Use of intravenous valproate in three pediatric patients with nonconvulsive or convulsive status epilepticus.
OBJECTIVE
To report the pharmacokinetics of intravenous valproate (VPA) in children with generalized convulsive status epilepticus (GCSE) or nonconvulsive status epilepticus (NCSE). To provide loading and maintenance dosing for patients with hepatic induction secondary to concurrent anticonvulsants.


METHODS
Two patients (10 y, 34 mo) with GCSE refractory to benzodiazepines, phenobarbital, phenytoin, and pentobarbital received intravenous VPA. Apparent volume of distribution (Vd) following a 20 mg/kg loading dose was 0.29 L/kg. Maintenance infusions of 4-6 mg/kg/h produced steady-state total concentrations of 66 mg/L and 92.4 mg/L (unbound concentration 44.6 mg/L). Clearance ranged from 63-66 mL/h/kg. An eight-year-old with NCSE received intravenous VPA (13.4 mg/kg load followed by 9 mg/kg every 8 h). Total and unbound steady-state VPA concentrations were 32.9 mg/L and 21.2 mg/L, respectively. Elimination half-life was eight hours.


CONCLUSIONS
We constructed a pharmacokinetic simulation using VPA parameters from children receiving mono- or polyanticonvulsants. Our Vd and elimination half-life rates were comparable with published pediatric values. Patients on hepatic inducers had clearance rates 2.5 times those of children receiving oral anticonvulsant polytherapy. Unbound fractions (48.3% and 66%) were significantly higher than normal.


CONCLUSIONS
A 20 mg/kg loading dose should produce a concentration after the bolus dose of approximately 75 mg/L. Initial infusion should consider hepatic induction (noninduced = 1 mg/kg/h, polyanticonvulsant therapy = 2 mg/kg/h, and high-dose pentobarbital = 4 mg/kg/h). Adjustments should be based on response and serum concentrations.
Hovinga
C A
CA
Pediatric Pharmacotherapy, The University of Tennessee, Memphis 38163, USA.
Chicella
M F
MF
Rose
D F
DF
Eades
S K
SK
Dalton
J T
JT
Phelps
S J
SJ
D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010424:Pentobarbital / Q000493:pharmacokinetics; D012640:Seizures / Q000188:drug therapy*; D013226:Status Epilepticus / Q000188:drug therapy*; D014635:Valproic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D014635:Valproic Acid; D010424:Pentobarbital