Comparison of valproate and levetiracetam for the prevention of busulfan-induced seizures in hematopoietic stem cell transplantation

Nakashima, Toshihisa; Tanaka, Takashi; Koido, Keiichi; Nishibuchi, Yukiko; Hashimoto, H.; Ito, Ayumu; Inamoto, Yoshihiro; Kurosawa, Saiko; Kim, Sung-Won; Fukuda, Takahiro; Terakado, Hiroyuki

doi:10.1007/s12185-019-02637-7

Cited by 8 publications

(14 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, if levetiracetam increased the hepatic clearance of Bu, such an effect would also be expected when Bu is administered intravenously. However, despite the widespread use of the combination of intravenous Bu and levetiracetam, such an interaction has not been reported, 6,8,15,16 although these studies focused primarily on the safety and efficacy of levetiracetam during conditioning rather than Bu PK. In particular, 1 study 15 found no significant difference between the expected and recommended dosages of IV Bu needed to achieve the target AUC with levetiracetam comedication, suggesting that levetiracetam did not have a significant effect on the PK of Bu.…”

Section: Discussionmentioning

confidence: 99%

“…Phenytoin has traditionally been used in adults, but in view of its significant adverse effects and potential drug-drug interactions, 5 it has been increasingly replaced by levetiracetam for antiseizure prophylaxis, with comparable efficacy. [6][7][8] Accordingly, in August 2019, oral levetiracetam became the standard antiepileptic prophylaxis used during Bu-based conditioning in our adult HSCT department. We have since observed an increasing number of patients with delayed Bu absorption and low exposure (measured as area under the Bu concentration over time curve during the 6-hour dosing interval, AUC 0-6 ), requiring substantial increases in Bu doses to reach target exposure.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Decreased Systemic Busulfan Exposure After Oral Dosing With Concomitant Levetiracetam Compared With Phenytoin

Artul

Henig

Nassar

et al. 2022

Therapeutic Drug Monitoring

View full text Add to dashboard Cite

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 (AUC 0-6 , C 0 , C max , and T max ) 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 AUC 0-6 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Decreased Systemic Busulfan Exposure After Oral Dosing With Concomitant Levetiracetam Compared With Phenytoin

Artul

Henig

Nassar

et al. 2022

Therapeutic Drug Monitoring

View full text Add to dashboard Cite

show abstract

“…E.g., Levetiracetam might be a better candidate for primary seizure prevention, though the published studies are not placebo-controlled or randomized. The benefit-risk ratio of newer agents like levetiracetam may be better in these vulnerable patients ( 7 , 14 , 15 ) E.g., levetiracetam has far fewer drug-drug interactions, while showing lesser side effects ( 15 ). However, in our study, we show that only two out of the 96 patients who received no prophylaxis, experienced seizures.…”

Section: Discussionmentioning

confidence: 99%

Phenytoin as seizure prophylaxis in hematopoietic stem cell transplantation with busulfan conditioning

2022

View full text Add to dashboard Cite

BackgroundPhenytoin is widely used as primary seizure prophylaxis in hematopoietic stem cell transplantation in patients undergoing myeloablative conditioning with busulfan. Because of the negative side effects of phenytoin, we abandoned phenytoin use in these patients. To assess the effect of this change, we performed a retrospective cohort study on all patients receiving busulfan.MethodsWe included 139 patients who underwent conditioning with busulfan for hematopoietic stem cell therapy. We registered the use of phenytoin, as well as the occurrence of seizures, until 7 days after busulfan administration. We compared seizure incidence between patients who received phenytoin and those who did not.ResultsOf the 43 patients who received phenytoin prophylaxis, four patients (9.3%) had a seizure during the conditioning regimen, of which two patients had cerebral non-Hodgkin lymphoma. Furthermore, all these 4 patients had very high levels of phenytoin (intoxication). Of the 96 patients that did not receive phenytoin prophylaxis, three patients (3.1%) had a seizure, and one of these patients had an undefined cerebral lesion. Phenytoin did not relate to seizure prevention in a logistic regression analysis.ConclusionWe conclude that phenytoin prophylaxis in patients treated with busulfan is obsolete and possibly harmful, as phenytoin intoxication can occur. We recommend discontinuing the use of phenytoin as primary seizure prophylaxis in these patients.

show abstract

“…Given the facts that phenytoin sodium has the disadvantages of being a strong inducer of cytochrome P450 (CYP) hepatic enzyme, which influences the metabolism of cyclophosphamide in the conditioning schedule of HSCT recipients, together with its narrow therapeutic window and the advent of new antileptic drugs, new research efforts in some SCT centers have shifted to using alternatives as prophylaxis against BIS, such as benzodiazepines, valproate, etc. (16,(21)(22)(23)(24). Levetiracetam stands out because it fulfills many of the properties of an ideal prophylactic agent, for example, it has ∼100% bioavailability, it lacks a significant drug-drug interaction, and can be rapidly loaded to effective doses, what is more, it shares a similar outcome with phenytoin in seizure prevention and overall effects (19,21,22,25).…”

Section: Chemotherapymentioning

confidence: 99%

“…(16,(21)(22)(23)(24). Levetiracetam stands out because it fulfills many of the properties of an ideal prophylactic agent, for example, it has ∼100% bioavailability, it lacks a significant drug-drug interaction, and can be rapidly loaded to effective doses, what is more, it shares a similar outcome with phenytoin in seizure prevention and overall effects (19,21,22,25). Chaguaceda et al (26) have suggested that the optimal dose of oral levetiracetam to prevent BIS in adults seemed to be 1,000 mg every 12 h, starting 12 h before the administration of iv Bu until 48 h after the last dose.…”

Section: Chemotherapymentioning

confidence: 99%

Epileptic Seizures After Allogeneic Hematopoietic Stem Cell Transplantation

2021

View full text Add to dashboard Cite

Technique in allogeneic hematopoietic stem cell transplantation has greatly advanced over the past decades, which has led to an increase in the number of patients receiving transplantation, but the complex procedure places these transplant recipients at high risk of a large spectrum of complications including neurologic involvement. As a common manifestation of neurological disorders, epileptic seizures after transplantation have been of great concern to clinicians because it seriously affects the survival rate and living quality of those recipients. The aim of this review is to elucidate the incidence of seizures after allogeneic hematopoietic stem cell transplantation, and to further summarize in detail its etiologies, possible mechanisms, clinical manifestations, therapeutic schedule, and prognosis, hoping to improve doctors' understandings of concurrent seizures following transplantation, so they can prevent, process, and eventually improve the survival and outlook for patients in a timely manner and correctly.

show abstract

Comparison of valproate and levetiracetam for the prevention of busulfan-induced seizures in hematopoietic stem cell transplantation

Cited by 8 publications

References 44 publications

Decreased Systemic Busulfan Exposure After Oral Dosing With Concomitant Levetiracetam Compared With Phenytoin

Decreased Systemic Busulfan Exposure After Oral Dosing With Concomitant Levetiracetam Compared With Phenytoin

Phenytoin as seizure prophylaxis in hematopoietic stem cell transplantation with busulfan conditioning

Epileptic Seizures After Allogeneic Hematopoietic Stem Cell Transplantation

Contact Info

Product

Resources

About