg every week to 15 μg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important. © American Association of Pharmaceutical Scientists 2006 |
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Abstract Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (SC) doses of 2.25 μg/kg every week and SC doses of 6.75 μg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after SC doses of 0.5 μg/kg every week to 15 μg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important. © American Association of Pharmaceutical Scientists 2006 |
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A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after SC doses of 0.5 μg/kg every week to 15 μg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. 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