Cyclosporin increases cellular idarubicin and idarubicinol concentrations in relapsed or refractory AML mainly due to reduced systemic clearance
The feasibility of adding both the multidrug resistance modulator cyclosporin (CsA) and granulocyte colony-stimulating factor (G-CSF) to a standard salvage regimen of idarubicin (IDA) and cytarabine was evaluated in patients with resistant or relapsed acute myeloid leukemia and myelodysplastic syndr...
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| Veröffentlicht in: | Leukemia 2001, Vol.15 (1), p.80-88 |
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| creator | SMEETS, M RAYMAKERS, R MUUS, P VIERWINDEN, G LINSSEN, P MASEREEUW, R DE WITTE, T |
| description | The feasibility of adding both the multidrug resistance modulator cyclosporin (CsA) and granulocyte colony-stimulating factor (G-CSF) to a standard salvage regimen of idarubicin (IDA) and cytarabine was evaluated in patients with resistant or relapsed acute myeloid leukemia and myelodysplastic syndrome. Three patients received IDA 12 mg/m2/day, the next four patients 9 mg/m2/day. The dose of CsA was 16 mg/kg/day. Six patients showed Pgp expression and none MRP1 expression. Grade III or IV toxicity (CTC-NCIC criteria) was registered in six patients for gastrointestinal, two patients for cardiovascular and one patient for neurological complications. Three patients died in hypoplasia and three patients showed leukemic regrowth. Three control patients were treated with IDA 12 mg/m2/day and cytarabine, but no CsA and G-CSF. The plasma IDA and idarubicinol (ida-ol) area under the curve's of patients treated with IDA 12 mg/m2 plus CsA were higher (P< 0.05) than in controls. Cellular IDA concentrations were almost similar, but cellular ida-ol concentrations were significantly higher (P < 0.05) in the presence of CsA than in controls. We conclude that the toxicity either with IDA 12 or 9 mg/m2/day was too high. The modulating effect of CsA was mainly based on changes in plasma kinetics of IDA and ida-ol, although ida-ol cellular clearance was delayed in the presence of CsA. |
| doi_str_mv | 10.1038/sj.leu.2401996 |
| format | Article |
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Three patients received IDA 12 mg/m2/day, the next four patients 9 mg/m2/day. The dose of CsA was 16 mg/kg/day. Six patients showed Pgp expression and none MRP1 expression. Grade III or IV toxicity (CTC-NCIC criteria) was registered in six patients for gastrointestinal, two patients for cardiovascular and one patient for neurological complications. Three patients died in hypoplasia and three patients showed leukemic regrowth. Three control patients were treated with IDA 12 mg/m2/day and cytarabine, but no CsA and G-CSF. The plasma IDA and idarubicinol (ida-ol) area under the curve's of patients treated with IDA 12 mg/m2 plus CsA were higher (P< 0.05) than in controls. Cellular IDA concentrations were almost similar, but cellular ida-ol concentrations were significantly higher (P < 0.05) in the presence of CsA than in controls. We conclude that the toxicity either with IDA 12 or 9 mg/m2/day was too high. The modulating effect of CsA was mainly based on changes in plasma kinetics of IDA and ida-ol, although ida-ol cellular clearance was delayed in the presence of CsA.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/sj.leu.2401996</identifier><identifier>PMID: 11243404</identifier><identifier>CODEN: LEUKED</identifier><language>eng</language><publisher>London: Nature Publishing</publisher><subject>Acute Disease ; Adolescent ; Adult ; Aged ; Antineoplastic agents ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biological and medical sciences ; Cell cycle ; Chemotherapy ; Cyclosporine - metabolism ; Cyclosporine - pharmacology ; Cyclosporine - therapeutic use ; Daunorubicin - analogs & derivatives ; Daunorubicin - metabolism ; Daunorubicin - pharmacokinetics ; Drug resistance ; Female ; Granulocytes ; Hematology ; Hepatitis ; Humans ; Idarubicin - metabolism ; Idarubicin - pharmacokinetics ; Immunosuppressive Agents - pharmacology ; Immunosuppressive Agents - therapeutic use ; Leukemia ; Leukemia, Myeloid - drug therapy ; Leukemia, Myeloid - metabolism ; Leukemia, Myeloid - pathology ; Male ; Medical sciences ; Middle Aged ; Myelodysplastic syndromes ; Pharmacology. Drug treatments ; Pilot Projects ; Prospective Studies ; Recurrence ; Toxicity</subject><ispartof>Leukemia, 2001, Vol.15 (1), p.80-88</ispartof><rights>2001 INIST-CNRS</rights><rights>COPYRIGHT 2001 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 2001</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c377t-7f2added95efe8428cb74f73cc4904667d6db1f23da72b77687ddf747370d963</citedby><cites>FETCH-LOGICAL-c377t-7f2added95efe8428cb74f73cc4904667d6db1f23da72b77687ddf747370d963</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,4010,27900,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1123163$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11243404$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SMEETS, M</creatorcontrib><creatorcontrib>RAYMAKERS, R</creatorcontrib><creatorcontrib>MUUS, P</creatorcontrib><creatorcontrib>VIERWINDEN, G</creatorcontrib><creatorcontrib>LINSSEN, P</creatorcontrib><creatorcontrib>MASEREEUW, R</creatorcontrib><creatorcontrib>DE