Article Text

TOPIRAMATE PHARMACOKINETICS IN THE NEONATES TREATED WITH PROLONGED SYSTEMIC HYPOTHERMIA FOR HYPOXIC ISCHAEMIC ENCEPHALOPATHY
  1. L Filippi1,
  2. P Fiorini1,
  3. G Fontanelli1,
  4. G la Marca2,
  5. S Malvagia2,
  6. F Sacco3,
  7. L Andaloro3,
  8. G Cristofori3,
  9. S Boccacci3,
  10. E Agazzani3,
  11. C Bottura3,
  12. G Cavallaro3
  1. 1Neonatal Intensive Care Unit, A. Meyer University Children's Hospital, Florence, Italy
  2. 2Clinic of Pediatric Neurology, A. Meyer University Children's Hospital, Florence, Italy
  3. 3Neonatal Intensive Care Unit, Carlo Poma Hospital, Mantova, Italy

Abstract

Objective Topiramate reduced cerebral damage in neonatal animal models of hypoxic ischaemic encephalopathy (HIE), and has been suggested as a useful therapy for newborns with perinatal HIE. However, hypothermia may modify drug pharmacokinetics. We investigated the pharmacokinetics of topiramate in neonates with HIE undergoing prolonged systemic hypothermia. Ten newborns (mean gestational age 40.6 weeks, weight 3443 g) with perinatal asphyxia (mean pH 6.88, HCO3- 6.4, BE −19.5) were treated with whole body hypothermia (30–33.5°C) started on average at 3.7 h of age, and maintained for 72 h. All infants were treated with topiramate at the dose of 5 mg/kg orally once a day for the first three days. Phenobarbital (20 mg/kg loading dose followed by 5 mg/kg/day maintenance dose) was administered to four infants.

Methods Topiramate concentrations were measured with liquid chromatography tandem mass spectrometry test in dried blood spot collected in the third day of hypothermia before the third dose of topiramate and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 20 and 24 h thereafter.

Results Mean maximal plasma concentration (Cmax) was 18.14 (±5.1) μg/dL, minimal plasma concentration (Cmin) was 10.86 (±2.9) μg/dL, time of the maximal concentration (Tmax) was 4.0 (±2.2) hours, the area under the time-concentration curve (AUC) was 349.04 (±102.1) μg/h/mL, the apparent total body clearance (CL/F) was 15.7 (±5.8) mL/kg/h.

Conclusions We observed Cmax and AUC very high if compared with dose, Tmax later and CL/F lower than values reported in literature. These data suggest a slower absorption and elimination and validate the decision to administrate topiramate once a day.

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