Pharmacokinetic and Safety Trial of Intravenous Levetiracetam in the Treatment of Neonatal Seizures

In adults, drug clearance is less than half of the glomerular filtration rate and the drug
half-life is 6-8 hours. Renal function in infants at birth is characterized by immature
glomerular filtration and is only 20% that of older children. The specific esterase
responsible for levetiracetam hydrolysis has not been identified and its expression in
newborn infants is unknown. Depending on its activity, the expected infant total
levetiracetam clearance will likely be between 15-45% of older populations. However, due to
immaturity in levetiracetam clearance in infants, accumulation with multiple dosing is
possible. Therefore the maintenance dose is reduced compared to older children according to
the anticipated impaired clearance.

These anticipated differences in levetiracetam clearance and volume of distribution, will
likely result in a prolonged drug half-life of 10-30 hours in infants. This prolonged
elimination will require longer sampling to adequately characterize levetiracetam
pharmacodynamics in this population.

The primary intent of the data analysis is to determine levetiracetam pharmacokinetics in
newborn infants and predict the dosage necessary to maintain concentrations similar to those
seen with effective therapy in other populations. Graphs of serum concentration vs. time will
be plotted for levetiracetam for each infant. Mean serum drug concentration vs. time curves
will also be constructed. Summary statistics (i.e., n, mean, standard deviation, minimum,
maximum, and coefficient of variation) will be calculated for serum concentrations for each
time point and each dose level.

Inclusion Criteria:

- Newborns admitted to the UCSD, Children's Hospital or Sharp Mary Birch NICUs with
seizures.

- Term infants (gestational age greater than or equal to 37 weeks.

- > 2500 grams (max blood for study 6mL =3%).

- Postnatal age < 14 days.

- Serum creatinine less than 1.2 at time of enrollment.

- Received loading dose of phenobarbital 20mg/kg.

- Are still experiencing either clinical or electroencephalographic seizures despite
this therapy.

- For whom parental consent to participate in the study is obtained.

Exclusion Criteria:

- Biochemical abnormality - hypoglycemia, hypocalcemia-that when treated result in
seizure cessation.

- Severe hypoxic ischemic injury likely to result in imminent death

- The only significant exclusions that will be made in recruitment and enrollment will
be the exclusion of infants who are judged by the attending neonatologist to be so
critically ill that death is imminent and benefit from neonatal intensive care is very
unlikely.

- No rule-based criteria, (using lab or clinical parameters) adequately capture the
complete nature of this clinical assessment.

- In general any child receiving active treatment with head cooling will not be
excluded.

- Mechanical ventilation and/or the use of inotropic agents to support blood pressure
will not be exclusion criteria.