Author Of 1 Presentation

 CONFERENCE CALENDAR

UGT2B7 AFFECTS PROPOFOL PHARMACOKINETICS IN NEONATES

Presenter
Authors
Room
Trakl Hall
Date
20.06.2019
Session Time
09:10 - 10:40
Session Name
Primary endpoints in drug trials
Duration
10 Minutes

Abstract

Background

Propofol is used in neonatal intensive care for procedural sedation. Genetic factors affecting its pharmacokinetics haven’t been researched before, and current dosing is based on empirical experience.

Objectives

We investigated the association of propofol pharmacokinetic variables to genomic factors.

Methods

We recruited 40 neonates, who were treated with propofol. Median (range) postmenstrual age was 32,8 (22,9–42,5) weeks. Propofol dosing was based on clinical judgement (average 2,0 mg/kg). Blood samples were collected for 24 h after drug dosing for propofol concentration assays. Later during the treatment period, a single blood sample was drawn for exomic sequencing. Drug concentrations were used to create a pharmacometric population model using NONMEM software. The model was used to simulate non-compartmental pharmacokinetic variables Cmax and AUC. Genetic variants were identified using GATK and VarScan. The genomic association analysis with simulated pharmacokinetic variables was performed with Plink software using linear regression. The false discovery rate was controlled by the Benjamini-Hochberg procedure.

Results

A single nucleotide polymorphism (c.372A>G, p.Arg124Arg, rs28365063) in UGT2B7, a phase II metabolism enzyme, was associated significantly with maximum concentration. Cmax was 6-fold higher in genotype GG and 4-fold higher in genotype AG when compared to genotype AA.

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Conclusion

UGT2B7 polymorphism seems to expose neonates to considerably high propofol maximum concentrations. The result needs to be prospectively validated before it can be used as a covariate in drug dosing.

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