Population pharmacokinetics of levetiracetam and dosing recommendation in children with epilepsy.
OBJECTIVE
To develop a population pharmacokinetic model to evaluate the demographic and physiologic determinants of levetiracetam (LEV) pharmacokinetics (PK) and to suggest recommended doses of LEV in children.


METHODS
LEV PK were investigated in a prospective open trial of LEV as adjunctive therapy using a population approach performed with NONMEM (Nonlinear Mixed Effects Model) on 170 LEV concentration-time records and covariate information from 44 children between 4 and 16 years of age. Possible associations between pharmacokinetic parameters and age, gender, body weight, creatinine clearance, and concomitant antiepileptic drugs (AEDs) were assessed. The final model was used to perform Monte Carlo simulations in order to identify the dosing regimens that should achieve the same nominal target concentration range as in adults.


RESULTS
LEV PK were well described by a one-compartment model with first-order absorption and elimination. Both LEV apparent clearance and distribution volume were related to body weight, and no pharmacokinetic interaction was observed. Monte Carlo simulations showed that a 10mg/kg twice daily (b.i.d.) regimen provides a plasma concentration similar to that obtained in adults for the recommended 500 mg b.i.d. starting dose, and that a 20 mg/kg b.i.d. regimen would achieve the previously described 6-20 mg/L target range for the trough concentration.


CONCLUSIONS
Our results support the use of a weight-based LEV dosing regimen and provide a basis for a recommended pediatric dosage regimen. The relationship between LEV plasma concentrations and clinical effect has not been evaluated fully and could differ between adults and children. Clinical studies should be able to validate these dosing recommendations.
Chhun
Stephanie
S
Université Paris Descartes, AP-HP, Service de pharmacologie clinique, Groupe hospitalier Cochin-Saint Vincent de Paul, Paris, France. stephanie.chhun@svp.aphp.fr
Jullien
Vincent
V
Rey
Elisabeth
E
Dulac
Olivier
O
Chiron
Catherine
C
Pons
Gérard
G
D000293:Adolescent; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008954:Models, Biological; D010889:Piracetam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011153:Population; D011446:Prospective Studies; D012016:Reference Values; D015203:Reproducibility of Results; D013997:Time Factors
D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam