F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan

Fludarabine is commonly used in combination with busulfan as part of conditioning regimens before allogeneic stem cell transplantation. So far, no data are available on busulfan-fludarabine drug interactions in transplant recipients. The pharmacokinetic (PK) properties of F-ara-A (9-beta-D-arabinosyl-2-fluoradenine) before and after application of busulfan were prospectively investigated in 16 patients with hematological malignancies. The conditioning regimen consisted of intravenous fludarabine 30 mg/m(2) over 30 min from day -6 to day -3, and oral busulfan given at 1 mg/kg every 6 h from day -5 to day -2. PK parameters of F-ara-A, derived from plasma and urine on day -6, -5, -4 and -3, were determined using high-performance liquid chromatography (HPLC). AUC, C-max, t(1/2), Cl-total and V-SS were 21.9 mu Mh, 3.5 mu M, 13.0 h, 4.3 l/h/m(2), 60.0 l/m(2) on day -6 and 22.4 mu Mh, 3.5 mu M, 14.0 h, 4.7 l/h/m(2), 69.0 l/m(2) on day -5 to (-2), respectively. Cl-renal and the urine-recovery were 4.8 l/h, 43.7% of the fludarabine dose on day -6 and 3.9 l/h, 44.2% of the fludarabine dose on day -5 to (-2), respectively. There were no changes in PK parameters of fludarabine given before and after intake of busulfan. This implies that a clinically relevant busulfan-fludarabine drug interaction is unlikely.