The pharmacokinetics of lamotrigine, a new anticonvulsant, were studied in three studies in normal volunteers. In the first study, five subjects received oral doses of lamotrigine up to 240 mg. A linear relationship was observed between dose administration and both peak drug concentration and AUC. In a second study 10 subjects received 120 mg lamotrigine and the mean (+/- SD) of the elimination half-life (t1/2) was 24.1 +/- 5.7 hours and of volume of distribution/bioavailability 1.2 +/- 0.12 L/kg. Saliva concentrations were 46% of the plasma concentration. Total urinary recovery of drug over 144 hours was 70.5% of the oral dose. A glucuronide conjugate accounted for 89.4% of the urinary recovery. In a third study the kinetics of repeated administration were studied. Fifteen subjects were randomized to lamotrigine (n = 10) or placebo (n = 5) and received multiple doses over 7 days. The overall plasma elimination t1/2 calculated from data during the 7 days was 25.5 +/- 10.2 hours. Observed pharmacokinetics on multiple administration obeyed closely those predicted from the single-dose experiment, suggesting the absence of autoinduction of metabolism. No clinically important side effects or changes in central nervous system or cardiovascular system variables, hematology, biochemistry, or urinalysis occurred during the 7 days.

Sixteen epileptic patients took single doses of lamotrigine, 120 mg or 240 mg. Six photosensitive patients showed reduction (with abolition in two) in photosensitivity after lamotrigine administration. Five subjects with frequent interictal spikes showed reduction in spike frequency over 24 h after lamotrigine administration. The half-life (t1/2) of lamotrigine in subjects taking sodium valproate was prolonged, whereas the t1/2 in subjects taking carbamazepine and/or phenytoin was reduced. The area under the curve of co-medication plasma levels was not affected by a single dose of lamotrigine. Five patients reported mild and generally transitory side effects; some of which represented exacerbation of preexisting complaints.

The antiepileptic effect of lamotrigine (LTG) was assessed in a double-blind, placebo-controlled crossover trial in 24 adult patients with refractory partial seizures. LTG or placebo was added to existing antiepileptic drugs (AEDs). The dose of LTG varied from 75 to 400 mg daily. Three patients did not complete the trial. One was withdrawn from the trial with ataxia, tiredness, dyspnea, and diplopia while receiving LTG and died 18 days later of invasive carcinoma involving the liver. A second patient was withdrawn during baseline for contravening admission criteria, and a third received LTG in error during both treatment periods. Twenty-one patients (12 men and 9 women) completed the trial. An analysis of seizure counts in the 12-week treatment period with LTG showed a statistically significant reduction in seizures as compared with placebo for total seizures (p less than 0.002), partial seizures (p less than 0.002), and secondarily generalized seizures (p less than 0.05). The analysis of total seizure days showed a significant reduction during LTG treatment (p less than 0.002). There were no statistically significant changes in plasma concentrations of phenytoin (PHT), carbamazepine (CBZ), primidone (PRM), or phenobarbital (PB) between the two treatment periods. The most common adverse events reported during the trial were diplopia, drowsiness, tiredness, ataxia, and headache, but although these were more frequent during LTG treatment, the differences from placebo were not statistically significant. No hematological or biochemical changes were noted.

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