Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT
CY in combination with BU is a widely used conditioning regimen for haematopoietic SCT (HSCT). The aim of this study was to evaluate the pharmacokinetics (PK) of CY and its major metabolite 4-hydroxyCY (HCY) in patients with thalassemia undergoing HSCT. A total of 55 patients received BU (16 mg/kg)...
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| Veröffentlicht in: | Bone marrow transplantation (Basingstoke) 2012-09, Vol.47 (9), p.1178-1185 |
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| creator | Balasubramanian, P Desire, S Panetta, J C Lakshmi, K M Mathews, V George, B Viswabandya, A Chandy, M Krishnamoorthy, R Srivastava, A |
| description | CY in combination with BU is a widely used conditioning regimen for haematopoietic SCT (HSCT). The aim of this study was to evaluate the pharmacokinetics (PK) of CY and its major metabolite 4-hydroxyCY (HCY) in patients with thalassemia undergoing HSCT. A total of 55 patients received BU (16 mg/kg) followed by CY (160–200 mg/kg) both over 4 days before HSCT. A population PK model was developed to describe the disposition of CY and HCY and the inter-individual (IIV) and inter-occasion variability (IOV). The model was also used to determine the effects covariates including: demographics, Lucarelli classification and polymorphisms in enzymes involved in the metabolism or biotransformation of CY had on CY and HCY disposition. Overall, 17–114% IIV and 12–103% IOV in CY and HCY PK parameters were observed. Body weight and age were the main covariates, which explained the largest portion of the IIV. In addition, CYP2C9
*
2 explained a significant portion of the IIV in the clearance (
P |
| doi_str_mv | 10.1038/bmt.2011.254 |
| format | Article |
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*
2 explained a significant portion of the IIV in the clearance (
P
<0.002) and thus the area under the concentration curve (
P
<0.05) of CY. This covariate model may be used to design and plan targeted dose therapy in this group of pediatric patients, if clinical outcome association with CY PK are proved and target range established.</description><identifier>ISSN: 0268-3369</identifier><identifier>EISSN: 1476-5365</identifier><identifier>DOI: 10.1038/bmt.2011.254</identifier><identifier>PMID: 22231460</identifier><identifier>CODEN: BMTRE9</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/154/436/1729 ; 631/250/1904 ; 631/532/1542 ; 692/699/1541/13 ; Adolescent ; Age ; Anemias. Hemoglobinopathies ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; beta-Thalassemia - drug therapy ; beta-Thalassemia - metabolism ; beta-Thalassemia - surgery ; beta-Thalassemia - therapy ; Biological and medical sciences ; Biotransformation ; Blood diseases ; Body weight ; Bone marrow ; Bone marrow transplantation ; Bone marrow, stem cells transplantation. Graft versus host reaction ; Care and treatment ; Cell Biology ; Child ; Child, Preschool ; Classification ; Cyclophosphamide ; Cyclophosphamide - administration & dosage ; Cyclophosphamide - pharmacokinetics ; Demographic aspects ; Demographics ; Demography ; Diagnosis ; Diseases of red blood cells ; Disposition ; Dosage and administration ; Enzymes ; Female ; Hematologic and hematopoietic diseases ; Hematology ; Hematopoietic Stem Cell Transplantation - adverse effects ; Hematopoietic Stem Cell Transplantation - methods ; Hematopoietic stem cells ; Humans ; Internal Medicine ; Male ; Medical sciences ; Medicine ; Medicine & Public Health ; Metabolism ; Metabolites ; original-article ; Patients ; Pediatrics ; Pharmacokinetics ; Pharmacology ; Public Health ; Stem cell transplantation ; Stem Cells ; Thalassemia ; Transfusions. Complications. Transfusion reactions. Cell and gene therapy ; Transplantation ; Transplantation Conditioning - methods</subject><ispartof>Bone marrow transplantation (Basingstoke), 2012-09, Vol.47 (9), p.1178-1185</ispartof><rights>Macmillan Publishers Limited 2012</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2012 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Sep 2012</rights><rights>Macmillan Publishers Limited 2012.