Pediatric Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics

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Chapter 56 Pediatric Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics

Interindividual variability in the response to similar doses of a given medication is an inherent characteristic of adult and pediatric populations. The role of genetic factors in drug disposition and response, pharmacogenetics, has resulted in many examples of how variations in human genes can lead to interindividual differences in pharmacokinetics and drug response at the level of individual patients. Just as in adults, pharmacogenetic variability contributes to the broad range of drug responses observed in children at any given age or developmental stage. Therefore, it is expected that children will benefit from the promise of personalized medicine: identifying the right drug for the right patient at the right time (see Fig. 56-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). However, pediatricians are keenly aware that children are not merely small adults. Numerous maturational processes occur from birth through adolescence, and using information resulting from the Human Gene Project and related initiatives must take into account the changing patterns of gene expression that occur over development to improve pharmacotherapeutics in children.

Figure 56-1 The promise of genomic medicine to human health and disease. The goal of personalized medicine will be achieved by identifying subgroups of patients who will respond favorably to a given drug with a minimum of side effects, as well as those who will not respond or who will show excessive toxicity with standard doses. A further benefit of pharmacogenomics will be the ability to select the most appropriate alternative drug for patients who cannot be treated successfully with conventional drugs and doses.

(Adapted from Yaffe SJ, Aranda JV: Neonatal and pediatric pharmacology, ed 3, Philadelphia, 2004, Lippincott Williams & Wilkins.)

Pharmacogenetics, Pharmacogenomics, and the Concept of Personalized Medicine

The terms pharmacogenomics and pharmacogenetics tend to be used interchangeably, and precise consensus definitions are often difficult to determine. Pharmacogenetics classically is defined as the study or clinical testing of genetic variations that give rise to interindividual response to drugs. The earliest examples of pharmacogenetic traits include specific adverse drug reactions, such as unusually prolonged respiratory muscle paralysis caused by succinylcholine, hemolysis associated with antimalarial therapy, and isoniazid-induced neurotoxicity, all of which were found to be a consequence of inherited variations in enzyme activity. The importance of pharmacogenetic differences is exemplified by the fact that the half-lives of several drugs are more similar in monozygotic twins than in dizygotic twins. However, in addition to pharmacogenetic differences, environmental factors (diet, smoking status, concomitant drug or toxin exposure), physiologic variables (age, sex, disease, pregnancy), and patients’ compliance all contribute to variations in drug metabolism and response. Ethnicity is another potential genetic determinant of drug variability. Chinese patients who are HLA-B*1502 positive have an increased risk of carbamazepine-induced Stevens-Johnson syndrome; white patients who are HLA-B*5701 positive have an increased risk of hypersensitivity to abacavir (Table 56-1).

Table 56-1 EXAMPLES OF EFFECTS OF GENE POLYMORPHISMS ON DRUG RESPONSE

Pharmacogenomics represents the marriage of pharmacology and genomics. It can be defined as the broader application of genome-wide technologies and strategies to identify disease processes that represent new targets for drug development and factors that predict efficacy and risk of adverse drug reactions.

Pharmacokinetics describes what the body does to a drug. It is often studied in conjunction with pharmacodynamics, which explores what a drug does to the body. The pharmacokinetic properties of a drug are determined by the genes that control the drug’s disposition in the body (absorption, distribution, metabolism, excretion [ADME]). Drug-metabolizing enzymes and drug transporters play a particularly important role in this process (Table 56-2), and the functional consequences of genetic variations in many drug-metabolizing enzymes have been described among subjects of similar and different ethnic groups. The most common clinical manifestation of pharmacogenetic variability in drug biotransformation is an increased risk of concentration-dependent toxicity resulting from reduced clearance and consequent drug accumulation. An equally important manifestation of this variability is lack of efficacy resulting from variations in metabolism of prodrugs. The pharmacogenetics of drug receptors and other target proteins involved in signal transduction or disease pathogenesis can also be expected to contribute significantly to interindividual variability in drug disposition and response.

Table 56-2 SOME IMPORTANT RELATIONSHIPS BETWEEN DRUGS AND CYTOCHROME P450 ENZYMES* AND P-GLYCOPROTEIN TRANSPORTER

Therapeutic drug monitoring programs recognize that all patients are unique and that the serum concentration-time data for an individual patient theoretically can be used to optimize pharmacotherapy. These programs have been the earliest application of personalized medicine; however, routine therapeutic drug monitoring does not necessarily translate to improved outcome in all situations.

The concept of personalized medicine is based on the premise that the application of genomic technologies to patient-related problems allows stratification of patient populations according to their response to a particular medication (e.g., lack of drug efficacy or excessive toxicity) and stratification of diseases into specific subtypes that are categorized according to genomic criteria and by response to particular treatments.

Definition of Pharmacogenetics Terms

Genetic polymorphisms (variations) result when copies of a specific gene in a population do not have identical nucleotide sequences. The term allele refers to one of a series of alternative DNA sequences for a particular gene. In humans, there are two copies of every gene. An individual’s genotype for a given gene is determined by the set of alleles that the individual possesses. The most common form of genetic variation involves a single base change at a given location, referred to as a single-nucleotide polymorphism (SNP) (Chapters 72 and 74).

At the other end of the spectrum are copy number variations (CNVs), which are the deletion or duplication of identical or near-identical DNA sequences that may be thousands to millions of bases in size. CNVs occur less often than SNPs, but can constitute 0.5 to 1% of an individual’s genome, and thereby contributing significantly to phenotypic variation.

Haplotypes are collections of SNPs and other allelic variations that are located close to each other; when inherited together these create a catalog of haplotypes, or HapMap. When the alleles at a particular gene locus on both chromosomes are identical, a homozygous state exists, whereas the term heterozygous refers to the situation in which different alleles are present at the same gene locus.

The term genotype refers to an individual’s genetic constitution, whereas the observable characteristics or physical manifestations constitute the phenotype, which is the net consequence of genetic and environmental effects (Chapters 72–77). Pharmacogenetics focuses on the phenotypic consequences of allelic variation in single genes.

Pharmacogenetic polymorphisms are monogenic traits that are functionally relevant to drug disposition and action and are caused by the presence (within one population) of >1 allele (at the same gene locus) and >1 phenotype with regard to drug interaction with the organism. The key elements of pharmacogenetic polymorphisms are heritability, the involvement of a single gene locus, functional relevance, and the fact that distinct phenotypes are observed within the population only after drug challenge.

