Abstracts

RATIONALE: Phenytoin (PHT) is a powerful inducer of lamotrigine (LTG) metabolism. Therefore, in refractory epilepsy patients it may be difficult to achieve adequate LTG serum concentrations during adjunctive treatment with PHT. Furthermore, a transient exacerbation of seizures may occur during conversion to monotherapy dependent upon the time course of deinduction of LTG glucuronidation enzymes. Analysis of data from the published active control, conversion to monotherapy trial suggested that LTG serum concentrations doubled following withdrawal of PHT. Furthermore, LTG serum concentrations did not increase until PHT was completely stopped. Interpretation of this study is potentially limited by the rapid withdrawal of PHT in weekly decrements of 20%, as a week may be insufficient for deinduction of hepatic enzymes to reach [dsquote]steady-state[dsquote]. Our objective is to reinvestigate the pharmacokinetics of LTG deinduction using three-week intervals between PHT decrements.
METHODS: Patients treated with PHT with either incomplete control or unacceptable side effects were recruited for conversion to LTG monotherapy. Four patients have thus far completed with three patients currently enrolled and a total of 10 patients anticipated. Lamotrigine was titrated to 400 to 500 mg total daily dose over three months. PHT was then withdrawn every three weeks in decrements of one-third the initial dose. Serum concentrations were measured weekly for ten weeks. Blood draws occurred on the same day of the week and at the same time of day. PHT dose reductions were scheduled to occur immediately after a blood draw. Patients did not alter other medications during the protocol: two patients were on no other medications, one patient was on nifedipine, and one on conjugated estrogen, aspirin, paroxetine, 1mg lorazepam per day, vitamin D, and calcitonin nasal spray. PHT was measured at our institution using the CEDIA Phenytoin II (ROCHE) immunoassay. LTG was measured at ARUP Laboratories by HPLC.
RESULTS: Four of four patients have thus far been successfully converted to monotherapy. Baseline serum concentrations of LTG ranged from 3.6 to 4.3 mcg/ml, attained on 400 mg total daily dose, with PHT serum concentrations ranging from 8.7 to 27.0 mcg/ml. Decrease in PHT doses up to 67 % did not impact on LTG serum concentrations. At that time PHT serum concentrations averaged 2.4 mcg/ml (range 2.2 to 2.7mcg/ml). One, two, and three weeks after PHT cessation, LTG serum concentration had increased 57, 68, and 80%, respectively.
CONCLUSIONS: LTG serum concentrations increase 70-80% following withdrawal of PHT. The increase does not occur until PHT dosing is completely stopped. The increase then occurs quite quickly with the majority occurring within the first week of complete PHT withdrawal. Complete deinduction of glucuronidation appears to require two to three weeks though our current small sample size limits complete accuracy of the time course. Highly refractory epilepsy patients may require special efforts at seizure prophylaxis during taper from PHT and for several weeks thereafter.
[Supported by: Investigator Initiated award from Glaxo-Smith-Kline.]; (Disclosure: Grant - Glaxo-Smith-Kline, Consulting - Glaxo-Smith-Kline, Honoraria - Glaxo-Smith-Kline)