Abstracts

Patients with malignant brain tumors frequently suffer from epileptic seizures as a complication, or often, the presenting sypmtom of the neoplasm. Levetiracetam (LEV) has been shown to have unique efficacy in the treatment of refractory seizures in brain cancer patients. LEV also does not have any clinically significant drug-drug intereaction with chemotherapy agents that may be used as a part of the patient cancer treatment program in either primary or secondary neoplasms. Data from rodents and limited human data have shown rapid central nervous system (CNS) peretration and a prolonged elimination half-time (T[sub]1/2[/sub]) as measured in the cerebrospinal fluid (CSF). We determined the temporal pharmacokincetic serum-CSF relationship in 9 patients with brain neoplasms requiring anti-epileptic treatment. The time to maximum concentration (T[sub]max[/sub]) and the half-life ( T[sub]1/2[/sub]) of LEV was measured concurrently in the serum and CSF in 9 patients after a single oral loading dose of LEV at 500, 750, 1000, 1500 and 2000 mg. CSF levels of LEV were obtained through an Ommaya reservoir which had been previously inserted in each patient to appropriately treat brain cancer. Serum and CSF LEV levels variously were obtained just before oral loading of LEV and after 1/2, 1, 2, 3, 5, 8, 12, 15, 24 and up to 48 hours after oral loading. All samples were stored at -75 [deg] C. The mean T[sub]max [/sub]of LEV in serum was 5.2 hours (range 1-7). The mean T[sub]max[/sub] of LEV in CSF was 7.3 hours (range 3-15) . The mean T[sub]1/2[/sub] of LEV in serum was 13.3 hours (range 4-20). The mean T[sub]1/2 [/sub]of LEV in CSF was 24 hours (range 13-40). Four of the 9 patients received a single dose of 2000 mg of LEV. The mean serum T[sub]max [/sub]for these 4 patients was 7.5 hours (range 7-11) with a mean CSF T[sub]max[/sub] of 9.4 hours (range 5-15) with peak LEV levels of 34.4 and 29.8 ug/ml respectively. The mean T[sub]1/2[/sub] of these 4 patients in serum was 17.6 hours (range 10.5-20) with a mean CSF T[sub]1/2[/sub] of 29.5 hours (range 18-40). There were no side effects at any dose except for transient somnolence in one patient after a 2000 mg loading dose. Peak levels of LEV are achieved rapidly in both the serum and CSF after a single oral loading dose. LEV CSF T [sub]1/2[/sub] is twice as long as that of LEV T [sub]1/2[/sub] in serum. Significant CSF levels may be reached in fewer than 10 hours after a single 2000 mg oral dose. LEV may be orally loaded to obtain rapid serum and CSF levels with good tolerance for patients who may need AED therapy with LEV. The sustained half-life of LEV in the CSF indicates a long central duration of action. (Supported by UCB)