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Pharmacogenetics may explain part of the interindividual variability of dobutamine pharmacodynamics in neonates
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  • Maarja Hallik,
  • Hiie Soeorg,
  • Tiina Kahre,
  • Ülle Murumets,
  • Mari-Liis Ilmoja,
  • Karin Kipper,
  • Tuuli Metsvaht
Maarja Hallik
University of Tartu
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Hiie Soeorg
University of Tartu
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Tiina Kahre
Tartu University Hospital
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Ülle Murumets
Tartu University Hospital
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Mari-Liis Ilmoja
Tallinn Children's Hospital
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Karin Kipper
Chalfont Centre for Epilepsy
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Tuuli Metsvaht
University of Tartu
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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.
29 Nov 2021Submitted to British Journal of Clinical Pharmacology
30 Nov 2021Submission Checks Completed
30 Nov 2021Assigned to Editor
26 Jan 2022Reviewer(s) Assigned
18 Feb 2022Review(s) Completed, Editorial Evaluation Pending
01 Mar 2022Editorial Decision: Revise Major
31 Mar 20221st Revision Received
01 Apr 2022Submission Checks Completed
01 Apr 2022Assigned to Editor
01 Apr 2022Review(s) Completed, Editorial Evaluation Pending
10 Apr 2022Editorial Decision: Accept