Clinical applications of pharmacogenomics to adverse drug reactions

Review

10.1586/17512433.1.2.251 © 2008 Future Drugs Ltd ISSN 1751-2433 251www.future-drugs.com

Clinical applications of pharmacogenomics to adverse drug reactionsExpert Rev. Clin. Pharmacol. 1(2), 251–260 (2008)

Amalia M IssaAssociate Professor and Director, Program in Personalized Medicine & Targeted Therapeutics, The University of Houston, 300 Technology Building, Houston, TX 77204, [email protected]

The problem of adverse drug reactions is a well-documented global public health problem.Recent withdrawals of several widely used prescription medications in the USA and othercountries have raised concerns among patients, clinicians, scientists and policy makers. Theincreasing interest and concern regarding withdrawal of previously approved prescriptionmedications and drug safety has prompted renewed research efforts aimed at improvingsurveillance of approved drugs and reducing adverse drug reactions. Pharmacogenomicsresearch is increasingly directed at developing genomic diagnostics and tests with predictiveability for adverse drug reactions. This paper focuses on the problem of adverse drug reactionsand reviews the evidence and the state of the science for the application ofpharmacogenomics to adverse drug reactions.

KEYWORDS: adverse drug reaction • β2-adrenergic receptor • cytochrome P450 • pharmacodynamics • pharmacokinetics • long QT syndrome • torsade de pointes • TPMT • UGT1

It is widely recognized that individuals responddifferently to drugs and that this interindividualvariability can result in toxicity and adverse drugreactions (ADRs). Indeed, ADRs are a globalpublic health problem [1–9]. In the UK, approxi-mately 7% of patients are affected by ADRs [5]

and, in the USA, ADRs are included among theleading causes of mortality [1–3]. A recent reportestimated that ADRs accounted for 2.5% of vis-its to hospital emergency units and 6.7% of hos-pitalizations [10]. Additionally, the costs incurredby hospitalization for ADRs have been esti-mated at US$150 per patient, with an averagehospitalization of 5 days per patient, suggestinga significant economic burden [7].

Pharmacogenomics, and the study of thegenetic differences that underlie interindividualvariability of drug response and the sciencebehind personalized medicine, offers the poten-tial for minimizing or eliminating ADRs [11–13].

Currently, there are numerous examples thatboth pharmacokinetic (PK) factors (includingdrug absorption, metabolism distribution andexcretion) and pharmacodynamic (PD) charac-teristics, such as receptor response, may beaffected, at least in part, by genetic poly-morphisms that encode drug-metabolizingenzymes (DMEs), drug transporters and/ordrug targets, such as receptors [14–17].

The purpose of this paper is to review ADRs,the clinical applications of pharmacogenomics,assess the potential for pharmacogenomics toreduce the frequency of ADRs, provide anassessment of the associated economic conse-quences and, finally, provide a perspective onthe evolution of the field of pharmacogenomicsand its application to the problem of ADRs.

Classification of ADRsThe focus of this review is on the current statusand potential of pharmacogenomics to mini-mize or eliminate ADRs and, therefore, the dis-cussion of adverse events will be limited to thosecovered by the WHO’s definition of an ADR as‘any noxious, unintended and undesired effectof a drug which occurs at doses used in humansfor prophylaxis, diagnosis, or therapy’ [18].

Adverse drug reactions are usually classifiedinto two broad categories: type A and type B,depending primarily on frequency, althoughseveral classification schemes have been pro-posed [11,19,20]. A more elaborate classificationscheme is shown in TABLE 1.

Type A, or ‘augmented’ ADRs, representingapproximately 80% of the overall proportion ofADRs observed, are common, fairly predicta-ble, dose related and tend to depend on drug

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252 Expert Rev. Clin. Pharmacol. 1(2), (2008)

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properties. Dose adjustment usually resolves type A reactions,which are exemplified by adverse events such as dizziness or diplo-pia, for instance. By contrast, type B (referred to as ‘bizarre’) reac-tions tend to be uncommon, idiosyncratic and frequently patientspecific, rather than dose related. Malignant hyperthermia orimmunological events, such as penicillin-induced rash, are exam-ples of type B adverse reactions. Genetically determined alterationsin DMEs can predispose to both type A and B reactions.

Impact of pharmacogenomics on PK & PD

There has been much interest in understanding the role of phar-macogenomics in ADRs, and this has centered mainly on theinvolvement of PK factors, in particular, drug metabolism. How-ever, there is now increasing recognition that PD (i.e., geneticvariation in drug targets) might also predispose to ADRs,although research into this area is not quite as far advanced asthat on the pharmacogenomics of PK [21,22]. Several examples ofdrugs that were withdrawn from the US market, owing to severeadverse events and their associated genetic polymorphisms, arehighlighted in TABLE 2.

