Pharmacogenomics and Implementation of Precision Therapeutics in the Neonatal ICU: a New Frontier?

Abstract

Neonatal medicine has progressed rapidly in the past 50 years, with major advances in nutrition, ventilation strategies, surgical techniques and infection control practices. These advances have allowed the intact survival of increased numbers of extremely preterm and critically ill full-term neonates. However, one key area lagging in medical advance is pharmacologic therapy for neonatal diseases. Certain diseases and drug classes are common in the neonatal ICU (NICU), and there are conditions that are unique to the neonatal population. Patent ductus arteriosus (PDA) is treated with nonsteroidal anti-inflammatory drugs or acetaminophen. Persistent pulmonary hypertension of the newborn (PPHN) is treated with inhaled nitric oxide or off-label vasodilators. Hypoxic ischemic encephalopathy (HIE) has no approved pharmacologic therapies, but drugs including erythropoietin are being researched. Bronchopulmonary dysplasia (BPD) is treated off-label with diuretics, steroids and β-agonists. Necrotizing enterocolitis (NEC) is treated with anti-infectives and at times, vasopressors for septic shock. In addition to these unique conditions, neonates are also treated for nonunique pathophysiology including seizures, hypotension, sepsis and pain.With the exception of surfactant and inhaled nitric oxide, no targeted drugs have been developed for neonatal conditions. Neonatologists often adapt currently approved drug therapies from other patient populations to treat NICU pathology. Thus, neonates are considered 'therapeutic orphans' in that meaningful drug development is scarce in this population. In a comprehensive review published in 2013, the ten most commonly used drugs in the NICU were anti-infectives (ampicillin, gentamicin, vancomycin), surfactant (beractant and calfactant), caffeine, furosemide, dopamine, fentanyl and midazolam. None of these drugs currently have actionable pharmacogenomic guidelines, thus the potential impact of pharmacogenomics in the neonatal population may appear very limited. Yet, there are certain diseases with such wide variability in phenotype (newborn opiate withdrawal, bronchopulmonary dysplasia) and response to drug therapy (PDA, pain and agitation) that there seems to be an urgent need to understand the underlying sources of variability, including genetics.A treating neonatologist faces many challenges in drug therapy, including uncertainties about variability in drug exposure and drug response. All of the typical pharmacokinetic (PK) processes are heterogeneous and rapidly changing in our patient population: absorption (developing acid production, villous development and variable amount of enteral feedings), distribution (transporter ontogeny, large fluid shifts in first weeks of life and variable fat content based on in utero environment), metabolism (immature enzyme expression) and elimination (rapidly developing glomelular filtration and biliary clearance). In addition, a neonatologist can rarely be sure that a certain drug target is adequately expressed and often-times, the goal drug exposu...

Pharmacogenetic profiling via genome sequencing in children with medical complexity

“…Genetic test utilization is already high in CMC, and exome sequencing and chromosomal microarray analysis are expected to be replaced by GS in the coming years. 13,15,16,24 Genotype-guided prescribing can have the greatest impact when initiated at a child's first point of contact with the healthcare system, 25 with the caveat that some findings may not be applicable until after the neonatal period or infancy. 25,26 GS-PGx profiling at the time of initial etiologic-based testing therefore warrants strong consideration in CMC (Fig.…”

“…26 Certain “established” PGx associations cannot be extrapolated to neonates because of key physiological differences (e.g., immature enzyme expression). 25 Clinical implementation of GS-PGx will need to be accompanied by continuing professional education and other initiatives to ensure appropriate interpretation of findings at the bedside. 9 …”

Current Trends in Genetics and Neonatal Care

“…The study of how a person's genes affect his or her response to drugs. 52 neurodevelopmental disorders, such as those caused by genetic conditions. 10 Head circumference is determined by measuring the widest portion of the infant's head, starting above the eyebrows, extending above the ears, and circling the most prominent portion at the back of the head.…”

“…A next step in pharmacogenetics, as it applies to the newborn setting, is to move toward research validation and translation of dosing models into drug-dosing tools. 52…”

The Impact of Pharmacogenetics on Pharmacokinetics and Pharmacodynamics in Neonates and Infants: A Systematic Review

“…When applied to clinical care, this holds the promise to be integrated in individualization and precision medicine. 2 , 3 In neonates, PGx has an additional complexity next to genetic variability (ie, polymorphisms) in the genes that code for proteins responsible for drug pharmacokinetics (PK) (like metabolism, transporter) or pharmacodynamics (PD) (like receptor, target enzyme). This is because there are rapidly evolving, ontogenic changes in expression of these same proteins or processes related to maturation of renal, cardiac, intestinal function, etc.…”