Background: Busulfan (Bu) is an integral part of conditioning regimens for patients with sickle cell anemia (SCA) undergoing transplantation. Patients with SCA might predispose to transplant-related neurological and pulmonary toxicities due to pre-existing disease-related cerebrovascular and lung injury. Bu therapy appears to be an important contributing factor in this context. Procedure: We studied the pharmacokinetics of intravenous Bu and clinical outcomes of 36 children with SCA undergoing bone marrow transplantation. Most patients had pre-existing organ system damage. Busulfan was administered every 6hr for 4 days with pharmacokinetic-guided dose adjustment to target a conservative area under the concentration versus time curve (AUC) range of 900-1,350μMol*min. Results: We found that the first-dose Bu clearance was significantly higher (P<0.0005) than the subsequent daily clearance, which remained unchanged during the following days. After the first-dose, 69% of patients achieved the target range. We adapted a new dose-adjustment strategy targeting exposures to the lower end (900μMol*min) of the AUC range after the first dose of Bu to avoid unnecessary dose increases on subsequent days due to differences in clearance. This strategy enabled most patients to maintain the AUC within therapeutic range following dose adjustments. Conclusions: Differences in Bu clearance after the first-dose and subsequent daily doses in patients with SCA should be considered for pharmacokinetic-guided dose adjustment. Conservative AUC range and targeting exposures to the lower end of the range after the first dose was associated with negligible toxicity, and high engraftment and sickle cell-free survival rates. Pediatr Blood Cancer 2015;62:680-686.

New insights into the pharmacokinetics of intravenous busulfan in children with sickle cell anemia undergoing bone marrow transplantation / Gaziev, J.; Isgro, A.; Mozzi, A. F.; Petain, A.; Nguyen, L.; Ialongo, C.; Dinallo, V.; Sodani, P.; Marziali, M.; Andreani, M.; Testi, M.; Paciaroni, K.; Gallucci, C.; De Angelis, G.; Alfieri, C.; Ribersani, M.; Lucarelli, G.. - In: PEDIATRIC BLOOD & CANCER. - ISSN 1545-5009. - 62:4(2015), pp. 680-686. [10.1002/pbc.25376]

New insights into the pharmacokinetics of intravenous busulfan in children with sickle cell anemia undergoing bone marrow transplantation

Nguyen L.;Ialongo C.;Sodani P.;Marziali M.;Ribersani M.;
2015

Abstract

Background: Busulfan (Bu) is an integral part of conditioning regimens for patients with sickle cell anemia (SCA) undergoing transplantation. Patients with SCA might predispose to transplant-related neurological and pulmonary toxicities due to pre-existing disease-related cerebrovascular and lung injury. Bu therapy appears to be an important contributing factor in this context. Procedure: We studied the pharmacokinetics of intravenous Bu and clinical outcomes of 36 children with SCA undergoing bone marrow transplantation. Most patients had pre-existing organ system damage. Busulfan was administered every 6hr for 4 days with pharmacokinetic-guided dose adjustment to target a conservative area under the concentration versus time curve (AUC) range of 900-1,350μMol*min. Results: We found that the first-dose Bu clearance was significantly higher (P<0.0005) than the subsequent daily clearance, which remained unchanged during the following days. After the first-dose, 69% of patients achieved the target range. We adapted a new dose-adjustment strategy targeting exposures to the lower end (900μMol*min) of the AUC range after the first dose of Bu to avoid unnecessary dose increases on subsequent days due to differences in clearance. This strategy enabled most patients to maintain the AUC within therapeutic range following dose adjustments. Conclusions: Differences in Bu clearance after the first-dose and subsequent daily doses in patients with SCA should be considered for pharmacokinetic-guided dose adjustment. Conservative AUC range and targeting exposures to the lower end of the range after the first dose was associated with negligible toxicity, and high engraftment and sickle cell-free survival rates. Pediatr Blood Cancer 2015;62:680-686.
2015
bone marrow transplantation; children; clearance; intravenous busulfan; pharmacokinetics; sickle cell anemia
01 Pubblicazione su rivista::01a Articolo in rivista
New insights into the pharmacokinetics of intravenous busulfan in children with sickle cell anemia undergoing bone marrow transplantation / Gaziev, J.; Isgro, A.; Mozzi, A. F.; Petain, A.; Nguyen, L.; Ialongo, C.; Dinallo, V.; Sodani, P.; Marziali, M.; Andreani, M.; Testi, M.; Paciaroni, K.; Gallucci, C.; De Angelis, G.; Alfieri, C.; Ribersani, M.; Lucarelli, G.. - In: PEDIATRIC BLOOD & CANCER. - ISSN 1545-5009. - 62:4(2015), pp. 680-686. [10.1002/pbc.25376]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1611338
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