Is brivaracetam-induced elevation of carbamazepine-epoxide levels common and clinically relevant? — A case series

Steinhoff, Bernhard J.; Bacher, Matthias; Blickhan, Marko; Bernedo, Viviane; Dietmann, Daniel; Intravooth, Tassanai; Kornmeier, Reinhold; Kurth, Christoph; Mahn, Patricia; Schneider, Matthias; Stockinger, Jakob; Staack, Anke M.

doi:10.1016/j.eplepsyres.2019.106236

Cited by 5 publications

(3 citation statements)

References 14 publications

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“…Carbamazepine and oxcarbazepine are metabolized differently by the cytochrome P450 system to their primary active metabolites (carbamazepine-10,11-epoxide for carbamazepine and 10monohydroxy derivative carbazepine); [29,30]). The link between carbamazepine use and discontinuation of BRV could relate to the adverse neurological effects associated with carbamazepine-10,11-epoxide [31].…”

Section: Discussionmentioning

confidence: 99%

Retention of brivaracetam in adults with drug-resistant epilepsy at a single tertiary care center

Green

Hare²,

Kassam³

et al. 2022

Epilepsy & Behavior

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Section: Discussionmentioning

confidence: 99%

Retention of brivaracetam in adults with drug-resistant epilepsy at a single tertiary care center

Green

Hare²,

Kassam³

et al. 2022

Epilepsy & Behavior

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“…When compared with EPHX1 ‐416G/A and ‐416A/A genotype subjects, their clearance of CBZE was reduced by approximately 50%. CBZE retains anticonvulsant activity but elevated plasma levels, secondary to concurrent brivaracetam therapy, have been associated with reduced tolerability to CBZ treatment and an increase in adverse events such as blurred vision, dizziness and fatigue 60 . Brivaracetam inhibits microsomal epoxide hydrolase and led to a rise in CBZE levels by a median of 83.9% (range 57.9–341.7%), which highlights that a 50% reduction in clearance that has been associated with EPHX ‐416G/G genotype may also be clinically relevant.…”

Section: Discussionmentioning

confidence: 99%

“…6 The with reduced tolerability to CBZ treatment and an increase in adverse events such as blurred vision, dizziness and fatigue. 60 Brivaracetam inhibits microsomal epoxide hydrolase and led to a rise in CBZE levels by a median of 83.9% (range 57.9-341.7%), which highlights that a 50% reduction in clearance that has been associated with EPHX -416G/G genotype may also be clinically relevant. One previous investigation reported that patients with the EPHX c.416A > G SNP had higher adjusted plasma CBZ levels 30 whilst another identified lower adjusted levels of DiOH-CBZ 27 in patients receiving CBZ.…”

Section: Base Model and Covariate Fittingmentioning

confidence: 96%

Evaluation of clinical and genetic factors in the population pharmacokinetics of carbamazepine

Yip

Pertinez

Meng

et al. 2020

Brit J Clinical Pharma

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Carbamazepine can cause hypersensitivity reactions in ~10% of patients. An immunogenic effect can be produced by the electrophilic 10,11-epoxide metabolite but not by carbamazepine. Hypothetically, certain SNPs might increase the formation of immunogenic metabolites, leading ultimately to hypersensitivity reactions. This study explores the role of clinical and genetic factors in the pharmacokinetics of carbamazepine and three metabolites known to be chemically reactive or formed through reactive intermediates. Methods: A combination of rich and sparse PK samples were collected from healthy volunteers and epilepsy patients. All subjects were genotyped for 20 SNPs in 11 genes known to be involved in the metabolism or transport of carbamazepine and carbamazepine 10,11-epoxide. Nonlinear mixed effects modelling was used to build a population-PK model. Results: In total 248 observations were collected from 80 subjects. A one-compartment PK model with first-order absorption and elimination best described the parent carbamazepine data, with a total CL of 1.96 L/h, central Vd of 164 L and ka of 0.45 h-1. Total daily dose and co-administration of phenytoin were significant covariates for total clearance of carbamazepine. EPHX1-416G/G genotype was a significant covariate for the clearance of carbamazepine 10,11-epoxide. Conclusion: Our data indicate that carbamazepine clearance was affected by total dose and phenytoin co-administration, but not by genetic factors, while carbamazepine 10,11-epoxide clearance was affected by a variant in the microsomal epoxide hydrolase gene. A much larger sample size would be required to fully evaluate the role of genetic variation in carbamazepine pharmacokinetics, and thereby predisposition to carbamazepine hypersensitivity.

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Brivaracetam/carbamazepine interaction

2021

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Is brivaracetam-induced elevation of carbamazepine-epoxide levels common and clinically relevant? — A case series

Cited by 5 publications

References 14 publications

Retention of brivaracetam in adults with drug-resistant epilepsy at a single tertiary care center

Retention of brivaracetam in adults with drug-resistant epilepsy at a single tertiary care center

Evaluation of clinical and genetic factors in the population pharmacokinetics of carbamazepine

Brivaracetam/carbamazepine interaction

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