Developmental or Pediatric Pharmacogenetics and Pharmacogenomics

Our understanding of pharmacogenetic principles involves enzymes responsible for drug biotransformation. Individuals are classified as being “fast,” “rapid,” or “extensive” metabolizers at one end of the spectrum, and “slow” or “poor” metabolizers at the other end. This might or might not also include an “intermediate” metabolizer group, depending on the particular enzyme. With regard to biotransformation, children are more complex than adults because fetuses and newborns may be phenotypically slow or poor metabolizers for certain drug-metabolizing pathways because of their stage of development, and they can acquire a phenotype consistent with their genotype at some point later in the developmental process as they mature. Examples of drug-metabolizing pathways that are significantly affected by ontogeny include glucuronidation and some activities of the cytochrome P450 isoenzymes (CYPs) (Chapter 57). It is also apparent that not all infants acquire drug metabolism activity at the same rate. This is due to interactions between genetics and environmental factors. Interindividual variability in the trajectory (i.e., rate and extent) of acquired drug biotransformation capacity may be considered a developmental phenotype (Fig. 56-2), and it helps to explain the considerable variability in some CYP activities observed immediately after birth.

Figure 56-2 Developmental phenotypes. Variability in developmental changes in gene expression and functional enzyme activity are superimposed on pharmacogenetic determinants. The top panel shows the developmental profile of a theoretical drug-metabolizing enzyme over a 25-yr span in 20 subjects. The lower panel shows that at maturity (adults), allelic variation within the coding region of the gene gives rise to 2 distinct phenotypes, high activity in 92% of the population (extensive metabolizers; red circles) and low activity in 8% of the population (poor metabolizers; yellow circles). However, there is also interindividual variability in the rate at which functional activity is acquired after birth. For example, the 2 phenotypes may not be readily distinguishable in newborn infants immediately after birth, and there may be discrete periods during childhood in which the genotype-phenotype relationship differs from that observed in adults (e.g., developmental stages at which enzyme activity appears to be greater in children than in adults).

(Adapted from Leeder JS: Translating pharmacogenetics and pharmacogenomics into drug development for clinical pediatric and beyond, Drug Discov Today 9:567–573, 2004.)

Pharmacogenetic, Pharmacogenomic, Pharmacoproteomic, and Metabolomic Tools

Several genotyping platforms are approved by the U.S. Food and Drug Administration (FDA) and are entering the clinical arena. The Roche Amplichip CYP450 Test was the first such device to receive FDA approval, and at least 6 additional products have since received approval. In general, applications are limited to 1 or 2 genes, such as CYP2C9 and VKORC1 genotyping to guide warfarin therapy or genotyping of UGT1A1 to reduce the risk of irinotecan toxicity. A more comprehensive chip that covers >90% of the ADME markers as defined by the PharmaADME group (http://pharmaadme.org) is available for drug development and research purposes.

In contrast to pharmacogenetic studies that typically target single genes, pharmacogenomic analyses are considerably broader in scope and focus on complex and highly variable drug-related phenotypes, with targeting of many genes. Genome-wide genotyping technologies make it possible to evaluate genetic variation at more than a million sites throughout an individual genome for SNP and CNV analyses using a single chip. One goal of this type of study is to identify novel genes involved in disease pathogenesis that can lead to new therapeutic targets. Genome-wide association studies (GWAS) are also being applied to identify genetic associations with response to drugs, such as warfarin and clopidogrel, and risk for drug-induced toxicity, including statin-induced myopathy and flucloxacillin hepatotoxicity. The Manhattan plot, a form of data presentation for GWAS, is one way to represent these data (Fig. 56-3A).

Figure 56-3 Presentations of pharmacogenomic data. A, Manhattan plot from a genome-wide association study (GWAS). The Manhattan plot derives its name from the similarity of such a plot to the Manhattan skyline and presents the genome-wide significance of several hundred thousand single-nucleotide polymorphisms (SNPs) distributed throughout the genome with the trait or phenotype of interest. In this example, each SNP included on the chip is plotted along the x-axis according to its chromosomal coordinate, with each color representing an individual chromosome from chromosome 1 to the X chromosome. The y-axis represents the inverse log₁₀ of the p value for the association: The higher the value on the y-axis, the smaller the p value. A value of 15 corresponds to a p value of 10⁻¹⁵. SNPs exceeding a particular threshold are subject to further verification and validation. B, Hierarchical clustering of genes discriminating MTX response. Each column represents an ALL sample labeled with red circles for MTX poor responders and with green circles for MTX good responders. Unlabeled patients are intermediate MTX responders. Each row represents a probe set labeled with the gene symbol. The “heat map” indicates high (red) or low (green) level of expression according to the scale shown.

(A from Search Collaborative Group: SLCO1B1 variants and statin-induced myopathy—a genomewide study, N Engl J Med 359:789-99, 2008; B from Sorich MJ, Pottier N, Pei D, et al: In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile, PLoS Med 5:e83, 2008.)

Investigating differential gene expression before and after drug exposure has the potential to correlate gene expression with variable drug responses and possibly uncover the mechanisms of tissue-specific drug toxicities. These types of studies use microarray technology to monitor global changes in expression of thousands of genes (the transcriptome) simultaneously. The underlying hypothesis of these global gene-profiling studies is that the measured intensity for each arrayed gene represents its relative expression level. Gene expression profiling data are used to improve disease classification and risk stratification and are used commonly in oncology. For example, this approach has been widely used to address treatment resistance in acute lymphoblastic leukemia and has provided clinically relevant insights into the mechanistic basis of drug resistance and the genomic basis of interindividual variability in drug response. Subsets of transcripts, or gene expression signatures, are being investigated as potential prognostic indicators for identifying patients at risk for treatment failure (Fig. 56-3B).

Proteomic studies use many different techniques to detect, quantify, and identify proteins in a sample (expression proteomics), and to characterize protein function in terms of activity and interactions between proteins or proteins and nucleic acids (functional proteomics). Two-dimensional electrophoresis (2DE) coupled with mass spectrometry detection (2DE-MS) is the mainstay of expression proteomics. Protein “spots” of interest are “picked”; digested with a proteolytic enzyme, such as trypsin; and identified by MS. The data generated are compared with theoretically derived peptide mass databases for protein identification.

