Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach

Abstract

Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7-10 kg; patient's postnatal age: 0-206 days; GA: 27-42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1-10.6 mg/kg) per day was administered by 30-min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model software). Data were modelled with an allometric pharmacokinetic model, using three-fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (Vd ) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, Vd , F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration.

Stevens‐Johnson syndrome and toxic epidermal necrolysis with antiepileptic drugs: An analysis of the US Food and Drug Administration Adverse Event Reporting System

“…One possible reason for this is the declining utilization of phenobarbital which has become a nonpreferred therapy option in treatment guidelines due to (1) its less favorable side effect profile, (2) inclusion in the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, (3) unfavorable pharmacokinetic properties, and (4) multiple drug-drug interactions. 36–38 …”

Phenobarbital population pharmacokinetics across the pediatric age spectrum

“…In addition, medical interventions, such as whole‐body hypothermia in neonates with hypoxic ischemic encephalopathy, may also alter the disposition of medications in pediatric patients . Bioavailability of phenobarbital has been documented at ~90%, but has been shown to be much less in neonates . The half‐life of phenobarbital is long; therefore, accurate empiric dosing is necessary to obtain target concentrations in a timely fashion …”

Challenges Associated with Route of Administration in Neonatal Drug Delivery

“…It should be noted that the initial changes in stomach pH are generally not seen in preterm infants who have little free acid during the first 2 weeks of life [12]. Due to reduced transfer of ionized drugs across a membrane, this time of relatively high pH gastric environment may increase absorption of weakly basic drugs and reduce absorption of weakly acidic drugs [10,13,14].…”