Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hypoxic ischemic encephalopathy

Luca Filippi, Giancarlo La Marca, Patrizio Fiorini, Chiara Poggi, Giacomo Cavallaro, Sabrina Malvagia, Domenico E. Pellegrini-Giampietro, Renzo Guerrini

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Purpose: Therapeutic hypothermia reduces mortality and neurologic impairment in neonates with hypoxic-ischemic encephalopathy. Topiramate exerts a neuroprotective effect in asphyxiated neonatal animal models. However, no studies have investigated the association of hypothermia and topiramate, because topiramate pharmacokinetics during hypothermia and the optimal administration schedule are unknown. The influence of hypothermia on topiramate pharmacokinetics was evaluated in asphyxiated neonates treated with prolonged whole-body hypothermia and topiramate. Methods: Thirteen term newborns were treated with mild or deep whole body hypothermia for 72 h; all received oral topiramate, 5 mg/kg once a day for the first 3 days of life, and seven had concomitant phenobarbital treatment. Topiramate concentrations were measured on serial dried blood spots. Results: Topiramate concentrations were within the reference range in 11 of 13 newborns, whereas concentrations exceeded the upper limit in 2 of 13, both newborns on deep hypothermia. Topiramate concentrations reached a virtual steady state in nine newborns, for whom pharmacokinetic parameters were calculated. Values of topiramate maximal and minimal concentration, half-life, average concentration, and area under the time - concentration curve resulted in considerably higher values than those reported in normothermic infants. With respect to normothermic infants, time of maximal concentration was mildly delayed and apparent total body clearance was lower, suggesting slower absorption and elimination. Pharmacokinetic parameters did not differ significantly between infants on deep versus mild hypothermia and in those on topiramate monotherapy versus add-on phenobarbital. Conclusion: Most neonates on prolonged hypothermia treated with topiramate 5 mg/kg once a day exhibited drug concentrations within the reference range for the entire treatment duration.

Original languageEnglish
Pages (from-to)2355-2361
Number of pages7
JournalEpilepsia
Volume50
Issue number11
DOIs
Publication statusPublished - Nov 2009

Fingerprint

Brain Hypoxia-Ischemia
Hypothermia
Newborn Infant
Pharmacokinetics
Phenobarbital
topiramate
Reference Values
Newborn Animals
Induced Hypothermia
Neuroprotective Agents
Nervous System
Half-Life
Appointments and Schedules

Keywords

  • Asphyxia
  • Neuroprotection
  • Newborn
  • Pharmacokinetics

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hypoxic ischemic encephalopathy. / Filippi, Luca; La Marca, Giancarlo; Fiorini, Patrizio; Poggi, Chiara; Cavallaro, Giacomo; Malvagia, Sabrina; Pellegrini-Giampietro, Domenico E.; Guerrini, Renzo.

In: Epilepsia, Vol. 50, No. 11, 11.2009, p. 2355-2361.

Research output: Contribution to journalArticle

Filippi, Luca ; La Marca, Giancarlo ; Fiorini, Patrizio ; Poggi, Chiara ; Cavallaro, Giacomo ; Malvagia, Sabrina ; Pellegrini-Giampietro, Domenico E. ; Guerrini, Renzo. / Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hypoxic ischemic encephalopathy. In: Epilepsia. 2009 ; Vol. 50, No. 11. pp. 2355-2361.
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AU - Filippi, Luca

AU - La Marca, Giancarlo

AU - Fiorini, Patrizio

AU - Poggi, Chiara

AU - Cavallaro, Giacomo

AU - Malvagia, Sabrina

AU - Pellegrini-Giampietro, Domenico E.

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N2 - Purpose: Therapeutic hypothermia reduces mortality and neurologic impairment in neonates with hypoxic-ischemic encephalopathy. Topiramate exerts a neuroprotective effect in asphyxiated neonatal animal models. However, no studies have investigated the association of hypothermia and topiramate, because topiramate pharmacokinetics during hypothermia and the optimal administration schedule are unknown. The influence of hypothermia on topiramate pharmacokinetics was evaluated in asphyxiated neonates treated with prolonged whole-body hypothermia and topiramate. Methods: Thirteen term newborns were treated with mild or deep whole body hypothermia for 72 h; all received oral topiramate, 5 mg/kg once a day for the first 3 days of life, and seven had concomitant phenobarbital treatment. Topiramate concentrations were measured on serial dried blood spots. Results: Topiramate concentrations were within the reference range in 11 of 13 newborns, whereas concentrations exceeded the upper limit in 2 of 13, both newborns on deep hypothermia. Topiramate concentrations reached a virtual steady state in nine newborns, for whom pharmacokinetic parameters were calculated. Values of topiramate maximal and minimal concentration, half-life, average concentration, and area under the time - concentration curve resulted in considerably higher values than those reported in normothermic infants. With respect to normothermic infants, time of maximal concentration was mildly delayed and apparent total body clearance was lower, suggesting slower absorption and elimination. Pharmacokinetic parameters did not differ significantly between infants on deep versus mild hypothermia and in those on topiramate monotherapy versus add-on phenobarbital. Conclusion: Most neonates on prolonged hypothermia treated with topiramate 5 mg/kg once a day exhibited drug concentrations within the reference range for the entire treatment duration.

AB - Purpose: Therapeutic hypothermia reduces mortality and neurologic impairment in neonates with hypoxic-ischemic encephalopathy. Topiramate exerts a neuroprotective effect in asphyxiated neonatal animal models. However, no studies have investigated the association of hypothermia and topiramate, because topiramate pharmacokinetics during hypothermia and the optimal administration schedule are unknown. The influence of hypothermia on topiramate pharmacokinetics was evaluated in asphyxiated neonates treated with prolonged whole-body hypothermia and topiramate. Methods: Thirteen term newborns were treated with mild or deep whole body hypothermia for 72 h; all received oral topiramate, 5 mg/kg once a day for the first 3 days of life, and seven had concomitant phenobarbital treatment. Topiramate concentrations were measured on serial dried blood spots. Results: Topiramate concentrations were within the reference range in 11 of 13 newborns, whereas concentrations exceeded the upper limit in 2 of 13, both newborns on deep hypothermia. Topiramate concentrations reached a virtual steady state in nine newborns, for whom pharmacokinetic parameters were calculated. Values of topiramate maximal and minimal concentration, half-life, average concentration, and area under the time - concentration curve resulted in considerably higher values than those reported in normothermic infants. With respect to normothermic infants, time of maximal concentration was mildly delayed and apparent total body clearance was lower, suggesting slower absorption and elimination. Pharmacokinetic parameters did not differ significantly between infants on deep versus mild hypothermia and in those on topiramate monotherapy versus add-on phenobarbital. Conclusion: Most neonates on prolonged hypothermia treated with topiramate 5 mg/kg once a day exhibited drug concentrations within the reference range for the entire treatment duration.

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