Metabolomics and metabonomics use sophisticated analytical platforms, such as nuclear magnetic resonance (NMR) spectroscopy and liquid or gas chromatography coupled with MS detection to measure the concentrations of all small molecules present in a sample. Metabolomics refers to the complete set of low molecular weight molecules (metabolites) present in a living system (cell, tissue, organ, or organism) at a particular developmental or pathologic state. Metabonomics is defined as the study of how the metabolic profile of biologic systems change in response to alterations resulting from pathophysiologic stimuli, toxic exposures, and dietary changes. Pharmacometabonomics is defined as the prediction of the outcome, efficacy or toxicity, of a drug or xenobiotic intervention in an individual based on a mathematical model of preintervention metabolite signatures. Integrating metabolomics with pharmacogenomics and transcriptomics will result in a more systems-based understanding of cellular processes, especially in the context of drug efficacy and toxicity.

Developmental Pharmacogenetics of Drug Biotransformation: Applications to Pediatric Drug Therapy Practice

The major consequence of pharmacogenetic polymorphisms in drug-metabolizing enzymes is concentration-dependent toxicity resulting from impaired drug clearance. In certain cases, reduced conversion of prodrug to therapeutically active compounds is also of clinical importance (see Table 56-2). Chemical modification of drugs via biotransformation reactions generally results in termination of biologic activity through decreased affinity for receptors or other cellular targets as well as more rapid elimination from the body. The process of drug biotransformation can be very complex, but it is characterized by 3 important features. First is the concept of broad substrate specificity: A single isozyme can metabolize a large variety of chemically diverse compounds. Second, many different enzymes may be involved in the biotransformation of a single drug (enzyme multiplicity). Finally, a given drug can undergo several different types of reactions. One example of this product multiplicity occurs with racemic warfarin, where at least 7 different hydroxylated metabolites are produced by different CYP isoforms.

Drug biotransformation reactions are conveniently classified into 2 main types, phase I and phase II reactions, which occur sequentially and serve to terminate biologic activity and enhance elimination (Chapter 57). Phase I reactions introduce or reveal (via oxidation, reduction, or hydrolysis) a functional group within the substrate drug molecule that serves as a site for a phase II conjugation reaction. Phase II reactions involve conjugation with endogenous substrates, such as acetate, glucuronic acid, glutathione, glycine, and sulfate. These reactions further increase the polarity of an intermediate metabolite, make the compound more water soluble, and thereby enhance its renal excretion. Interindividual variability in drug biotransformation activity (for both phase I and phase II reactions) is a consequence of the complex interplay among genetic (genotype, sex, race, or ethnic background) and environmental (diet, disease, concurrent medication, other xenobiotic exposure) factors. The pathway and rate of a given compound’s biotransformation is a function of each individual’s unique phenotype with respect to the forms and amounts of drug-metabolizing enzymes expressed.

The CYPs are quantitatively the most important of the phase I enzymes. These heme-containing proteins catalyze the metabolism of many lipophilic endogenous substances (steroids, fatty acids, fat-soluble vitamins, prostaglandins, leukotrienes, and thromboxanes) as well as exogenous compounds, including a multitude of drugs and environmental toxins. CYP nomenclature is based on evolutionary considerations. CYPs that share at least 40% homology are grouped into families denoted by an Arabic numeral after the CYP root. Subfamilies, designated by a letter, appear to represent clusters of highly related genes. Members of the human CYP2 family, for example, have >67% amino acid sequence homology. Individual CYPs in a subfamily are numbered sequentially (e.g., CYP3A4, CYP3A5). CYPs that have been identified as being important in human drug metabolism are predominantly found in the CYP1, CYP2, and CYP3 gene families. Importantly, enzyme activity may be induced or inhibited by various agents (see Table 56-2).

Phase II enzymes include arylamine N-acetyltransferases (NAT1, NAT2), glucuronosyl transferases (UGTs), epoxide hydrolase, glutathione S-transferases (GSTs), sulfotransferases (SULTs), and methyltransferases (catechol O-methyltransferase, thiopurine S-methyltransferase, several N-methyltransferases). Like the CYPs, UGTs, SULTs, and GSTs are gene families with multiple individual isoforms, each having its own preferred substrates, mode of regulation, and tissue-specific pattern of expression.

For most CYPs, genotype-phenotype relationships are influenced by development in that fetal expression is limited (with the exception of CYP3A7) and functional activity is acquired postnatally in isoform-specific patterns. Clearance of some compounds appears to be greater in children than in adults, and the correlation between genotype and phenotype in neonatal life through adolescence may be obscured.

CYP2D6

The CYP2D6 gene locus is highly polymorphic, with >75 allelic variants identified to date (http://www.imm.ki.se/CYPalleles/cyp2d6.htm; see Table 56-2). Individual alleles are designated by the gene name (CYP2D6) followed by an asterisk, and an Arabic number. By convention, CYP2D6*1 designates the fully functional wild-type allele. Allelic variants are the consequence of point mutations, single base pair deletions or additions, gene rearrangements, or deletion of the entire gene, resulting in a reduction or complete loss of activity. Inheritance of 2 recessive loss-of-function alleles results in the poor-metabolizer phenotype, which is found in approximately 5-10% of white subjects and approximately 1-2% of Asian subjects. In white subjects, the *3, *4, *5, and *6 alleles are the most common loss-of-function alleles and account for approximately 98% of poor-metabolizer phenotypes. In contrast, CYP2D6 activity on a population basis tends to be lower in Asian and African-American populations owing to a lower frequency of nonfunctional alleles (*3, *4, *5, and *6) and a relatively high frequency of population-selective alleles that are associated with decreased activity relative to the wild-type CYP2D6*1 allele. The CYP2D6*10 allele occurs at a frequency of approximately 50% in Asians, whereas CYP2D6*17 and CYP2D6*29 occur at relatively high frequencies in subjects of black African origin.

CYP2D6 is involved in the biotransformation of >40 therapeutic entities, including several β-receptor antagonists, antiarrhythmics, antidepressants, antipsychotics, and morphine derivatives (for an updated list, see http://medicine.iupui.edu/flockhart; see Table 56-2). CYP2D6 substrates commonly encountered in pediatrics include selective serotonin reuptake inhibitors (SSRIs; fluoxetine, paroxetine, sertraline), risperidone, atomoxetine, promethazine, tramadol, and codeine. Further, over-the-counter cold remedies such as dextromethorphan, diphenhydramine, and chlorphenirame, are also CYP2D6 substrates. An analysis of CYP2D6 ontogeny in vitro that used a relatively large number of samples revealed that CYP2D6 protein and activity remain relatively constant after 1 week of age up to 18 yr. Similarly, results from an in vivo longitudinal phenotyping study involving more than 100 infants over the 1st yr of life demonstrated considerable interindividual variability in CYP2D6 activity but no relationship between CYP2D6 activity and postnatal age between 2 weeks and 12 mo of age. A cross-sectional study involving 586 children reported that the distribution of CYP2D6 phenotypes in children was comparable to that observed in adults by at least 10 yr of age. Thus, available in vitro and in vivo data, albeit based on phenotype data rather than information on drug clearance from pharmacokinetic studies, imply that genetic variation is more important than developmental factors as a determinant of CYP2D6 variability in children.