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c584t-7fcefc20b80b9991d8147b3050299cfad25b6861cde3de2608553ec6a840c8053</citedby><cites>FETCH-LOGICAL-c584t-7fcefc20b80b9991d8147b3050299cfad25b6861cde3de2608553ec6a840c8053</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26351558$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22231460$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Balasubramanian, P</creatorcontrib><creatorcontrib>Desire, S</creatorcontrib><creatorcontrib>Panetta, J C</creatorcontrib><creatorcontrib>Lakshmi, K M</creatorcontrib><creatorcontrib>Mathews, V</creatorcontrib><creatorcontrib>George, B</creatorcontrib><creatorcontrib>Viswabandya, A</creatorcontrib><creatorcontrib>Chandy, M</creatorcontrib><creatorcontrib>Krishnamoorthy, R</creatorcontrib><creatorcontrib>Srivastava, A</creatorcontrib><title>Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT</title><title>Bone marrow transplantation (Basingstoke)</title><addtitle>Bone Marrow Transplant</addtitle><addtitle>Bone Marrow Transplant</addtitle><description>CY in combination with BU is a widely used conditioning regimen for haematopoietic SCT (HSCT). The aim of this study was to evaluate the pharmacokinetics (PK) of CY and its major metabolite 4-hydroxyCY (HCY) in patients with thalassemia undergoing HSCT. A total of 55 patients received BU (16 mg/kg) followed by CY (160–200 mg/kg) both over 4 days before HSCT. A population PK model was developed to describe the disposition of CY and HCY and the inter-individual (IIV) and inter-occasion variability (IOV). The model was also used to determine the effects covariates including: demographics, Lucarelli classification and polymorphisms in enzymes involved in the metabolism or biotransformation of CY had on CY and HCY disposition. Overall, 17–114% IIV and 12–103% IOV in CY and HCY PK parameters were observed. Body weight and age were the main covariates, which explained the largest portion of the IIV. In addition, CYP2C9
*
2 explained a significant portion of the IIV in the clearance (
P
<0.002) and thus the area under the concentration curve (
P
<0.05) of CY. This covariate model may be used to design and plan targeted dose therapy in this group of pediatric patients, if clinical outcome association with CY PK are proved and target range established.</description><subject>631/154/436/1729</subject><subject>631/250/1904</subject><subject>631/532/1542</subject><subject>692/699/1541/13</subject><subject>Adolescent</subject><subject>Age</subject><subject>Anemias. Hemoglobinopathies</subject><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>beta-Thalassemia - drug therapy</subject><subject>beta-Thalassemia - metabolism</subject><subject>beta-Thalassemia - surgery</subject><subject>beta-Thalassemia - therapy</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Blood diseases</subject><subject>Body weight</subject><subject>Bone marrow</subject><subject>Bone marrow transplantation</subject><subject>Bone marrow, stem cells transplantation. Graft versus host reaction</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Classification</subject><subject>Cyclophosphamide</subject><subject>Cyclophosphamide - administration & dosage</subject><subject>Cyclophosphamide - pharmacokinetics</subject><subject>Demographic aspects</subject><subject>Demographics</subject><subject>Demography</subject><subject>Diagnosis</subject><subject>Diseases of red blood cells</subject><subject>Disposition</subject><subject>Dosage and administration</subject><subject>Enzymes</subject><subject>Female</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Hematology</subject><subject>Hematopoietic Stem Cell Transplantation - adverse effects</subject><subject>Hematopoietic Stem Cell Transplantation - methods</subject><subject>Hematopoietic stem cells</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>original-article</subject><subject>Patients</subject><subject>Pediatrics</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Public Health</subject><subject>Stem cell transplantation</subject><subject>Stem Cells</subject><subject>Thalassemia</subject><subject>Transfusions. Complications. Transfusion reactions. 