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Pharmacogenomic applications in pediatrics
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Pharmacogenomics is rapidly becoming a field of study and research with applications likely to have a significant impact on the use of medicines in the foreseeable future.
As clinicians, we currently attempt to individualize drug therapy for infants and children, considering factors such as body weight, age, drug allergy history, past response to drugs (including efficacy and adverse effects), organ function and concomitant medications (drug-drug interactions).
Edward A. Bell
Even better, it is now possible to additionally consider the impact of an individual’s genome — how an individual’s unique genetic makeup affects the pharmacokinetics and pharmacodynamics (drug effects) for some drugs. Pharmacogenomics is the study of the human genome and its effects upon drug behavior and response. Pharmacogenetics, a more specific term, describes the study of specific genetic variations and their effects upon drug use. These fields of study are now beginning to produce potential clinical applications for the use of some drugs.
Human genes may affect the use of medicines through several means: proteins that transport drugs, drug-metabolizing enzymes and sites of drug action (drug receptors). Specific gene polymorphisms (DNA sequencing variations) have recently been elucidated that affect drug transport, metabolism and pharmacologic effect. Predicting how these polymorphisms determine specific clinical drug response is difficult, however, as it is likely that clinical drug response results from a combination of effects, including drug absorption, distribution, metabolism and receptor site action. Added to the application of pharmacogenomics in pediatrics is another area of complexity — the effects of ontogeny (developmental maturation) upon how drugs behave and act in the body. Although the combined effects of ontogeny and pharmacogenomics are very complex, research is progressing toward patient-specific clinical applications.
Effects upon drug metabolism and response
Numerous families of drug-metabolizing enzymes have been identified in humans. These drug-metabolizing enzyme families can have genetic variations, each with unique effects upon drug behavior. For example, most Caucasians and about 50% of African Americans do not functionally express the drug-metabolizing enzyme CYP3A5. The benzodiazepine midazolam is metabolized by CYP3A5 and CYP3A4, and genetic polymorphisms of these enzymes have been elucidated, resulting in reduced drug clearance.
An example of genetic polymorphisms affecting drug metabolism and response that may be more familiar to pediatric clinicians is codeine metabolism. In 2006, Koren published a case report of the death of an infant that was believed to be caused by morphine intoxication from breast-feeding. The infant’s blood concentration of morphine was measured at 70 ng/mL vs. more typical concentrations of about 1 ng/mL to 2 ng/mL when breast-feeding from mothers using codeine therapeutically. The infant’s mother was taking a codeine/acetaminophen analgesic product for episiotomy pain. Codeine is hepatically metabolized to morphine by the enzyme CYP2D6. Further testing revealed that the mother was heterozygous for the CYP2D6*2A allele and was an ultra-rapid metabolizer of codeine. This genetic polymorphism resulted in an excessive production of morphine, which distributed into the mother’s breast milk. It has been estimated that CYP2D6 ultra-rapid metabolism occurs in 1% of Scandinavians, 10% of Spaniards and Greeks, and 30% of Ethiopians.
Carbamazepine, also commonly used in the pediatric population, represents another example of clinically important drug effects due to genetic polymorphism. The package labeling for carbamazepine now includes a black-box warning for the potential of serious dermatologic adverse reactions, such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), in individuals with the HLA-B*1502 allele of the HLA-B gene (human leukocyte antigen complex, distinguishing self from non-self). This allele is found nearly exclusively in individuals with Asian ancestry. Carbamazepine’s package labeling includes recommendations to consider testing for the HLA-B allele before initiation of use.
Although not as commonly used in children, warfarin represents another drug that has recently seen changes to its package labeling related to pharmacogenomic information. Warfarin is eliminated almost entirely by hepatic metabolism to inactive metabolites. The CYP450 enzymes metabolizing warfarin include CYP2C9, among other CYP enzymes. CYP2C9 is the principal enzyme responsible for warfarin’s metabolism. Two allelic forms of this enzyme, CYP2C9*2 and CYP2C*3, have been identified that cause decreased metabolism. Warfarin’s package inserts states that these alleles occur in 11% and 7%, respectively, of the Caucasian population. Additionally affecting the use of warfarin is a genetic polymorphism of the enzyme involved with vitamin K metabolism (VKOR). These two polymorphic enzymes may account for 30% to 50% of warfarin dosing variability. Although testing for these enzymes may be available in some situations, their interpretation and clinical applicability have not been widely demonstrated.
The specific drugs listed above are examples of advances in pharmacogenomics and their application to drug use. The FDA currently lists 112 drug products that have incorporated pharmacogenomic information into their package labeling (www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm). Examples of drugs listed here that are more commonly used in infants and children include atomoxetine (Strattera, Eli Lilly and Company), carbamazepine, codeine, fluoxetine, phenytoin, rifampin and valproic acid.
Pharmacogenomics and asthma
Genetic variations in proteins acting as drug receptors can additionally affect drug use by altering pharmacodynamic response. Polymorphisms in the beta-2 adrenergic receptor (coded by the ADRB2 gene) have been identified that may alter a child’s response to beta-2 receptor agonists (eg, albuterol, levalbuterol) when treating asthma.
Several single nucleotide polymorphisms have been identified that can result in increased or decreased (eg, tachyphylaxis) drug effects, as well as heightened adverse effects. Variants of the gene coding for ALOX5, an enzyme involved in leukotriene production, may affect an individual’s response to the medications affecting these pathways, such as montelukast (Singulair, Merck).
A small subset of children and adults with asthma may be poorly controlled because of a decreased response to glucocorticoids and their anti-inflammatory effects. Some research has identified genetic variations in cytokine production (eg, interleukin-4, tumor necrosis factor) that in part may be responsible for steroid-resistance in these individuals.
References:
Evans WE. N Engl J Med. 2003;348:538-549.
Koren G. Lancet. 2006;368:704.
Neville KA. Paediatr Anaesth. 2011;21:255-265.
Silverman ES. Pharmacogenomics J. 2001;1:27-37.