One consequence of CYP2D6 developmental pharmacogenetics may be the syndrome of irritability, tachypnea, tremors, jitteriness, increased muscle tone, and temperature instability in neonates born to mothers receiving SSRIs during pregnancy. Controversy exists as to whether these symptoms reflect a neonatal withdrawal (hyposerotoninergic) state or represent manifestations of serotonin toxicity analogous to the hyperserotoninergic state associated with the SSRI-induced serotonin syndrome in adults (Chapter 100.1). Delayed expression of CYP2D6 (and CYP3A4) in the first few weeks of life is consistent with a hyperserotoninergic state due to delayed clearance of paroxetine and fluoxetine (CYP2D6) or sertraline (CYP3A4) in neonates exposed to these compounds during pregnancy. Decreases in plasma SSRI concentrations and resolution of symptoms would be expected with increasing postnatal age and maturation of these pathways. Given that treatment of a withdrawal reaction may include administration of an SSRI, there is considerable potential for increased toxicity in affected neonates. Resolution of the question whether symptoms are due to withdrawal versus a hyperserotoninergic state is essential for appropriate management of SSRI-induced neonatal adaptation syndromes. Until further data are available, it would be prudent to consider newborns and infants younger than 28 days of age to be CYP2D6 poor metabolizers.

In older children, drug accumulation and resultant concentration-dependent toxicities in CYP2D6 genotypic poor metabolizers should be anticipated in the same way that they are in adults owing to the risk of significant morbidity and mortality. Although a fluoxetine-related death has been reported in a 9 yr old child with a CYP2D6 poor metabolizer genotype, experience with paroxetine indicates that the risk of drug accumulation can also occur, under certain conditions, in persons at the opposite end of the activity spectrum. The pharmacokinetics of paroxetine and nefazodone, both CYP2D6 substrates, correlate with the CYP2D6 phenotype in children and adolescents 7-17 yr of age. However, chronic dosing of paroxetine can lead to greater-than-anticipated drug accumulation in children classified as CYP2D6 extensive metabolizers. In depressed children and adolescents as well as in adults, there is a disproportionate increase in peak concentrations and area under the serum concentration-time curve (AUC) at higher dose levels. However, nonlinearity is more prominent in patients who are CYP2D6 extensive metabolizers, especially those with gene duplications and 3 or more functional alleles. The largest decreases in paroxetine clearance observed with ascending doses are seen in patients who have the greatest clearance at the initial dose level (10 mg/day) and are predicted to have the greatest CYP2D6 activity based on CYP2D6 genotype. This seemingly paradoxical effect is best explained in the context of data from in vitro studies. One proposed mechanism involves oxidation of paroxetine within the CYP2D6 active site to form a reactive intermediate that is associated with irreversible modification of the CYP2D6 protein in or near the active site. In theory, the greater the initial CYP2D6 activity, the greater the burden of reactive metabolite that is formed and thereby an increased loss of CYP2D6 catalytic activity. As a consequence, as the paroxetine dose is increased in patients with higher initial drug clearance, the risk of excessive drug accumulation increases disproportionately.

Theoretically, younger children can experience decreased efficacy or therapeutic failure with drugs such as codeine and tramadol that depend on functional CYP2D6 activity for conversion to the pharmacologically active species. CYP2D6 catalyzes the O-demethylation of codeine to morphine. Infants and children appear capable of converting codeine to morphine and achieving morphine:codeine ratios comparable to those of adults. However, in one study, morphine and its metabolites were not detected in 36% of children receiving codeine, making the level of analgesia from codeine unreliable in the studied pediatric population. Interestingly, in this study levels of morphine and its metabolites were not related to CYP2D6 phenotype. Finally, ultrarapid CYP2D6 metabolism of codeine can result in opiate intoxication, including maternal ultrarapid metabolism of codeine, which can result in high serum and breast milk concentrations of morphine and can have adverse effects in the breast-fed neonate.

CYP2C9

Although several clinically useful compounds are substrates for CYP2C9 (http://medicine.iupui.edu/flockhart) (see Table 56-2), the effects of allelic variation are most profound for drugs with a narrow therapeutic index, such as phenytoin, warfarin, and tolbutamide. In vitro studies show a progressive increase in CYP2C9 expression from 1-2% of mature levels in the first trimester to approximately 30% at term. Considerable variability (approximately 35-fold) in expression is apparent over the first 5 mo of life, with approximately half of the samples studied exhibiting values equivalent to those observed in adults. One interpretation of these data is that there is broad interindividual variability in the rate at which CYP2C9 expression is acquired after birth, and in general, the ontogeny of CYP2C9 activity in vivo, as inferred from pharmacokinetic studies of phenytoin in newborns, is consistent with the in vitro results. The apparent half-life of phenytoin is prolonged (∼75 hr) in preterm infants, but it decreases to approximately 20 hr in term newborns. By 2 wk of age, the half-life has further declined to 8 hr. The appearance of concentration-dependent (saturable) metabolism of phenytoin, reflecting the functional acquisition of CYP2C9 activity, does not appear until approximately 10 days of age. The maximal velocity of phenytoin metabolism has been reported to decrease from an average of 14 mg/kg/day in infants to 8 mg/kg/day in adolescents, which might reflect changes in the ratio of liver mass to total body mass observed over this period of development, as has been observed for warfarin.

