High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.
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.
Long-Boyle
J R
JR
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
Green
K G
KG
Brunstein
C G
CG
Cao
Q
Q
Rogosheske
J
J
Weisdorf
D J
DJ
Miller
J S
JS
Wagner
J E
JE
McGlave
P B
PB
Jacobson
P A
PA
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
D007166:Immunosuppressive Agents; D011355:Prodrugs; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D014740:Vidarabine; C024352:fludarabine
Pediatr Blood Cancer. 2007 Feb;48(2):213-7
16365853
Cancer Res. 1980 Oct;40(10):3610-5
6254636
J Neurol. 1999 May;246(5):339-46
10399863
Blood. 2007 Oct 15;110(8):3064-70
17569820
Blood. 2003 Sep 15;102(6):2021-30
12791654
Bone Marrow Transplant. 1995 Jun;15(6):825-8
7581076
Pharmacotherapy. 1998 Nov-Dec;18(6):1224-9
9855320
Nephron. 1976;16(1):31-41
1244564
Clin Pharmacokinet. 2002;41(2):93-103
11888330
Haematologica. 2008 Feb;93(2):257-64
18223284
Bone Marrow Transplant. 2007 Feb;39(4):201-6
17211431
Pharmacotherapy. 2001 May;21(5):528-33
11349741
J Clin Oncol. 1994 Oct;12(10):2216-28
7931492
Cancer Chemother Pharmacol. 1986;17(3):277-80
2427240
Clin Cancer Res. 1998 Jan;4(1):45-52
9516951
Am J Hematol. 2002 May;70(1):51-4
11994982
Blood. 2003 Aug 1;102(3):820-6
12676781
Expert Rev Ophthalmol. 2008 Feb;3(1):97-109
18461151
Blood. 2005 Oct 15;106(8):2912-9
15994282
Cancer Chemother Pharmacol. 1986;18(2):145-52
2431803
J Pharmacol Exp Ther. 2007 Dec;323(3):935-45
17855478
Clin Pharmacol Ther. 2005 Nov;78(5):486-500
16321615
Cancer Res. 1984 Sep;44(9):4183-6
6204752
Leuk Lymphoma. 2003 Oct;44(10):1815-8
14692540
Cancer Res. 1980 May;40(5):1405-10
6245791
Transplantation. 2008 Nov 27;86(10):1474-8
19034021
Semin Oncol. 1990 Oct;17(5 Suppl 8):3-17
1699280
Semin Oncol. 1990 Oct;17(5 Suppl 8):18-32
1699279
Leukemia. 2005 Jan;19(1):64-8
15510196
Biol Blood Marrow Transplant. 2009 Jan;15(1):92-100
19135947
Hematol Cell Ther. 1999 Aug;41(4):183-6
10543375
Biol Blood Marrow Transplant. 2008 Sep;14(9):985-992
18721761
Mol Ther. 2006 Jan;13(1):26-41
16280257
Blood. 1990 Aug 1;76(3):624-9
2378989
J Clin Pharmacol. 2009 Jan;49(1):88-102
18927240
Leukemia. 1987 Sep;1(9):638-43
3478543
Clin Pharmacol Ther. 2009 Jun;85(6):615-22
19295506
Cancer Res. 1990 Nov 15;50(22):7226-31
1699658
Blood. 2005 Jan 15;105(2):767-74
15454483
Cancer Invest. 2002;20(7-8):904-13
12449721
Leuk Lymphoma. 2002 Feb;43(2):433-6
11999583