WITTE, T</creatorcontrib><title>Cyclosporin increases cellular idarubicin and idarubicinol concentrations in relapsed or refractory AML mainly due to reduced systemic clearance</title><title>Leukemia</title><addtitle>Leukemia</addtitle><description>The feasibility of adding both the multidrug resistance modulator cyclosporin (CsA) and granulocyte colony-stimulating factor (G-CSF) to a standard salvage regimen of idarubicin (IDA) and cytarabine was evaluated in patients with resistant or relapsed acute myeloid leukemia and myelodysplastic syndrome. Three patients received IDA 12 mg/m2/day, the next four patients 9 mg/m2/day. The dose of CsA was 16 mg/kg/day. Six patients showed Pgp expression and none MRP1 expression. Grade III or IV toxicity (CTC-NCIC criteria) was registered in six patients for gastrointestinal, two patients for cardiovascular and one patient for neurological complications. Three patients died in hypoplasia and three patients showed leukemic regrowth. Three control patients were treated with IDA 12 mg/m2/day and cytarabine, but no CsA and G-CSF. The plasma IDA and idarubicinol (ida-ol) area under the curve's of patients treated with IDA 12 mg/m2 plus CsA were higher (P< 0.05) than in controls. Cellular IDA concentrations were almost similar, but cellular ida-ol concentrations were significantly higher (P < 0.05) in the presence of CsA than in controls. We conclude that the toxicity either with IDA 12 or 9 mg/m2/day was too high. The modulating effect of CsA was mainly based on changes in plasma kinetics of IDA and ida-ol, although ida-ol cellular clearance was delayed in the presence of CsA.</description><subject>Acute Disease</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Cell cycle</subject><subject>Chemotherapy</subject><subject>Cyclosporine - metabolism</subject><subject>Cyclosporine - pharmacology</subject><subject>Cyclosporine - therapeutic use</subject><subject>Daunorubicin - analogs & derivatives</subject><subject>Daunorubicin - metabolism</subject><subject>Daunorubicin - pharmacokinetics</subject><subject>Drug resistance</subject><subject>Female</subject><subject>Granulocytes</subject><subject>Hematology</subject><subject>Hepatitis</subject><subject>Humans</subject><subject>Idarubicin - metabolism</subject><subject>Idarubicin - pharmacokinetics</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>Immunosuppressive Agents - therapeutic use</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid - drug therapy</subject><subject>Leukemia, Myeloid - metabolism</subject><subject>Leukemia, Myeloid - pathology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Myelodysplastic syndromes</subject><subject>Pharmacology. 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Three patients received IDA 12 mg/m2/day, the next four patients 9 mg/m2/day. The dose of CsA was 16 mg/kg/day. Six patients showed Pgp expression and none MRP1 expression. Grade III or IV toxicity (CTC-NCIC criteria) was registered in six patients for gastrointestinal, two patients for cardiovascular and one patient for neurological complications. Three patients died in hypoplasia and three patients showed leukemic regrowth. Three control patients were treated with IDA 12 mg/m2/day and cytarabine, but no CsA and G-CSF. The plasma IDA and idarubicinol (ida-ol) area under the curve's of patients treated with IDA 12 mg/m2 plus CsA were higher (P< 0.05) than in controls. Cellular IDA concentrations were almost similar, but cellular ida-ol concentrations were significantly higher (P < 0.05) in the presence of CsA than in controls. We conclude that the toxicity either with IDA 12 or 9 mg/m2/day was too high. The modulating effect of CsA was mainly based on changes in plasma kinetics of IDA and ida-ol, although ida-ol cellular clearance was delayed in the presence of CsA.</abstract><cop>London</cop><pub>Nature Publishing</pub><pmid>11243404</pmid><doi>10.1038/sj.leu.2401996</doi><tpages>9</tpages></addata></record> |
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| subjects | Acute Disease Adolescent Adult Aged Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological and medical sciences Cell cycle Chemotherapy Cyclosporine - metabolism Cyclosporine - pharmacology Cyclosporine - therapeutic use Daunorubicin - analogs & derivatives Daunorubicin - metabolism Daunorubicin - pharmacokinetics Drug resistance Female Granulocytes Hematology Hepatitis Humans Idarubicin - metabolism Idarubicin - pharmacokinetics Immunosuppressive Agents - pharmacology Immunosuppressive Agents - therapeutic use Leukemia Leukemia, Myeloid - drug therapy Leukemia, Myeloid - metabolism Leukemia, Myeloid - pathology Male Medical sciences Middle Aged Myelodysplastic syndromes Pharmacology. Drug treatments Pilot Projects Prospective Studies Recurrence Toxicity |
| title | Cyclosporin increases cellular idarubicin and idarubicinol concentrations in relapsed or refractory AML mainly due to reduced systemic clearance |
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