At least 34 allelic variants of CYP2C9 have been reported, but not all have been evaluated for their functional consequences. The CYP2C9*2 allele is associated with approximately 5.5-fold decreased intrinsic clearance for S-warfarin relative to the wild-type enzyme. Allelic variations resulting in amino acid changes within the enzyme active site, such as the CYP2C9*3, CYP2C9*4, and CYP2C9*5 alleles, are associated with activities that are approximately 5% of the wild-type protein. Approximately 1/3 of the white population carries a variant CYP2C9 allele (*2 and *3 alleles, most commonly), whereas the *2 and *3 alleles are virtually nonexistent in African-American, Chinese, Japanese, or Korean populations. In contrast, the *5 allele has been detected in African-Americans, but not in white subjects. The risk of bleeding complications in patients treated with warfarin and of concentration-dependent toxicity in patients treated with phenytoin is most pronounced for persons with a CYP2C9*3/*3 genotype. Although the relationship between the CYP2C9 genotype and warfarin dosing and pharmacokinetics has not been as extensively studied in children, consequences of allelic variation can be expected to be similar to those observed in adults. In adults, CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotype and the patient’s age, sex, and weight can account for 50-60% of the variation in warfarin dose requirements. A large part of the variation is still unknown, but it may be at least partially attributed to interactions with other drugs and foods.

CYP2C19

In vitro, CYP2C19 protein and catalytic activity can be detected at levels representing 12-15% of mature values by 8 weeks of gestation and remain essentially unchanged throughout gestation and at birth. Over the first 5 mo of postnatal life, CYP2C19 activity increases linearly. Adult levels are achieved by 10 yr of age, although variability in expression is estimated to be approximately 21-fold between 5 mo and 10 yr of age. The major source of this variability is likely pharmacogenetic in nature. The CYP2C19 poor-metabolizer phenotype (also known as mephenytoin hydroxylase deficiency) is present in 3-5% of the white population and 20-25% of Asians. Although 25 variant alleles have been reported to date, the 2 most common variant alleles, CYP2C19*2 and CYP2C19*3, result from single base substitutions that introduce premature stop codons and, consequently, truncated polypeptide chains that possess no functional activity. Despite consistent increases in CYP2C19 activity observed in vitro over the first 5 mo of life, the results of an in vivo phenotyping study with omeprazole in Mexican children revealed a broad range of activity and implied that 17% of infants younger than 4 mo could be classified as poor metabolizers (no poor metabolizers were detected beyond that point). In contrast, 20% of children 3-9 mo old were classified as ultrarapid metabolizers compared with 6% of infants 1-3 mo of age. For omeprazole, pharmacokinetic parameters comparable to those observed in adults are achieved by 2 yr of age.

CYP2C19 also plays an important role in the metabolism of lansoprazole. In Japanese adults treated with lansoprazole, amoxicillin, and clarithromycin for Helicobacter pylori infection, the eradication rate for CYP2C19 poor metabolizers (97.8%) and heterozygous extensive metabolizers (1 functional CYP2C19 allele; 92.1%) was significantly greater than that observed in homozygous extensive metabolizers (72.7%). Of the 35 patients in whom initial treatment did not eradicate H. pylori, 34 had at least 1 functional CYP2C19 allele, and eradication could be achieved with higher lansoprazole doses in almost all cases. Given that the frequency of the functional CYP2C19*1 allele is considerably greater in white subjects (about 0.84) compared with Japanese subjects (about 0.55), eradication failure can be expected to occur more often in whites. Because proton pump inhibitors are widely used in children, pharmacogenetic and developmental considerations should guide pediatric dosing strategies.

CYP3A4, CYP3A5, and CYP3A7

The CYP3A subfamily consists of 4 members in humans (CYP3A4, 3A5, 3A7, and 3A43) and is quantitatively the most important group of CYPs in terms of human hepatic drug biotransformation. These isoforms catalyze the oxidation of many different therapeutic entities, several of which are of potential importance to pediatric practice (for an updated list, see http://medicine.iupui.edu/flockhart; see Tables 56-2 and 56-3). CYP3A7 is the predominant CYP isoform in fetal liver and can be detected in embryonic liver as early as 50-60 days’ gestation. CYP3A4, the major CYP3A isoform in adults, is essentially absent in fetal liver but increases gradually throughout childhood. Over the first 6 mo of life, CYP3A7 expression exceeds that of CYP3A4, although its catalytic activity toward most CYP3A substrates is rather limited compared with that of CYP3A4. CYP3A4 is also abundantly expressed in intestine, where it contributes significantly to the first-pass metabolism of orally administered drugs that are substrates (e.g., midazolam). CYP3A5 is polymorphically expressed and is present in approximately 25% of adult liver samples studied in vitro.

Table 56-3 INTERNET RESOURCES FOR PHARMACOGENETICS AND PHARMACOGENOMICS *

INTRODUCTION TO PHARMACOGENOMICS
http://www.ornl.gov/TechResources/Human_Genome/medicine/pharma.html http://www.ama-assn.org/ama/pub/physician-resources/medical-science/genetics-molecular-medicine/current-topics/pharmacogenomics.shtml http://www.ncbi.nlm.nih.gov/About/primer/pharm.html http://learn.genetics.utah.edu/content/health/pharma/ http://www.pgxnews.org/web http://www.pharmgkb.org
PHARMACOGENETICS: ALLELIC VARIANTS OF DRUG METABOLIZING-ENZYMES
CYP2C9	http://www.imm.ki.se/CYPalleles/cyp2c9.htm
CYP2C19	http://www.imm.ki.se/CYPalleles/cyp2c19.htm
CYP2D6	http://www.imm.ki.se/CYPalleles/cyp2d6.htm
CYP3A4	http://www.imm.ki.se/CYPalleles/cyp3a4.htm
CYP3A5	http://www.imm.ki.se/CYPalleles/cyp3a5.htm
UGTs	http://som.flinders.edu.au/FUSA/ClinPharm/UGT/allele_table.html
NAT1 and NAT2	http://www.louisville.edu/medschool/pharmacology/NAT.html
PHARMACOGENETICS: SUBSTRATES OF DRUG-METABOLIZING ENZYMES
http://www.drug-interactions.com
INTRODUCTION TO PROTEOMICS
http://www.ama-assn.org/ama/pub/physician-resources/medical-science/genetics-molecular-medicine/current-topics/proteomics.shtml

* All sites were accessible on November 5, 2009.

