Drug-drug interactions of lamotrigine with other antiepileptics

Increasingly prescribed for acute treatment and prophylaxis of bipolar depression, lamotrigine will doubtless become a participant in pharmacokinetic drug-drug interactions of patients whose normative polytherapeutic regimens will include three to four other drugs prescribed for psychiatric or medical indications. Disproportionately represented among the latter are antiepileptic drugs, including carbamazepine, valproic acid, and others, such as oxcarbazepine and topiramate, that have been reported to have mood stabilizing activity and/or to ameliorate symptoms of comorbid disorders.

A study published recently by a Croatian group (M. Lovric and colleagues, Croatian Medical Journal 59(1):13-19, 2018) compared bioavailability of lamotrigine in epileptic patients receiving coadministered antiepileptics and in those receiving lamotrigine monotherapy, and in so doing corroborated previously reported pharmacokinetic drug-drug interactivity between lamotrigine and other antiepileptic drugs.

The authors identified 304 adult patients (18- to 70-years-old) with epilepsy who were taking lamotrigine, and retrospectively compared the latter’s steady-state blood concentrations 12 hours after dosing in patients receiving no other medication and in patients taking lamotrigine with valproic acid, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, topiramate, and, in some cases, two of the foregoing (when one had been reported to inhibit and the other, to induce lamotrigine metabolism).

Lamotrigine blood concentrations (corrected or not by dosage) were significantly higher in patients co-treated with valproic acid (600 to 1500 mg/day) than in patients receiving lamotrigine monotherapy. Dose-corrected lamotrigine blood concentrations were significantly lower in lamotrigine-treated patients co-treated with metabolic inducers carbamazepine and oxcarbazepine (the decrement appearing similar in patients receiving highest inducer dosages). Neither topiramate nor phenobarbital affected lamotrigine bioavailability.

Effects of phenytoin coadministration and coadministration of inhibitors with inducers could not be analyzed because of insufficient sample sizes.

The authors’ findings corroborate previous reports of valproate-related inhibition of lamotrigine metabolism and induction of lamotrigine metabolism by carbamazepine and oxcarbazepine (the latter no less robust than induction by carbamazepine). As speculated by the authors of prior reports, the authors attribute the effects of valproate to inhibition of hepatic conjugation (glucuronidation of lamotrigine by UGT 1A4) and those of carbamazepine and oxcarbazepine to increased expression of genes coding for enzymes of hepatic phase I metabolism. Their sample sizes and statistical analysis preclude speculation about whether or to what extent metabolic inhibition or induction of lamotrigine may be related to dosages of inhibitors or inducers.

 

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