Pharmacokinetics

Pharmacokinetics describes drug processes, including absorption,distribution, metabolism and elimination [23]. Drug absorptiondepends upon a variety of factors, including drug solubility(lipophilicity), formulation, molecular weight and route ofadministration. Factors influencing drug distribution includemembrane permeability and plasma protein binding. Thebiotransformation or metabolism of drugs is generally classifiedinto two types; phase I and phase II reactions. Drugs undergoingphase I or no synthetic reactions are oxidized or reduced to a morepolar form. Oxidation is usually undertaken by the cytochromeP450 (CYP) enzymes. In phase II or synthetic reactions, a polargroup is conjugated to the drug to increase drug polarity, thereforemaking the drug more soluble. Many drugs that cause ADRs aremetabolized by CYP enzymes. The association between CYP

enzymes and predisposition to ADRs has been reviewed compre-hensively [24–26]. Polymorphisms in the genes encoding for PKaffect drug plasma levels and may result in increases (toxicity) ordecreases (lack of drug action) in drug levels, either of which canlead to an adverse event.

Pharmacodynamics

Pharmacodynamics refers to the relationships between drugconcentration at its site of action and the magnitude of its bio-logical effect. Most drugs bind to cellular receptors, where theyinitiate a series of biochemical reactions that alter the cell’sphysiology. The main determinants of a given drug’s PD prop-erties are the specific molecular interactions between the drugand its target (i.e., receptor, ion channel or transporter).

The function of drug target proteins can also be influencedby genetic polymorphisms. An important example, discussedfurther below, is the variation in the efficacy of the β2-agonistsalbutamol due to a polymorphism of the gene that codes forβ2-adrenergic receptors (ARs).

State of the science: the potential for pharmacogenomics to minimize or prevent ADRsPharmacogenomic & PK considerationsMuch of the research related to the contribution of pharmaco-genomics has been conducted on the DMEs undergoingphase I and II reactions.

The CYP DMEs, which are known to play a major role in theoxidative and reductive metabolism of a large number of drugs, areamong the most extensively studied and many drugs that result inADRs are metabolized by CYP enzymes. Interindividual geneticvariability, including interethnic differences, has been demon-strated in the CYP gene superfamily that codes for many CYPenzymes [26–30]. The known CYP polymorphisms have beenreviewed extensively [24–26] and a comprehensive discussion of theADRs that have been demonstrated to be associated with the CYPpolymorphisms is beyond the scope of this review.

Table 1. Classification scheme of adverse drug reactions.

Category of adverse drug reaction

Nature of adverse drug reaction and mode of action

A (augmented) Dose related; depend on pharmacological properties of drug; adjustment of dose usually resolves type A reactions

B (bizarre) Not usually dose related; idiosyncratic; rare and frequently patient specific

C (chronic) Long-term adverse effects observed after prolonged use of a drug

D (delayed) Reactions that occur following prolonged use of a drug, usually for chronic conditions

E (end of treatment) End of treatment reactions occur as a result of the discontinuation of a drug (e.g., β-blocker withdrawal-induced rebound arrhythmia)

F (failure) Therapeutic failure of a drug; typically associated with the introduction of another drug and concomitant interactions

Clinical applications of pharmacogenomics to adverse drug reactions Review

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Interindividual variation in the CYP gene results in variationin enzyme activity. CYP genetic polymorphisms may result inreduced or altered activity, such that substrate specificity isaffected, abolished activity if the gene is deleted leading to non-functionality of the affected CYP enzyme protein, or aug-mented activity that results in multiple copies of a given CYPenzyme and increased enzyme metabolic capacity [24,31]. Clini-cally, the phenotypic manifestations of these differences inactivity are classified into three types: poor metabolizers (PMs),extensive metabolizers (EMs) and ultrarapid metabolizers(UMs) [31]. The CYP3A4, CYP2C9, CYP2D6 representapproximately 60–70% of phase I drug metabolism [31].

Clinical implications of CYP2D6One of the best studied genetic polymorphisms in drug metab-olism is CYP2D6 [31,201]. The original discovery of theCYP2D6 polymorphism occurred as a result of observed inter-individual differences in the metabolism of the antihyperten-sive drug debrisoquin [32] and the antiarrhythmic drugspartein [33]. Debrisoquin and spartein were subsequently usedas probes to identify human subjects as either PMs or EMs, andthe approach of administering a drug to probe for metabolismby a genetically polymorphic enzyme is now a commonly usedmethod in pharmacogenomic research studies [34].

Further molecular work on CYP2D6 revealed a series ofgenetic variants that result in a range of phenotypicallyexpressed enzyme activity [35,201,202].

The clinical relevance of variability in CYP2D6 expressiondepends on factors such as:

• The contribution of CYP2D6 to the overall metabolism ofthe drug;

• The therapeutic index of the drug and whether drug activityis due to the parent drug, to a metabolite or both.