Several methods have been proposed to measure CYP3A activity. Using these various phenotyping probes, CYP3A4 activity has been reported to vary widely (up to 50-fold) among individuals, but the population distributions of activity are essentially unimodal, and evidence for polymorphic activity has been elusive. Although 20 allelic variants have been identified (http://www.imm.ki.se/CYPalleles/CYP3A4.htm), most occur relatively infrequently and do not appear to be of clinical importance. Of interest to pediatrics is the CYP3A4*1B allele present in the CYP3A4 promoter region. The clinical significance of this allelic variant appears limited with respect to drug biotransformation activity, despite being associated with 2-fold increased activity over the wild-type CYP3A4*1 allele in in vitro assays. Although there does not appear to be an association between the CYP3A4*1B allele and age of menarche, a significant relationship does exist between the number of CYP3A4*1B alleles and the age at onset of puberty, as defined by Tanner breast score. In one study, 90% of 9 yr old girls with a CYP3A4*1B/*1B genotype had a Tanner breast score of ≥2 compared with 56% of CYP3A4*1A/*1B heterozygotes and 40% of girls homozygous for the CYP3A4*1A allele. Because CYP3A4 plays an important role in testosterone catabolism, it is proposed that the estradiol:testosterone ratio may be shifted toward higher values in the presence of the CYP3A4*1B allele and trigger the hormonal cascade that accompanies puberty. Intestinal CYP3A4 activity is inhibited by grapefruit juice and can result in higher levels of the many drugs metabolized by this enzyme; very large quantities of grapefruit juice can also inhibit the hepatic CYP3A4.

Polymorphic CYP3A5 expression is largely due to a SNP in intron 3 that creates a cryptic splice site and gives rise to mRNA splice variants that retain part of intron 3 with a premature stop codon. The truncated mRNA transcripts associated with this allele, CYP3A5*3, cannot be translated into a functional protein. Individuals with at least 1 wild-type CYP3A5*1 allele express functional CYP3A5 protein, whereas those homozygous for CYP3A5*3 (CYP3A5*3/*3) do not express appreciable amounts of functional protein. Approximately 60% of African-Americans show functional hepatic CYP3A5 activity compared with only 33% of European-Americans. Clinically important consequences of CYP3A5 allelic variation have been reported in children. In pediatric heart transplant patients with a CYP3A5*1/*3 genotype, tacrolimus concentrations were approximately 50% of those observed in patients with CYP3A5*3/*3 genotypes, when corrected for dose, 3 mo, 6 mo, and 12 mo after transplant. Thus, larger doses of tacrolimus are required in patients with functional CYP3A5 protein to achieve comparable blood levels and to minimize the risk of rejection.

Glucuronosyl Transferases

The UGT gene superfamily catalyzes the conjugation (with glucuronic acid) of several drugs used clinically in pediatrics, including morphine, acetaminophen, nonsteroidal anti-inflammatory drugs, and benzodiazepines. The effect of development on glucuronidation capacity has been well described and is illustrated by hyperbilirubinemia, gray baby syndrome (the cardiovascular collapse associated with high doses of chloramphenicol in newborns), and the 3.5-fold increase in morphine clearance observed in premature neonates at 24-39 wk postconceptional age. As with the CYPs, there are multiple UGT isoforms, and the acquisition of functional UGT activity appears to be isoform- and substrate-specific.

UGT1A1 is the major UGT gene product responsible for bilirubin glucuronidation, and >100 genetic alterations have been reported (see Table 56-3), most of which are rare and are more properly considered mutations rather than gene polymorphisms (Chapters 96 and 349.1). Inheritance of 2 defective alleles is associated with reduced bilirubin-conjugating activity and gives rise to clinical conditions, such as Crigler-Najjar syndrome and Gilbert syndrome. More frequently occurring polymorphisms involve a dinucleotide (TA) repeat in the atypical TATA box of the UGT1A1 promoter. The wild-type UGT1A1*1 allele has 6 repeats (TA₆), and the TA₅ (UGT1A1*33), TA₇ (UGT1A1*28), and TA₈ (UGT1A1*34) variants are all associated with reduced activity. UGT1A1*28, the most common variant, is a contributory factor to prolonged neonatal jaundice. This variant is also associated with impaired glucuronidation and thus toxicity of the active metabolite, SN-38 of the chemotherapeutic agent irinotecan. Allelic variations in UGT1A7 and UGT1A9 have also been associated with irinotecan toxicity in adults with colorectal cancer.

The consequences of allelic variation in the UGT2B family are less certain. The predominant routes of morphine elimination include biotransformation to the pharmacologically active 6-glucuronide (M6G) and the inactive 3-glucuronide (M3G). M6G formation is almost exclusively catalyzed by UGT2B7, whereas several UGTs in the UGT1A subfamily and UGT2B7 contribute to M3G formation. Increased M6G:morphine ratios have been reported in persons homozygous for the SNPs constituting the UGT2B7*2 allele. Although persons genotyped as UGT2B7*2/*2 can produce higher-than-anticipated concentrations of pharmacologically active morphine and its metabolites, prospective pharmacogenetic studies addressing phenotype-genotype correlations and the consequences of morphine analgesia have had conflicting results.

Arylamine N-Acetyltransferases

One of the most widely recognized genetic polymorphisms is the NAT2 polymorphism. Approximately 50% of whites and African-Americans in North America are phenotypically slow metabolizers, placing a substantial number of persons at increased risk for the development of adverse drug effects, such as sulfasalazine-induced hemolysis, hydrazine- or arylamine-induced peripheral neuropathy, procainamide- or isoniazid-induced systemic lupus erythematosus, and Stevens-Johnson syndrome or toxic epidermal necrolysis associated with sulfonamide administration. NAT2 function is inherited in an autosomal dominant fashion, with the inheritance of 2 “slow” alleles required for expression of the slow-metabolizer phenotype. The relative proportion of rapid and slow metabolizers varies considerably with ethnic or geographic origin. The percentage of slow acetylators among Canadian Inuit population is 5%, but it approaches 90% in some Mediterranean populations.

In vivo, with the use of caffeine as a phenotyping probe, all infants 0-55 days of age appear to be phenotypically slow acetylators, whereas 50% and 62% of infants 122-224 and 225-342 days of age, respectively, can be characterized as fast acetylators. Several independent studies indicate that maturation of the NAT2 phenotype occurs during the first 4 yr of life. Phenotype-genotype discordance is likely to be most apparent in the first 2-4 mo of life, and drugs that are highly dependent on NAT2 function for their elimination should be used with caution.

Thiopurine S-Methyltransferase

Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of aromatic and heterocyclic sulfur-containing compounds, such as 6-mercaptopurine (6MP), azathioprine, and 6-thioguanine, used in treating acute lymphoblastic anemia (ALL), inflammatory bowel disease, and juvenile arthritis and for preventing renal allograft rejection. To exert its cytotoxic effects, 6MP requires metabolism to thioguanine nucleotides by a multistep process that is initiated by hypoxanthine guanine phosphoribosyl transferase. TPMT prevents thioguanine nucleotide production by methylating 6MP (Fig. 56-4A). TPMT activity is usually measured in erythrocytes, with activity in erythrocytes reflecting that found in other tissues, including liver and leukemic blasts.

