Effect of antiepileptic drug comedication on lamotrigine concentrations

Abstract

Aim To estimate the effect size of concomitant antiepileptic therapy on the concentrations of lamotrigine, a drug often prescribed in combination with other antiepileptic drugs (AED), which can act as enzyme inducers or inhibitors. Methods A total of 304 patients with epilepsy, aged 18-70 years, were divided into a lamotrigine monotherapy group and groups receiving lamotrigine with AEDs that act as enzyme inducers, enzyme inhibitors, or both. We compared lamotrigine monotherapy serum concentrations with those where lamotrigine was administered with a metabolic inhibitor valproate, metabolic inducers carbamazepine, oxcarbazepine, phenobarbital, phenytoin, or topiramate, and both an inducer and an inhibitor. Results Comparison of trough lamotrigine monotherapy concentrations and lamotrigine polytherapy concentrations showed an almost similar median concentration in case of drug-inducers, and higher lamotrigine concentration in case of comedication with valproate as an inhibitor. A significant difference was confirmed after dose correction ( P < 0.001). Significant positive correlations of lamotrigine trough serum concentrations with valproate were observed before and after the dose correction (r = 0.480, P < 0.001 and r = 0.561, P < 0.001, respectively). Positive correlations between the dose-corrected lamotrigine trough concentration and carbamazepine (r = 0.439; P < 0.001) or monohydroxy metabolite of oxcarbazepine (MHD) (r = 0.675; P < 0.001) were also significant. Conclusion Higher valproate levels resulted in higher inhibition potency and higher lamotrigine levels. Increased dose-corrected concentrations of inducers carbamazepine and MHD, after the process of induction was finished, did not lower lamotrigine concentrations. These findings can be of clinical significance for optimal AED dosing.

Adverse Event Profiles of Antiseizure Medications and the Impact of Coadministration on Drug Tolerability in Adults with Epilepsy

“…This assumption is confirmed by the significantly higher correlation between LAEP and clinical presentation of relevant depressive symptoms (NDDI-E and HADS) compared with the correlation between LAEP and antidepressant use based on Fisher’s z -transformation. In contrast with other studies on this topic that report relevant interactions in up to 30% of cases [ 17 , 18 , 64 ], there were no indications of a relevant potentiation of the AE spectrum or the tolerability of ASMs by CDs detected in this study, which is partly attributable to the limited number of participants and other methodological aspects in the present study. Incompatible drug combinations can lead to relevant interactions, even when drugs are taken for only a short time, as described most recently in the context of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic for combinations of antivirals and ASMs [ 65 , 66 ].…”

Lamotrigine‐induced neutropenia after high‐dose concomitant initiation with phenytoin

“…Since lamotrigine was initially intended as adjunctive therapy, pharmacokinetic studies, upon which dosing recommendations were based, have only evaluated its concentrations when added to chronic EIAEDs 29,30 . In a recent study, lamotrigine concentrations were measured twenty‐one days after its addition to EIAEDs 31 …”

“… 29 , 30 In a recent study, lamotrigine concentrations were measured twenty‐one days after its addition to EIAEDs. 31 The few days apart, commencement sequence or adding an inducer to chronic lamotrigine was not studied sufficiently to suggest an initial dosing schedule based on the expected interaction time course. Unlike cytochromes P‐450 enzymes, studies are lacking for UGT primary substrates induction time course.…”

Analysis of the clinical characteristics of lamotrigine‐induced haemophagocytic lymphohistiocytosis

“…Seven patients had concomitant medications that might alter the concentration of lamotrigine, including valproic acid, primidone, phenytoin and phenobarbital. [16][17][18][20][21][22] Val proate can double lamotrigine plasma levels 30 ; primidone, phenytoin and phenobarbital may induce the metabolism of lamotrigine, which may result in a 40% decrease in the lamotrigine concentration. 22 However, these drug-drug interactions were considered to be less likely to contribute to the development of HLH because these drugs can both increase and decrease the concentration of lamotrigine.…”