Pharmacogenetics may explain part of the interindividual variability of
dobutamine pharmacodynamics in neonates
Abstract
Aim: To determine whether the known single nucleotide polymorphisms in
adrenoreceptor associated genes affect the hemodynamic response to
dobutamine in critically ill neonates. Methods: Alleles in the known
genetic single nucleotide polymorphisms in β1 and β2 adrenoceptor (AR)
genes and Gs protein α-subunit gene (GNAS) possibly affecting inotropic
effect were identified in patients of neonatal dobutamine
pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were
used to describe the effect of genetic polymorphisms to heart rate (HR),
left ventricular output (LVO) and right ventricular output (RVO) during
dobutamine treatment. Results: 26 neonates (5 term, 21 preterm) were
studied. Dobutamine plasma concentration and exposure time respective HR
(adjusted to gestational age) is dependent on β1-AR Arg389Gly
polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes
dobutamine increases HR more than in C/C (Arg) homozygotes, with
parameter estimate (95% CI) of 38.3 (15.8 – 60.7) bpm per AUC of 100
mg·h, p=0.0005. LVO (adjusted to antenatal glucocorticoid administration
and illness severity) and RVO (adjusted to gestational age and illness
severity) is dependent on GNAS c.393C>T polymorphism so
that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes
LVO and RVO increase with dobutamine treatment, 24.5 (6.2 – 42.9) mL
kg-1 min-1 per AUC of 100 mg·h, p=0.0116 and 33.2 (12.1 – 54.3) mL kg-1
min-1 per AUC of 100 mg·h, p=0.0025, respectively. Conclusion: In
critically ill neonates, β1-AR Arg389Gly and GNAS c.393C>T
polymorphisms may play a role in the haemodynamic response to dobutamine
during the first hours and days of life.