Results of phase II pharmacokinetic study of levetiracetam for prevention of post‐traumatic epilepsy

Abstract

Levetiracetam (LEV) has anti-epileptogenic effects in animals and is a candidate for prevention of epilepsy after traumatic brain injury. Pharmacokinetics of LEV in TBI patients are unknown. We report pharmacokinetics of TBI subjects ≥6 years with high PTE risk treated with LEV 55 mg/kg/day orally, nasogastrically or intravenously for 30 days starting ≤8 hours after injury in a phase 2 safety and pharmacokinetic study. 41 subjects (26 adults, 15 children) were randomized to PK studies on treatment days 3 and 30. 36/41 randomized subjects underwent PK study on treatment day 3, and 24/41 subjects on day 30. On day 3, mean Tmax was 2.2 hours, Cmax 60.2 μg/ml and AUC 403.7 h*/μg/ml. Tmax was longer in the elderly than in children and non-elderly adults (5.96 h vs. 1.5 h and 1.8 h, p=0.0001). AUC was non-significantly lower in children compared with adults and the elderly (317.4 h*/μg/ml vs. 461.4 and 450.2, p=0.08). Cmax trended higher in i.v.- versus tablet- or n.g.-treated subjects (78.4 μg/ml vs. 59 and 48.2, p=0.07). AUC for n.g. and i.v. administrations were 79% and 88% of oral administration. There were no significant PK differences between days 3 and 30. Treatment of TBI patients with high PTE risk with 55 mg/kg/day LEV, a dose with antiepileptogenic effect in animals, results in plasma LEV levels comparable to those in animal studies.

Levetiracetam Use in the Critical Care Setting

“…In ICU patients who have received LEV for seizure prophylaxis (500 mg every 12 h) the clearance of LEV was faster when compared to the similar values obtain in healthy controls and patients in status epilepticus (SE); Monte Carlo simulation determined the most optimal LEV doses in these patients to achieve appropriate serum concentration should be either 1,000 mg every 8 h or 1,500–2,000 mg every 12 h (5). In patients with or without preexisting epilepsy who presented with SE and who were taking between none and several concomitant AEDs the pharmacokinetic data of IV infusion were comparable to the previously published values derived from healthy volunteers (6) while doses of IV LEV that were antiepileptogenic in animal models of epilepsy (55 mg/kg/day) administered to patients with traumatic brain injury (TBI) resulted in comparable pharmacokinetics (PK) in children, adults, and elderly with similar results observed between days 3 and 30 of treatment (delay in T max in elderly was observed but this was of unclear clinical significance) (7). One study in patients with subarachnoid hemorrhage (SAH) compared the plasma concentrations of LEV while receiving IV or parenteral forms for seizure prevention – when switched to parenteral form the levels decreased to 70% of the IV levels but complications in response to this change were not observed (8).…”

“…For example, Uges et al analyzed safety and PK of IV infusion of LEV in patients with SE ages 44–75 years of age (median 60 years) to show PK values in the studied group similar to norms obtained from healthy (and younger) volunteers (6). Another study by Klein et al showed that T max was longer in subjects older than 65 years of age when compared to children and young adults at the initiation of the therapy and at 30 days (7). In the elderly LEV appears to be safe and associated with a relatively low level of adverse events.…”

“…While the IV formulation is reported to be bioequivalent to the oral formulation and doses should be interchangeable some differences in bioavailability between the IV and parenteral doses have been reported (8). There are also some age-related differences in PK (7) but it is unclear whether these differences are of clinical significance. In one study, Wheless et al assessed rapid infusion (over 5–6 min) of 20, 40, and 60 mg/kg ( N  = 15 per group) of IV LEV in children and adults (4–32 years of age).…”

Anticonvulsant Efficacy in Sturge-Weber Syndrome

“…5 Intractable or prolonged seizures are associated with worse cognitive impairment and neurological injury. 6–9 …”

Role of Intravenous Levetiracetam in Seizure Prophylaxis of Severe Traumatic Brain Injury Patients

“…Between days 3 and 30, the PKs are not significantly different. The authors conclude that TBI study subjects with a high PTS risk are treated with the same dose with antiepileptogenic effect in animals (55 mg/kg/day) achieve plasma LEV levels comparable to those in animal studies (24). …”