title: Pharmacokinetics - Neonatal Intensive Care Drug Manual
text: Pharmacokinetics: In children, phenytoin loading dose 20 mg/kg may result in supratherapeutic concentrations.5 (LOE IV)
  During the first week after birth, plasma half-life is so variable that no fixed dosage regimen can be derived. Beyond the second week, 8 mg/kg/24 hours is probably inadequate for most infants.9 (LOE IV) In preterm infants the t½ was much longer (75.4 ± 64.5 h) and more variable.9 (LOE IV)
  Postnatal age independently influenced clearance. Switching from enteral to intravenous routes may require a dosage adjustment (enteral bioavailability 0.76, 95% CI 0.44 to 1.07), although similar serum concentrations have been reported in preterm infants irrespective of route.10,11 (LOE IV, GOR C)
  In a small case series of term neonates on phenytoin as single drug or in combination with phenobarbitone, the mean daily dose of phenytoin was significantly higher in neonates on ECMO compared to non-ECMO neonates (20 vs 11mg/kg/day; p=0.04) with comparable drug levels (8.4 vs 7.4 mg/L; p=0.56 ).8
  Monitoring: Therapeutic target for total phenytoin is 10 to 20 mg/L (40 to 80 micromol/L) and for free phenytoin 0.5 to 1.4 mg/L (2 to 5.6 micromol/L).12 (LOE IV, GOR C). Total phenytoin concentrations are unreliable for directing therapy in critically ill children. Free phenytoin concentrations should be routinely measured in critically ill children to prevent possible intoxications and ensure therapeutic dosing.13
  When free phenytoin concentrations cannot be routinely measured, use total phenytoin concentration with a derivative of the Sheiner-Tozer equation:
  Ctotaladjusted = [Ctotalmeasured x 10.2 – 0.24 x (ALB – 42) + 0.067 x (UREA – 7)+ 2.53 x VALP] ÷ 10.2.13-14 Note, however, that the Sheiner-Tozer equation and all its derivatives are regarded, in general, as biased and imprecise.14
  In children with hypoalbuminaemia, uraemia or concomitant valproic acid use, ensure close treatment monitoring and consider a dose reduction of phenytoin a priori.13 (LOE IV, GOR C)
  To convert from mg/L (microgram/mL) the factor is 3.964. Simply multiply the mg/L value to obtain the value in micromol/L.
  Hypothermia can significantly reduce clearance of phenytoin compared with normothermic patients and during and after rewarming phase. There is limited data about saturable metabolism and modelled using Michaelis-Menten Kinetics in neonates. It is advisable to closely monitor the concentration of phenytoin in neonates during therapeutic cooling and rewarming phase.7
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