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


CONCLUSIONS
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.
Filippi
Luca
L
Neonatal Intensive Care Unit, Department of Critical Care Medicine, A. Meyer University Children's Hospital, Florence, Italy. l.filippi@meyer.it
la Marca
Giancarlo
G
Fiorini
Patrizio
P
Poggi
Chiara
C
Cavallaro
Giacomo
G
Malvagia
Sabrina
S
Pellegrini-Giampietro
Domenico E
DE
Guerrini
Renzo
R
D001238:Asphyxia Neonatorum / Q000628:therapy; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000628:therapy*; D007231:Infant, Newborn; D008297:Male; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D010634:Phenobarbital / Q000627:therapeutic use; D000077236:Topiramate; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose; D010634:Phenobarbital