Pharmacogenomics

Introduction

Pharmacogenetic variants are DNA variants that influence the metabolism and elimination or the action of medications. Research in pharmacogenetics seeks to understand how these variants influence variability in medication response. For the perinatal pharmacologist, genetic variations that affect drug disposition in the fetus, the mother, and the neonate must be considered as one of many sets of variables, along with developmental changes in fetal and neonatal gene expression, organ maturation, placental transfer and metabolism of drugs, and a host of hormonal and environmental influences, which can combine to produce unique patterns of toxicity in mother and child upon medication exposure. Therefore knowledge of potential genetic contributions to drug-induced toxicity in pregnancy, in utero, and in postnatal life can be important in optimizing dosing of drugs, as well as in understanding adverse drug reactions (ADRs) and preventing their further occurrence in patients.

The field of pharmacogenomics is rapidly expanding, and the number of medications with genetic information in the drug label is increasing. Several actionable gene-drug pairs have been clinically implemented in hospitals across the world. Most pharmacogenetic research has been performed in adults, but many of the associations also could apply to children and neonates that are prescribed the same medications.

There are several resources that provide guidance on pharmacogenetic research and implementation. The first step in pharmacogenetics is defining the variants that influence the medication absorption, distribution, metabolism, elimination, or response. The Pharmacogene Variation Consortium ( PharmVar.org ) is a repository of pharmacogene variation that focuses on haplotype structure and allelic variation. Pharmacogenetic alleles can contain one or more variants, and sometimes individual variants are included in the definition of more than one allele. Thus, it is very important to have a common terminology for allele nomenclature, which PharmVar provides. The Pharmacogenomics Knowledge Base ( PharmGKB.org ) is an NIH-funded resource that curates pharmacogenetic literature, including in vitro and in vivo knowledge from medication labels, clinical trials, clinical research, and basic research. Every gene-drug pair in the literature is given a level of evidence based on the association of individual variants with clinical and/or in vitro data. The Clinical Pharmacogenetics Implementation Consortium ( CPIC, cpicpgx.org ) is a group that publishes evidence-based clinical practice guidelines, facilitating the implementation of pharmacogenetics into clinical care. Currently, there are 23 guidelines that impact 49 medications and involve 18 genes ( Table 18.1 ). CPIC utilizes standard nomenclature for allele functionality and activity and provides guidance on electronic health record integration of pharmacogenetic results.

Most individuals have at least one pharmacogenetic variant but may not receive the medication whose dosing would be informed by that variant. ^, This chapter provides an overview and examples of some selected pharmacogenes that influence the pharmacokinetics, pharmacodynamics, and severe adverse reactions to drugs; where possible, these examples were chosen to provide particular relevance to medication use in children.

Pharmacogenetic Variants Affecting Drug Metabolism

The most well-established pharmacogenes are those encoding drug-metabolizing enzymes; variants in these genes affect the exposure by altering the rate of metabolism of the drugs. For example, slow metabolism of a pro-drug would result in decreased exposure to the active metabolite and the potential for inefficacy, but slow metabolism of an active drug into an inactive compound would result in increased exposure to the active drug and the potential for toxicity. The opposite is true for faster metabolism due to genetic variants. For pharmacogenes that influence pharmacokinetics, often the recommendations are to adjust dosage, but for some medications, an alternative medication is recommended. There are two phases of drug metabolism—the first is oxidation or hydrolysis, and the second is conjugation (e.g., glucuronidation). Many drugs are metabolized by oxidation through the cytochrome P450 family of enzymes expressed highly in the liver ( Fig. 18.1 ).