title: High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.
abstract: Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT.
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Long-Boyle
authors.forename: K G
authors.initials: KG
authors.lastname: Green
authors.forename: C G
authors.initials: CG
authors.lastname: Brunstein
authors.forename: Q
authors.initials: Q
authors.lastname: Cao
authors.forename: J
authors.initials: J
authors.lastname: Rogosheske
authors.forename: D J
authors.initials: DJ
authors.lastname: Weisdorf
authors.forename: J S
authors.initials: JS
authors.lastname: Miller
authors.forename: J E
authors.initials: JE
authors.lastname: Wagner
authors.forename: P B
authors.initials: PB
authors.lastname: McGlave
authors.forename: P A
authors.initials: PA
authors.lastname: Jacobson
mesh_terms: D000328:Adult; D000368:Aged; D016903:Drug Monitoring; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D006086:Graft vs Host Disease / Q000453:epidemiology; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D015994:Incidence; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D020556:Neutrophil Infiltration / Q000187:drug effects; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051437:Renal Insufficiency / Q000150:complications / Q000378:metabolism; D012307:Risk Factors; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000097:blood; D001084:Vidarabine Phosphate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D011355:Prodrugs; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D014740:Vidarabine; C024352:fludarabine
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