The Effect of Levetiracetam Compared with Enzyme-Inducing Antiseizure Medications on Apixaban and Rivaroxaban Peak Plasma Concentrations.

BACKGROUND AND OBJECTIVE: Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM. METHODS: In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (Cmax) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC Cmax of patients taking LEV were compared with the other two groups. RESULTS: In 203 patients, 55% were female and the mean age was 78 ± 0.8 years. One hundred and eighty-six patients received apixaban and 17 patients received rivaroxaban. The proportion of patients with DOAC Cmax below their therapeutic range was 7.1% in the LEV group, 10.6% in the non-ASM group, and 36.4% in the EI-ASM group (p < 0.001). The odds of having DOAC Cmax below the therapeutic range (compared with control groups) was not significantly different in patients taking LEV (adjusted odds ratio 0.70, 95% confidence interval 0.19-2.67, p = 0.61), but it was 12.7-fold higher in patients taking EI-ASM (p < 0.001). In an analysis in patients treated with apixaban, there was no difference in apixaban Cmax between patients treated with LEV and non-ASM controls, and LEV clinical use was not associated with variability in apixaban Cmax in a multivariate linear regression. CONCLUSIONS: In this study, we show that unlike EI-ASMs, LEV clinical use was not significantly associated with lower apixaban Cmax and was similar to that in patients not treated with any ASM. Our findings suggest that the combination of LEV with apixaban and rivaroxaban may not be associated with decreased apixaban and rivaroxaban Cmax. Therefore, prospective controlled studies are required to examine the possible non-pharmacokinetic mechanism of the effect of the LEV-apixaban or LEV-rivaroxaban combination on patients' outcomes.

Interactions Between Direct Oral Anticoagulants (DOACs) and Antiseizure Medications: Potential Implications on DOAC Treatment.

The use of direct oral anticoagulants (DOACs) is increasing because of their superior efficacy and safety compared with vitamin K antagonists. Pharmacokinetic drug interactions, particularly those involving cytochrome P450- mediated metabolism and P-glycoprotein transport, significantly affect the efficacy and safety of DOACs. In this article, we assess the effects of cytochrome P450- and P-glycoprotein-inducing antiseizure medications on DOAC pharmacokinetics in comparison to rifampicin. Rifampicin decreases to a varying extent the plasma exposure (area under the concentration-time curve) and peak concentration of each DOAC, consistent with its specific absorption and elimination pathways. For apixaban and rivaroxaban, rifampicin had a greater effect on the area under the concentration-time curve than on peak concentration. Therefore, using peak concentration to monitor DOAC concentrations may underestimate the effect of rifampicin on DOAC exposure. Antiseizure medications that are cytochrome P450 and P-glycoprotein inducers are commonly used with DOACs. Several studies have observed a correlation between the concomitant use of DOACs and enzyme-inducing antiseizure medications and DOAC treatment failure, for example, ischemic and thrombotic events. The European Society of Cardiology recommends avoiding this combination, as well as the combination of DOACs with levetiracetam and valproic acid, owing to a risk of low DOAC concentrations. However, levetiracetam and valproic acid are not cytochrome P450 or P-glycoprotein inducers, and the implications of their use with DOACs remain to be elucidated. Our comparative analysis suggests DOAC plasma concentration monitoring as a possible strategy to guide dosing owing to the predictable correlation between DOACs' plasma concentration and effect. Patients taking concomitant enzyme-inducing antiseizure medications are at risk for low DOAC concentrations and subsequently, treatment failure and thus can benefit from DOAC concentration monitoring to prophylactically identify this risk.