Pharmacogenomics and Personalized Medicine (Jun 2022)
The Impact of Pharmacogenetics on Pharmacokinetics and Pharmacodynamics in Neonates and Infants: A Systematic Review
Abstract
Nadir Yalçin,1,2 Robert B Flint,2,3 Ron HN van Schaik,3,4 Sinno HP Simons,3 Karel Allegaert2,5– 7 1Department of Clinical Pharmacy, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey; 2Department of Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands; 3Division of Neonatology, Department of Pediatrics, Erasmus MC, Rotterdam, the Netherlands; 4Department of Clinical Chemistry, Erasmus MC, Rotterdam, the Netherlands; 5Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; 6Department of Development and Regeneration, KU Leuven, Leuven, Belgium; 7Child and Youth Institute, KU Leuven, Leuven, BelgiumCorrespondence: Karel Allegaert, Neonatal Intensive Care Unit, UZ Leuven, Herestraat 49, Leuven, 3000, Belgium, Tel +32-016-342020, Fax +32-016-343209, Email [email protected]: In neonates, pharmacogenetics has an additional layer of complexity. This is because in addition to genetic variability in genes that code for proteins relevant to clinical pharmacology, there are rapidly maturational changes in these proteins. Consequently, pharmacotherapy in neonates has unique challenges. To provide a contemporary overview on pharmacogenetics in neonates, we conducted a systematic review to identify, describe and quantify the impact of pharmacogenetics on pharmacokinetics and -dynamics in neonates and infants (PROSPERO, CRD42022302029). The search was performed in Medline, Embase, Web of Science and Cochrane, and was extended by a PubMed search on the ‘top 100 Medicines’ (medicine + newborn/infant + pharmacogen*) prescribed to neonates. Following study selection (including data in infants, PGx related) and quality assessment (Newcastle–Ottawa scale, Joanna Briggs Institute tool), 55/789 records were retained. Retained records relate to metabolizing enzymes involved in phase I [cytochrome P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8/C9/C18, CYP2C19, CYP2D6, CYP3A5, CYP2E1)], phase II [glutathione-S-transferases, N-acetyl transferases, UDP-glucuronosyl-transferase], transporters [ATP-binding cassette transporters, organic cation transporters], or receptor/post-receptor mechanisms [opioid related receptor and post-receptor mechanisms, tumor necrosis factor, mitogen-activated protein kinase 8, vitamin binding protein diplotypes, corticotrophin-releasing hormone receptor-1, nuclear receptor subfamily-1, vitamin K epoxide reductase complex-1, and angiotensin converting enzyme variants]. Based on the available overview, we conclude that the majority of reported pharmacogenetic studies explore and extrapolate observations already described in older populations. Researchers commonly try to quantify the impact of these polymorphisms in small datasets of neonates or infants. In a next step, pharmacogenetic studies in neonatal life should go beyond confirmation of these associations and explore the impact of pharmacogenetics as a covariate limited to maturation of neonatal life (ie, fetal malformations, breastfeeding or clinical syndromes). The challenge is to identify the specific factors, genetic and non-genetic, that contribute to the best benefit/risk balance.Keywords: developmental pharmacology, infant, ontogeny, child development, genetic variation
