Author Of 1 Presentation
UGT2B7 AFFECTS PROPOFOL PHARMACOKINETICS IN NEONATES
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.
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.
Presentation files
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Matias_Rantanen_UGT2B7_affects_propofol_pharmacokinetics_in_neonates 18.06.2019 15:33