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Hemoglobinopathies</topic><topic>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</topic><topic>beta-Thalassemia - drug therapy</topic><topic>beta-Thalassemia - metabolism</topic><topic>beta-Thalassemia - surgery</topic><topic>beta-Thalassemia - therapy</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>Blood diseases</topic><topic>Body weight</topic><topic>Bone marrow</topic><topic>Bone marrow transplantation</topic><topic>Bone marrow, stem cells transplantation. Graft versus host reaction</topic><topic>Care and treatment</topic><topic>Cell Biology</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Classification</topic><topic>Cyclophosphamide</topic><topic>Cyclophosphamide - administration & dosage</topic><topic>Cyclophosphamide - pharmacokinetics</topic><topic>Demographic aspects</topic><topic>Demographics</topic><topic>Demography</topic><topic>Diagnosis</topic><topic>Diseases of red blood cells</topic><topic>Disposition</topic><topic>Dosage and administration</topic><topic>Enzymes</topic><topic>Female</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Hematology</topic><topic>Hematopoietic Stem Cell Transplantation - adverse effects</topic><topic>Hematopoietic Stem Cell Transplantation - methods</topic><topic>Hematopoietic stem cells</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>original-article</topic><topic>Patients</topic><topic>Pediatrics</topic><topic>Pharmacokinetics</topic><topic>Pharmacology</topic><topic>Public Health</topic><topic>Stem cell transplantation</topic><topic>Stem Cells</topic><topic>Thalassemia</topic><topic>Transfusions. 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The aim of this study was to evaluate the pharmacokinetics (PK) of CY and its major metabolite 4-hydroxyCY (HCY) in patients with thalassemia undergoing HSCT. A total of 55 patients received BU (16 mg/kg) followed by CY (160–200 mg/kg) both over 4 days before HSCT. A population PK model was developed to describe the disposition of CY and HCY and the inter-individual (IIV) and inter-occasion variability (IOV). The model was also used to determine the effects covariates including: demographics, Lucarelli classification and polymorphisms in enzymes involved in the metabolism or biotransformation of CY had on CY and HCY disposition. Overall, 17–114% IIV and 12–103% IOV in CY and HCY PK parameters were observed. Body weight and age were the main covariates, which explained the largest portion of the IIV. In addition, CYP2C9
*
2 explained a significant portion of the IIV in the clearance (
P
<0.002) and thus the area under the concentration curve (
P
<0.05) of CY. This covariate model may be used to design and plan targeted dose therapy in this group of pediatric patients, if clinical outcome association with CY PK are proved and target range established.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>22231460</pmid><doi>10.1038/bmt.2011.254</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0268-3369 |
| ispartof | Bone marrow transplantation (Basingstoke), 2012-09, Vol.47 (9), p.1178-1185 |
| issn | 0268-3369 1476-5365 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1069199666 |
| source | MEDLINE; Nature; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | 631/154/436/1729 631/250/1904 631/532/1542 692/699/1541/13 Adolescent Age Anemias. Hemoglobinopathies Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy beta-Thalassemia - drug therapy beta-Thalassemia - metabolism beta-Thalassemia - surgery beta-Thalassemia - therapy Biological and medical sciences Biotransformation Blood diseases Body weight Bone marrow Bone marrow transplantation Bone marrow, stem cells transplantation. Graft versus host reaction Care and treatment Cell Biology Child Child, Preschool Classification Cyclophosphamide Cyclophosphamide - administration & dosage Cyclophosphamide - pharmacokinetics Demographic aspects Demographics Demography Diagnosis Diseases of red blood cells Disposition Dosage and administration Enzymes Female Hematologic and hematopoietic diseases Hematology Hematopoietic Stem Cell Transplantation - adverse effects Hematopoietic Stem Cell Transplantation - methods Hematopoietic stem cells Humans Internal Medicine Male Medical sciences Medicine Medicine & Public Health Metabolism Metabolites original-article Patients Pediatrics Pharmacokinetics Pharmacology Public Health Stem cell transplantation Stem Cells Thalassemia Transfusions. Complications. Transfusion reactions. Cell and gene therapy Transplantation Transplantation Conditioning - methods |
| title | Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT |
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