Pharmacogenetics may explain part of the interindividual variability of dobutamine pharmacodynamics in neonates

Abstract

Aims: To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the haemodynamic 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: Twenty-six 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) beats/min per AUC of 100 μg L^-1 h, P = .0008. 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 μg L^-1 h, P = .0095 and 33.2 (12.1-54.3) mL kg^-1 min^-1 per AUC of 100 μg L^-1 h, P = .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.

Keywords: cardiovascular pharmacology; intensive care; neonatology; pharmacogenetics.