Figure 56-4 Thiopurine S-methyltransferase (TPMT) polymorphism. A, 6-Mercaptopurine (6MP) undergoes metabolism to thioguanine nucleotides (TGNs) to exert its cytotoxic effects. TPMT and xanthine oxidase reduce the amount of 6MP available for the bioactivation pathway to TGNs. TPMT can also methylate 6-thioinosine 5′-monophosphate (TIMP) to generate a methylated compound capable of inhibiting de novo purine synthesis. B, Distribution of TPMT activity in humans. Of the population, 89% has high activity and 11% has intermediate activity. Approximately 1 in 300 individuals homozygous for 2 loss-of-function alleles has very low activity. C, Correlation between the TPMT genotype and intracellular TGN concentrations. In TPMT poor metabolizers, more 6MP is available to go down the bioactivation pathway to form TGNs; this situation is associated with an increased risk of myelosuppression. D, The most common variant TPMT allele is the result of 2 mutations that give rise to an unstable protein product that undergoes proteolytic degradation. 6TU, 6-thiouric acid; MeMP, 6-methylmercaptopurine; HPRT, 6-thiomethylinosine 5-monophosphate; MeTIMP, hypoxanthine-guanine phosphoribosyl transferase; wt, wild type; mut, mutant.

(Modified with permission from Relling MV, Dervieux T: Pharmacogenetics and cancer therapy, Nat Rev Cancer 11:99–108, 2001;

Although approximately 89% of whites and African-Americans have high TPMT activity and 11% have intermediate activity, 1 in 300 persons inherit TPMT deficiency as an autosomal recessive trait (Fig. 56-4B). In newborn infants, peripheral blood TPMT activity is reported to be 50% greater than in race-matched adults and shows a distribution of activity that is consistent with the polymorphism characterized in adults. No data currently indicate how long this higher activity is maintained, although TPMT activities were comparable to previously reported adult values in a population of Korean schoolchildren aged 7-9 yr. In patients with intermediate or low activity, more drug is shunted toward production of cytotoxic thioguanine nucleotides.

TPMT can also methylate 6-thioinosine 5′-monophosphate to generate a methylated metabolite that is capable of inhibiting de novo purine synthesis (Fig. 56-4C). Three mutations have been identified in the TPMT gene (*2, *3A, *3C), which account for 98% of white subjects with low activity. These mutations encode proteins that undergo rapid proteolysis resulting in low enzyme activity.

TPMT*3A is the most common mutant allele and is characterized by 2 nucleotide transition mutations, G460A and A719G, that lead to 2 amino acid substitutions Ala154Thr and Tyr240Cys (Fig. 56-4D). Although the *3A allele only has a frequency of 0.03% in the general population, it represents 55% of all mutant alleles. Either mutation alone results in loss of functional activity through the production of unstable proteins that are subject to accelerated proteolytic degradation. Less-common allelic variants involve SNPs that produce amino acid substitutions in the coding region and defective intron-exon splicing. A polymorphic locus has been identified in the promoter region of the TPMT gene involving 4-8 repeats of a specific nucleotide sequence in tandem. Although these repeats appear to modulate TPMT activity when expressed in vitro, their role in regulating activity in vivo has not been clearly established.

The relatively few patients with low to absent TPMT activity (0.3%) are at increased risk for severe myelosuppression if treated with routine doses of thiopurines; thus, they require a 10-15–fold reduction in dose to minimize this risk. Furthermore, if the drug is not dosed properly, patients may be at increased risk for relapse as a result of inadequate or absent treatment with thiopurines. Given the expanding use of 6MP and azathioprine in pediatrics to treat inflammatory bowel disease and juvenile arthritis and to prevent renal allograft rejection, TPMT pharmacogenetics is not a trivial matter.

Pharmacogenetics of Drug Transporters

There are several major types of membrane transporters, including organic anion transporter (OATs), organic anion transporting polypeptides (OATPs), organic cation transporting proteins (OCTs), and the adenosine triphosphate (ATP)-binding cassette (ABC) transporters, such as p-glycoprotein and the multidrug-resistant proteins (MRPs). Membrane transporters are heavily involved in drug disposition and actively transport substrate drugs between organs and tissues. Drug transporters are expressed at numerous epithelial barriers, such as intestinal epithelial cells, hepatocytes, renal tubular cells, and at the blood-brain barrier (Fig. 56-5). Transporters often are also determinants of drug resistance, and many drugs work by affecting the function of transporters. Polymorphisms in the genes encoding these proteins can have a significant effect on the ADME and the pharmacodynamic effect of a wide variety of compounds.

Figure 56-5 Schematic diagram of important transport proteins and their known locations in humans. Spheres correspond to drug molecules.

(From Ritschel WA, Kearns GL, editors: Handbook of basic pharmacokinetics including clinical applications, ed 7, Washington, DC, 2009, American Pharmacists Association, p 45.)

The ABC Superfamily

The ABC transporters belong to the largest known transporter gene family and translocate a variety of substrates, including chemotherapy agents. ABC multidrug transporter expression has been implicated in tumor cell resistance to anticancer therapy, altered disposition of chemotherapy drugs, and toxic side effects associated with chemotherapy. The genetic heterogeneity of a number of the ABC transporter genes has been described; apart from having at least one ATP-binding domain, these transporters are characterized by a signature sequence of amino acid residues within the ATP-binding domain. In humans, the ABC transporters function as efflux pumps, which together with detoxification enzymes, constitute a complex integrated chemical-immunologic defense system against drugs and other foreign chemicals. A variety of epithelial barriers, including the kidney, liver, and blood-brain barrier, have abundant expression of ABC transporters, such as P-glycoprotein (P-gp; also known as MDR1), and multidrug resistance proteins (MRPs) 1, 2, and 3 (MRP1, MRP2, and MRP3, respectively). Powered by ATP, these transporters actively extrude substrates from the respective cell and organ.

Considerable genetic variation has been reported to exist in the superfamily of ABC transporter genes. Many studies have been designed to investigate the relationship between ABCB1 genotype or haplotype and P-glycoprotein expression, activity, or drug response. Unfortunately, many of these studies have yielded inconsistent results largely owing to methodologic limitations.

