Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia

The purpose of this study was to assess the effect of the multidrug resistance modulator cyclosporine (CsA) on the pharmacokinetics of etoposide and mitoxantrone in children with de novo acute myeloid leukemia (AML). Serial blood samples for pharmacokinetic studies were obtained in 38 children over...

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Bibliographic Details
Published in:	Leukemia Vol. 16; no. 5; pp. 920 - 927
Main Authors:	LACAYO, N. J, LUM, B. L, BECTON, D. L, WEINSTEIN, H, RAVINDRANATH, Y, CHANG, M. N, BOMGAARS, L, LAUER, S. J, SIKIC, Bl, DAHL, G. V
Format:	Journal Article
Language:	English
Published:	London Nature Publishing 01-05-2002 Nature Publishing Group
Subjects:	Acute Disease Acute myeloid leukemia Adolescent Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - blood Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics Area Under Curve Biological and medical sciences Chemotherapy Child Child, Preschool Children Chromatography, High Pressure Liquid Complications and side effects Cyclosporine Cyclosporine - administration & dosage Cyclosporine - pharmacokinetics Cyclosporine - toxicity Cyclosporins Cytotoxins Dosage and administration Drug dosages Drug Interactions Drug Resistance, Multiple Drug therapy Etoposide Etoposide - administration & dosage Etoposide - blood Etoposide - pharmacokinetics Female High-performance liquid chromatography Humans Infant Iterative methods Leukemia Leukemia, Myeloid - complications Leukemia, Myeloid - drug therapy Liquid chromatography Male Medical sciences Metabolic Clearance Rate - drug effects Mitoxantrone Mitoxantrone - administration & dosage Mitoxantrone - blood Mitoxantrone - pharmacokinetics Mitoxantrone hydrochloride Multidrug resistance Multidrug resistant organisms Pharmacokinetics Pharmacology Pharmacology. Drug treatments Reduction Statistical methods Stomatitis Toxicity United States Human Antineoplastic agent Drug combination Treatment resistance Anthraquinone derivatives Acute P Glycoprotein Etoposide Malignant hemopathy Podophyllotoxine derivatives Chemotherapy Treatment Multiple resistance Ciclosporin Drug interaction Immunosuppressive agent Mitoxantrone Pharmacokinetics Child Acute myelocytic leukemia
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Summary:	The purpose of this study was to assess the effect of the multidrug resistance modulator cyclosporine (CsA) on the pharmacokinetics of etoposide and mitoxantrone in children with de novo acute myeloid leukemia (AML). Serial blood samples for pharmacokinetic studies were obtained in 38 children over a 24-h period following cytotoxin treatment with or without CsA on days 1 and 4. Drug concentrations were quantitated using validated HPLC methods, and pharmacokinetic parameters were determined using compartmental modeling with an iterative two-stage approach, implemented on ADAPT II software. Etoposide displayed a greater degree of interindividual variability in clearance and systemic exposure than mitoxantrone. With CsA treatment, etoposide and mitoxantrone mean clearance declined by 71% and 42%, respectively. These effects on clearance, in combination with the empiric 40% dose reduction for either cytotoxin, resulted in a 47% and 12% increases in the mean AUC for etoposide and mitoxantrone, respectively. There were no differences in the rates of stomatitis or infection between the two groups. CsA treatment resulted in an increased incidence of hyperbilrubinemia, which rapidly reversed upon conclusion of drug therapy. The variability observed in clearance, combined with the empiric 40% dose reduction of the cytotoxins, resulted in statistically similar systemic exposure and similar toxicity.
ISSN:	0887-6924 1476-5551
DOI:	10.1038/sj.leu.2402455