Decreased Systemic Busulfan Exposure After Oral Dosing With Concomitant Levetiracetam Compared With Phenytoin.
Journal
Therapeutic drug monitoring
ISSN: 1536-3694
Titre abrégé: Ther Drug Monit
Pays: United States
ID NLM: 7909660
Informations de publication
Date de publication:
01 06 2022
01 06 2022
Historique:
received:
23
08
2021
accepted:
11
10
2021
pubmed:
6
11
2021
medline:
18
5
2022
entrez:
5
11
2021
Statut:
ppublish
Résumé
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. 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. 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 μM*min; IQR = 806 to 1101 μM*min) than in the phenytoin group (1208 μM*min; IQR = 1087 to 1389 μM*min; P < 0.001). This is a clinically significant difference of 258 μM*min (21%). Azole use was not associated with Bu exposure. 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.
Sections du résumé
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 μM*min; IQR = 806 to 1101 μM*min) than in the phenytoin group (1208 μM*min; IQR = 1087 to 1389 μM*min; P < 0.001). This is a clinically significant difference of 258 μM*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.
Identifiants
pubmed: 34739424
doi: 10.1097/FTD.0000000000000938
pii: 00007691-202206000-00010
doi:
Substances chimiques
Anticonvulsants
0
Levetiracetam
44YRR34555
Phenytoin
6158TKW0C5
Busulfan
G1LN9045DK
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
414-418Informations de copyright
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
Références
Ruutu T, van der Werf S, van Biezen A, et al. Use of busulfan in conditioning for allogeneic hematopoietic stem cell transplantation in adults: a survey by the Transplant Complications Working Party of the EBMT. Bone Marrow Transpl. 2019;54:2013–2019.
Palmer J, McCune JS, Perales MA, et al. Personalizing Busulfan-based conditioning: considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transpl. 2016;22:1915–1925.
Lombardi LR, Kanakry CG, Zahurak M, et al. Therapeutic drug monitoring for either oral or intravenous busulfan when combined with pre- and post-transplantation cyclophosphamide. Leuk Lymphoma. 2016;57:666–675.
Marcus RE, Goldman J. Convulsions due to high-dose busulfan. Lancet. 1984;324:1463.
Eberly AL, Anderson GD, Bubalo JS, et al. Optimal prevention of seizures induced by high-dose busulfan. Pharmacotherapy. 2008;28:1502–1510.
Akiyama K, Kume T, Fukaya M, et al. Comparison of levetiracetam with phenytoin for the prevention of intravenous busulfan-induced seizures in hematopoietic cell transplantation recipients. Cancer Chemother Pharmacol. 2018;82:717–721.
Chaguaceda C, Aguilera-Jiménez V, Gutierrez G, et al. Oral levetiracetam for prevention of busulfan-induced seizures in adult hematopoietic cell transplant. Int J Clin Pharm. 2020;42:351–354.
Nakashima T, Tanaka T, Koido K, et al. Comparison of valproate and levetiracetam for the prevention of busulfan-induced seizures in hematopoietic stem cell transplantation. Int J Hematol. 2019;109:694–699.
Hassan M, Ehrsson H. Gas chromatographic determination of busulfan in plasma with electron-capture detection. J Chromatogr. 1983;277:374–380.
R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: Foundation for Statistical Computing; 2020. Available at: https://www.R-project.org/ .
Wickham H. Ggplot2: Elegant Graphics for Data Analysis . New York, NY Springer; 2016.
Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet. 2004;43:707–724.
Wright C, Downing J, Mungall D, et al. Clinical pharmacology and pharmacokinetics of levetiracetam. Front Neurol. 2013;4:192.
Myers AL, Kawedia JD, Champlin RE, et al. Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review. Expert Opin Drug Metab Toxicol. 2017;13:901–923.
Tsujimoto SI, Shirai R, Utano T, et al. Comparison of clonazepam and levetiracetam in children for prevention of busulfan-induced seizure in hematopoietic stem cell transplantation. Int J Hematol. 2020;111:463–466.
Soni S, Skeens M, Termuhlen AM, et al. Levetiracetam for busulfan-induced seizure prophylaxis in children undergoing hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2012;59:762–764.
Salem HA, Al-Shorbagy MY. Evaluation of the relaxant effect of levetiracetam on isolated rat duodenum. Fundam Clin Pharmacol. 2017;31:75–82.
Hassan M, Oberg G, Björkholm M, et al. Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics. Cancer Chemother Pharmacol. 1993;33:181–186.
Aggarwal C, Gupta S, Vaughan WP, et al. Improved outcomes in intermediate- and high-risk aggressive non-Hodgkin lymphoma after autologous hematopoietic stem cell transplantation substituting intravenous for oral busulfan in a busulfan, cyclophosphamide, and etoposide preparative regimen. Biol Blood Marrow Transpl. 2006;12:770–777.
Madden T, de Lima M, Thapar N, et al. Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule. Biol Blood Marrow Transpl. 2007;13:56–64.
Nguyen L, Leger F, Lennon S, et al. Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study. Cancer Chemother Pharmacol. 2006;57:191–198.
Buggia I, Zecca M, Alessandrino EP, et al. Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation. GITMO (Gruppo Italiano Trapianto di Midollo Osseo). Anticancer Res. 1996;16:2083–2088.
El-Serafi I, Terelius Y, Abedi-Valugerdi M, et al. Flavin-containing monooxygenase 3 (FMO3) role in busulphan metabolic pathway. Passi AG, ed. PLoS One. 2017;12:e0187294.
Zwaveling J, Bredius RG, Cremers SC, et al. Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity. Bone Marrow Transpl. 2005;35:17–23.