Studies conducted in children need to also consider the ontogeny of P-gp expression. Based on studies using human lymphocytes, it appears that P-gp activity is high at birth, decreases between the ages of 0 and 6 mo, and stabilizes between 6 mo and 2 yr of age. In contrast, P-gp can be detected in human neural stem and progenitor cells and decreases with differentiation. P-gp has been proposed as an endothelial marker for development of the blood-brain barrier, and expression increases with postnatal age as the blood-brain barrier matures. Thus, the developmental patterns of P-gp expression likely are tissue-specific, but data are very limited in this regard. Nevertheless, it is likely that expression of P-gp at a young age in gut and liver represents a protective mechanism in which both endogenous and exogenous toxins are efficiently excreted from the body.

However, developmental patterns of expression in tissues of drug response, such as lymphocytes and tumors, can also affect the efficacy of intracellular drugs. For example, polymorphisms in the gene have been shown to predict the ability to wean steroids after heart transplantation, as well as the susceptibility to and clinical outcome of treatment for pediatric acute lymphoblastic leukemia (ALL). On the other hand, immaturity of P-gp expression in the developing blood-brain barrier might contribute to discrete periods of increased susceptibility to drug toxicity in the CNS. However, for most other drugs, including immunosuppressants and protease inhibitors, studies investigating the effect of ABCB1 polymorphisms in drug disposition and response have yielded conflicting results.

Organic Anion Transporting Polypeptides

OATPs in the solute carrier organic anion transporter (SLCO) represent a family of glycoprotein transporters with 12 transmembrane-spanning domains and are expressed in various epithelial cells. There are 11 OATPs in humans, some of which are ubiquitously expressed and others whose expression is restricted to specific tissues. Typical substrates include bile salts, hormones and their conjugates, toxins, and various drugs. The solute carrier, human OATP1A2 (also called OATP-A, OATP1, and OATP) is highly expressed in the intestine, kidney, cholangiocytes, and the blood-brain barrier and may be important in the absorption, distribution, and excretion of a broad array of clinically important drugs. Several nonsynonymous polymorphisms have been identified in the gene encoding OATP1A2, SLCO1A2 (SLC21A3), with some of these variants demonstrating functional changes in the transport of OATP1A2 substrates.

OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) are liver-specific transporters and promote the cellular uptake of endogenous substrates, such as bilirubin, bile acids, DHEA sulfate, and leukotriene C4, as well as various drugs, including several statins, methotrexate, and enalapril. Allelic variation in OATP1B1 (specifically, the SLCO1B1*5 allele) results in reduced clearance and increased systemic exposure of several statin drugs (atorvastatin, pravastatin, and simvastatin) and has been associated with an increased risk of musculoskeletal side effects from simvastatin. The ontogeny of OATP1B1 has not been extensively studied in children, but the results of a small pharmacogenetic study conducted in children with familial hypercholesterolemia and pediatric cardiac transplant patients revealed an association between SLCO1B1*5 and pravastatin concentrations that was the opposite to that observed in adults.

Organic Cation Transporters

Organic cation transporters (OCTs) in the SCL22A subfamily are primarily expressed on the basolateral membrane of polarized epithelia and mediate the renal secretion of small organic cations. Originally, OCT1 (also known as SLC22A1) was thought to be primarily expressed in liver, but studies have also localized its expression to the apical side of proximal and distal renal tubules. OCT2 (SLC22A2) is predominantly expressed on the basolateral surface of proximal renal tubules. In adults, allelic variation in OCT1 and OCT2 is associated with increased renal clearance of metformin. The role of genetic variation of OCT1 and OCT2 has not been studied in children, but developmental factors appear to be operative. For example, neonates possess very limited ability to eliminate organic cations, but this function increases rapidly during the first few mo of life, and when standardized for body weight or surface area, it tends to exceed adult levels during the toddler stage.

Pharmacogenetics of Drug Response: Polymorphisms in Drug Receptors, Ion Channels, and Other Drug Targets during Growth and Development

Receptors are the targets for drugs and endogenous transmitters owing to their inherent molecular recognition sites. Drugs and transmitters bind to the receptor to produce a pharmacologic effect. Variability in the receptor protein or the ion channel can determine the magnitude of the pharmacologic response. For example, polymorphisms of the β₂-adrenergic receptor gene (ADRB2) have been associated with variable responses to bronchodilator drugs.

Drug responses are seldom monogenic events because multiple genes are involved in drug binding to the pharmacologic target and in the subsequent downstream signal transduction events that ultimately collectively manifest as a therapeutic effect. Although genotypes at a particular locus can show a statistically significant effect on the outcome of interest, they might account for only a relatively small amount of the overall population variability for that outcome. For example, a particular group of SNPs in the corticotropin-releasing hormone receptor 1 (CRHR1) gene is associated with a statistically significant improvement in forced expiratory volume in 1 second (FEV₁), but accounts for only 6% of the overall variability in response to inhaled corticosteroids (Chapter 138). A series of subsequent studies has determined that allelic variation in several genes in the steroid pathway contributes to overall response to this form of therapy.

The listing and classification of receptors is a major initiative of the International Union of Pharmacology (IUPHAR). The list of receptors and voltage-gated ion channels is available on the IUPHAR website (http://www.iuphar-db.org). The effect of growth and development on the activities and binding affinities of these receptors, effectors, and ion channels has been studied in animals to some extent, but it remains to be elucidated in humans.

Applications for Pharmacogenetics and Pharmacogenomics in Pediatrics

Progress being made in the treatment of ALL provides an outstanding example of how the application of pharmacogenomic principles can improve pediatric drug therapy (Chapter 489). Despite improved understanding of the genetic determinants of drug response, however, many complexities remain to be resolved. Patients with ALL who have 1 wild-type allele and intermediate TPMT activity tend to have a better response to 6MP therapy than patients with 2 wild-type alleles and full activity. Reduced TPMT activity also places patients at risk for irradiation-induced secondary brain tumors and etoposide-induced acute myeloid leukemias. Pharmacogenetic polymorphisms of several additional genes also have the potential to influence successful treatment of ALL. Multiple genetic and treatment-related factors interact to create patient subgroups with varying degrees of risk, and these represent an opportunity for pharmacogenomic approaches to identify subgroups of patients who will benefit from specific treatment regimens and those who will be at risk for short- and long-term toxicities (Fig. 56-6).