Pharmacokinetics and safety of lamotrigine (Lamictal) in patients with epilepsy.

In a double-blind parallel study, patients with epilepsy on stable regimen of antiepileptic drugs (AEDs) were given lamotrigine (8 pts) or placebo (3 pts). Patients were sequentially dosed with 100, 200 and 300 mg/day given as a b.i.d. regimen. After steady state was achieved, timed plasma lamotrigine levels were obtained post dose. No medical, psychogenic, neurologic, or hematologic changes were observed and no subjective effects were detected as a result of treatment with lamotrigine. No changes in heart rhythm or blood pressure were observed related to lamotrigine. Pharmacokinetic parameters were calculated using 1-compartment and non-compartment models. The results were similar using both models. Area under the plasma concentration vs. time curves increased linearly with dose. Mean half life (13.5 h), volume of distribution (1.36 l/kg) and clearance (1.27 ml/min/kg) were similar to previously reported results and did not change with increasing dose. These findings indicate that lamotrigine pharmacokinetics can be described by the 1-compartment model, has linear kinetics, and does not induce its own metabolism in patients on concomitant AEDs.

Long-term tolerability, pharmacokinetic and preliminary efficacy study of lamotrigine in patients with resistant partial seizures.

Four adult men with resistant partial seizures underwent an intensive open-label protocol designed to evaluate long-term add-on lamotrigine (LTG) therapy. Following an 8-week baseline, LTG was added to their background medication(s) (carbamazepine in three; carbamazepine and phenytoin in one). Incremental LTG doses of 50, 100, 150, and 200 mg every 12 h were given on days 58-60, 61-63, 64-127, and 128-176, respectively. The patients were hospitalized during and after each of the dose increases for a total of 25 days. Frequent outpatient visits were performed biweekly, weekly, or monthly, depending on the phase of the protocol. Frequent clinical, electrocardiographic (ECG), and laboratory evaluations were performed. Serial blood levels and 24-h urine collections were performed sequentially. In patients 1, 2, and 3, LTG was well tolerated at 200 mg b.i.d. Patient 4 did not tolerate 150 mg, b.i.d., but tolerated and maintained complete seizure control on 100 b.i.d. All four patients tolerated LTG and continued to receive it for 39, 46, 105, and 104 weeks, respectively. Serial 12-h plasma LTG levels were obtained on days 63, 70, and 133. On these days, the mean (+/- SD) LTG clearances (dose/AUC) were 0.0436 +/- 0.0171, 0.0468 +/- 0.0093, and 0.0575 +/- 0.0160 L/h/kg, respectively. Some 43-87% of the LTG was recovered in the urine, predominantly as the glucuronide metabolite. In the four patients, the mean weekly seizure frequency per patient was 6.5 in baseline, 5.0 on submaximal LTG doses, and 3.5 on the maximum administered doses. Three of the four patients eventually experienced a greater than 50% decrease in seizure frequency. In conclusion, when given for long periods of time (9.5 months to 2 years), LTG was well tolerated in doses up to 400 mg/day and mean trough levels of 3.0 +/- 0.6 microgram/ml; LTG has a favorable pharmacokinetic profile and appears to exhibit first-order linear kinetics during long-term chronic dosing; LTG shows preliminary evidence of efficacy during long-term administration; and to date, our patients represent the longest reported experience of continuous and closely monitored LTG therapy in the literature.

Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, cross-over trial.

The efficacy and safety of lamotrigine (LTG), a new antiepileptic drug (AED), were evaluated in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 98 patients with refractory partial seizures. Each treatment period lasted 14 weeks. Most patients were titrated to a LTG maintenance dose of 400 mg/day. Seizure frequency with LTG decreased by > or = 50%, as compared with placebo, in one fifth of patients. Overall median seizure frequency decreased by 25% with LTG as compared with placebo (p < 0.001). With LTG, the number of seizure days decreased by 18% as compared with placebo (p < 0.01), and investigator global evaluation of overall patient clinical status favored LTG by 2:1 (p = 0.013). Plasma LTG concentrations appeared to be linearly related to dosage. LTG had no clinically important effects on the plasma concentrations of concomitant AEDs. Adverse experiences were generally minor and most frequently were CNS-related (e.g., ataxia, dizziness, diplopia, headache). Most were transient and resolved without discontinuing treatment. Five patients withdrew as a result of adverse experiences while receiving LTG, including 3 patients with rash. One placebo patient was also withdrawn because of rash. The addition of twice-daily LTG to an existing AED regimen was safe, effective, and well tolerated in these medically refractory partial seizure patients.