TY - JOUR
T1 - Decreased Systemic Busulfan Exposure After Oral Dosing With Concomitant Levetiracetam Compared With Phenytoin
AU - Artul, Tareq
AU - Henig, Israel
AU - Nassar, Laila
AU - Yehudai-Ofir, Dana
AU - Scherb, Inna
AU - Lurie, Yael
AU - Efrati, Edna
AU - Zuckerman, Tsila
AU - Kurnik, Daniel
N1 - Publisher Copyright:
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - Background: Busulfan (Bu) conditioning used in hematopoietic stem cell transplantation may induce seizures, and prophylactic antiepileptic treatment is recommended. Following updated guidelines, in August 2019, the adult hematopoietic stem cell transplantation department of the Rambam Health Care Campus (Haifa, Israel) switched the antiepileptic prophylaxis protocol from phenytoin to oral levetiracetam during oral Bu conditioning. The aim of this study was to compare the pharmacokinetic parameters of Bu after oral dosing between patients receiving phenytoin and those receiving levetiracetam prophylaxis. Methods: This study was a retrospective cohort study in adults undergoing myoablative conditioning with oral Bu between August 2018 and August 2020. Bu pharmacokinetic parameters (AUC0-6, C0, Cmax, and Tmax) were compared in patients treated with phenytoin comedication (during the year before the change in policy) and levetiracetam comedication (during the year after the change). Potential confounders were accounted for including age, azole comedication, and body weight. Results: There were no significant differences in demographic and clinical parameters or weight-corrected Bu dose between the phenytoin group (n = 28) and the levetiracetam group (n = 25). There was no difference in the rate of voriconazole comedication, but fluconazole was more common in the phenytoin group (P = 0.026). The median AUC0-6 was significantly lower in the levetiracetam group (949 mM*min; IQR = 806 to 1101 mM*min) than in the phenytoin group (1208 mM*min; IQR = 1087 to 1389 mM*min; P, 0.001). This is a clinically significant difference of 258 mM*min (21%). Azole use was not associated with Bu exposure. Conclusions: The findings suggest that, after treatment with oral Bu, oral levetiracetam comedication is associated with reduced systemic exposure compared with phenytoin comedication, possibly because of decreased bioavailability.
AB - Background: Busulfan (Bu) conditioning used in hematopoietic stem cell transplantation may induce seizures, and prophylactic antiepileptic treatment is recommended. Following updated guidelines, in August 2019, the adult hematopoietic stem cell transplantation department of the Rambam Health Care Campus (Haifa, Israel) switched the antiepileptic prophylaxis protocol from phenytoin to oral levetiracetam during oral Bu conditioning. The aim of this study was to compare the pharmacokinetic parameters of Bu after oral dosing between patients receiving phenytoin and those receiving levetiracetam prophylaxis. Methods: This study was a retrospective cohort study in adults undergoing myoablative conditioning with oral Bu between August 2018 and August 2020. Bu pharmacokinetic parameters (AUC0-6, C0, Cmax, and Tmax) were compared in patients treated with phenytoin comedication (during the year before the change in policy) and levetiracetam comedication (during the year after the change). Potential confounders were accounted for including age, azole comedication, and body weight. Results: There were no significant differences in demographic and clinical parameters or weight-corrected Bu dose between the phenytoin group (n = 28) and the levetiracetam group (n = 25). There was no difference in the rate of voriconazole comedication, but fluconazole was more common in the phenytoin group (P = 0.026). The median AUC0-6 was significantly lower in the levetiracetam group (949 mM*min; IQR = 806 to 1101 mM*min) than in the phenytoin group (1208 mM*min; IQR = 1087 to 1389 mM*min; P, 0.001). This is a clinically significant difference of 258 mM*min (21%). Azole use was not associated with Bu exposure. Conclusions: The findings suggest that, after treatment with oral Bu, oral levetiracetam comedication is associated with reduced systemic exposure compared with phenytoin comedication, possibly because of decreased bioavailability.
KW - busulfan
KW - drug–drug interaction
KW - hematopoietic stem cell transplant
KW - levetiracetam
KW - therapeutic drug monitoring
UR - http://www.scopus.com/inward/record.url?scp=85130638059&partnerID=8YFLogxK
U2 - 10.1097/FTD.0000000000000938
DO - 10.1097/FTD.0000000000000938
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C2 - 34739424
AN - SCOPUS:85130638059
SN - 0163-4356
VL - 44
SP - 414
EP - 418
JO - Therapeutic Drug Monitoring
JF - Therapeutic Drug Monitoring
IS - 3
ER -