Abstract
Patients undergoing hematopoietic cell transplantation (HCT) with reduced intensity conditioning (RIC) commonly receive fludarabine. Higher exposure of F-ara-A, the active component of fludarabine, has been associated with a greater risk of nonrelapse mortality (NRM). We sought to develop a model for fludarabine dosing in adult HCT recipients that would allow for precise dose targeting and predict adverse clinical outcomes. We developed a pharmacokinetic model from 87 adults undergoing allogeneic RIC HCT that predicts F-ara-A population clearance (Clpop) accounting for ideal body weight and renal function. We then applied the developed model to an independent cohort of 240 patients to identify whether model predictions were associated with NRM and acute graft versus host disease (GVHD). Renal mechanisms accounted for 35.6% of total F-ara-A Clpop. In the independent cohort, the hazard ratio of NRM at day 100 was significantly higher in patients with predicted F-ara-A clearance (Clpred) <8.50 L/h (P < 0.01) and area under the curve (AUCpred) >6.00 μg × h/mL (P = 0.01). A lower Clpred was also associated with more NRM at month 6 (P = 0.01) and trended toward significance at 12 months (P = 0.05). In multivariate analysis, low fludarabine clearance trended toward higher risk of acute GVHD (P = 0.05). We developed a model that predicts an individual's systemic F-ara-A exposure accounting for kidney function and weight. This model may provide guidance in dosing especially in overweight individuals and those with altered kidney function.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 103-115.e4 |
| Journal | Translational Research |
| Volume | 175 |
| DOIs | |
| State | Published - Sep 1 2016 |
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Personalized fludarabine dosing to reduce nonrelapse mortality in hematopoietic stem-cell transplant recipients receiving reduced intensity conditioning. / Sanghavi, Kinjal J; Wiseman, Anthony; Kirstein, Mark N; Cao, Qing; Brundage, Richard; Jensen, Kyle; Rogosheske, John; Kurtzweil, Andy; Long-Boyle, Janel; Wagner, John E; Warlick, Erica D; Brunstein, Claudio G; Weisdorf, Daniel J; Jacobson, Pamala A.
In: Translational Research, Vol. 175, 01.09.2016, p. 103-115.e4.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Personalized fludarabine dosing to reduce nonrelapse mortality in hematopoietic stem-cell transplant recipients receiving reduced intensity conditioning
AU - Sanghavi, Kinjal J
AU - Wiseman, Anthony
AU - Kirstein, Mark N
AU - Cao, Qing
AU - Brundage, Richard
AU - Jensen, Kyle
AU - Rogosheske, John
AU - Kurtzweil, Andy
AU - Long-Boyle, Janel
AU - Wagner, John E
AU - Warlick, Erica D
AU - Brunstein, Claudio G
AU - Weisdorf, Daniel J
AU - Jacobson, Pamala A
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Patients undergoing hematopoietic cell transplantation (HCT) with reduced intensity conditioning (RIC) commonly receive fludarabine. Higher exposure of F-ara-A, the active component of fludarabine, has been associated with a greater risk of nonrelapse mortality (NRM). We sought to develop a model for fludarabine dosing in adult HCT recipients that would allow for precise dose targeting and predict adverse clinical outcomes. We developed a pharmacokinetic model from 87 adults undergoing allogeneic RIC HCT that predicts F-ara-A population clearance (Clpop) accounting for ideal body weight and renal function. We then applied the developed model to an independent cohort of 240 patients to identify whether model predictions were associated with NRM and acute graft versus host disease (GVHD). Renal mechanisms accounted for 35.6% of total F-ara-A Clpop. In the independent cohort, the hazard ratio of NRM at day 100 was significantly higher in patients with predicted F-ara-A clearance (Clpred) <8.50 L/h (P < 0.01) and area under the curve (AUCpred) >6.00 μg × h/mL (P = 0.01). A lower Clpred was also associated with more NRM at month 6 (P = 0.01) and trended toward significance at 12 months (P = 0.05). In multivariate analysis, low fludarabine clearance trended toward higher risk of acute GVHD (P = 0.05). We developed a model that predicts an individual's systemic F-ara-A exposure accounting for kidney function and weight. This model may provide guidance in dosing especially in overweight individuals and those with altered kidney function.
AB - Patients undergoing hematopoietic cell transplantation (HCT) with reduced intensity conditioning (RIC) commonly receive fludarabine. Higher exposure of F-ara-A, the active component of fludarabine, has been associated with a greater risk of nonrelapse mortality (NRM). We sought to develop a model for fludarabine dosing in adult HCT recipients that would allow for precise dose targeting and predict adverse clinical outcomes. We developed a pharmacokinetic model from 87 adults undergoing allogeneic RIC HCT that predicts F-ara-A population clearance (Clpop) accounting for ideal body weight and renal function. We then applied the developed model to an independent cohort of 240 patients to identify whether model predictions were associated with NRM and acute graft versus host disease (GVHD). Renal mechanisms accounted for 35.6% of total F-ara-A Clpop. In the independent cohort, the hazard ratio of NRM at day 100 was significantly higher in patients with predicted F-ara-A clearance (Clpred) <8.50 L/h (P < 0.01) and area under the curve (AUCpred) >6.00 μg × h/mL (P = 0.01). A lower Clpred was also associated with more NRM at month 6 (P = 0.01) and trended toward significance at 12 months (P = 0.05). In multivariate analysis, low fludarabine clearance trended toward higher risk of acute GVHD (P = 0.05). We developed a model that predicts an individual's systemic F-ara-A exposure accounting for kidney function and weight. This model may provide guidance in dosing especially in overweight individuals and those with altered kidney function.
UR - http://www.scopus.com/inward/record.url?scp=84964905002&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964905002&partnerID=8YFLogxK
U2 - 10.1016/j.trsl.2016.03.017
DO - 10.1016/j.trsl.2016.03.017
M3 - Article
VL - 175
SP - 103-115.e4
JO - Translational research : the journal of laboratory and clinical medicine
JF - Translational research : the journal of laboratory and clinical medicine
SN - 1931-5244
ER -