Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia

Abstract

Background: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance.

Objectives: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines.

Methods: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs.

Results: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam.

Conclusions: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.

Keywords: Hypoxic-ischaemic encephalopathy; Midazolam; Neonates; Pharmacokinetics; Phenobarbital.

Fig. 1

Observed phenobarbital plasma concentrations versus time after birth. Dotted lines indicate the proposed therapeutic window of 20–40 mg/L.

Fig. 2

Observed midazolam plasma concentrations versus time after birth. Dotted line indicates the minimal effective plasma concentration of 0.1 mg/L. Solid line represents toxic upper limit of 2.4 mg/L.

Fig. 3

Simulated phenobarbital plasma concentrations after a dose of 20 mg/kg (a), 30 mg/kg (b), and 40 mg/kg (c). Solid lines indicate the mean phenobarbital plasma concentrations. Dotted lines indicate the proposed therapeutic window; grey area represents the 95% prediction interval.

Fig. 4

Simulated midazolam plasma concentrations after a loading dose of 0.1 mg/kg followed by continuous infusion of 0.15 mg/kg/h. Upper solid line indicates the mean midazolam plasma concentration without phenobarbital co-medication. Bottom solid line indicates the mean midazolam plasma concentration with phenobarbital co-medication; grey areas represent the interquartile ranges.