Individuals who are classified as PMs tend to have ahigher parent drug concentration and may develop toxicconcentrations with standard doses. In some cases, when theCYP metabolite is more active than the parent, a decreaseddrug effect may occur because of reduced production of theactive metabolite. On the other hand, UMs eliminateCYP2D6 substrates very quickly and may not achieve thera-peutic levels with standard doses. Specific examples areoutlined below.

CYP2D6 variations occur relatively frequently in the genepool, although the incidence differs by population group[34,35,201,202]. Approximately 5–10% of Caucasians have agenetic profile that makes them PMs of drugs broken downby CYP2D6, whereas among Asians, the proportion isapproximately 15–20%. Almost 30% of people from NorthAfrica and the Middle East are UMs, meaning they may needhigher than standard doses of various drugs.

A significant number of clinically important drugs, includ-ing many cardiovascular and psychotropic drugs, are substratesof CYP2D6 biotransformation (BOX 1) [36,201,202]. Many of thesedrugs are not only intended for long-term use, but also have anarrow therapeutic index, thus increasing the likelihood ofadverse reactions. For example, tricyclic antidepressants carry arelatively high risk of cardiotoxicity [37,38].

Table 2. Selected examples of drugs that were withdrawn from the US market (1990–2007) due to severe adverse drug reactions and associated genetic polymorphisms.

Drug Indication prescribed for

Date withdrawn from market

ADRs precipitating withdrawal

Known or possible associated genetic polymorphisms

Ref.

Terodiline Urinary incontinence September 1991

Torsade de pointes CYP2C19*2 [99]

Dexfenfluramine (Redux®)

Appetite suppression September 1997

Cardiac valvular disease; primary pulmonary hypertension

CYP2D6 [91,92]

Terfenadine (Seldane®)

Antihistamine February 1998 Torsade de pointes IKr (rectifier potassium voltage-gated channel)

[93,95]

Troglitazone (Rezulin®)

Diabetes January 2000 Hepatotoxicity GSTT1-GSTM1 (glutathione S-transferaseµ1; glutathione S-transferase 01)

[97,98]

Cisapride (Propulsid®)

Nocturnal symptoms of gastroesophageal reflux (GERD)

July 2000 Torsade de pointes; prolongation of QT interval

KCNQ1SCN5A

[96]

Cerivastatin (Baycol®)

Cholesterol lowering August 2001 Rhabdomylosis CYP2C8 [94]

Astemizole (Hismanal®)

Antihistamine June 1999 Risk of fatal cardiac abnormalities

CYP3A4 [93,95]

ADR: Adverse drug reaction; GERD: Gastroesophageal reflux disease.


Review Issa

In schizophrenic patients administered antipsychotics knownto be metabolized by CYP26, a series of CYP2D6 variant alleleshas been found [39]. In particular, patients with the CYP2D6*4/*4and *4/*5 alleles, considered PMs, have been shown to exhibitextrapyramidal symptoms, including tardive dyskinesia [39–41].However, these studies were based on small sample sizes andother studies have failed to confirm an association between theseCYP2D6 variant alleles and extrapyramidal events [202,203]. Giventhese contradictory findings in the literature, the clinical utilityof CYP2D6 genotyping prior to prescribing antipsychotics ispresently questionable and not generally performed.

Clinical implications of CYP2C9CYP2C9 constitutes approximately 18% of the CYP2Cenzyme subfamily in the human liver [42,201,202]. Several allelicvariants of CYP2C9 have been identified [36]. From the perspec-tive of clinical relevance, it is noteworthy that CYP2C9 metabo-lism is pertinent to a number of drugs with a narrow therapeuticindex [36,201,202].

One notable example of the importance of CYP2C9 that hasbeen studied extensively is warfarin [43–46]. Warfarin is an anti-coagulant that has been prescribed for the treatment and pre-vention of thromboses for more than 40 years [47,48]. Warfarinis a classic example of a drug with a narrow therapeutic index,with the potential for adverse events as serum drug concentra-tions rise above or fall below the therapeutic range, resulting ineither hemorrhages or thrombotic events, respectively [47,48]. Ameta-analysis of over 30 original studies revealed that serioushemorrhages occur at a rate of 7.2 per 100 patient-years [49].

To date, clinicians have used the international normalizedratio (INR) when administering warfarin therapy, with an idealrange of 2–3 [47,48]. Despite vigilant monitoring, requiring fre-quent clinic visits, in many instances, patients still have varia-bility in the required dosage, failing to achieve an acceptableINR [50,51]. Indeed, Boulanger et al. found that, out of 6454patients administered warfarin for atrial fibrillation, the INRwas outside the acceptable range of 2–3 50% of the time [50].

Warfarin is administered as a racemic mixture of R and Senantiomers, with the S enantiomer being the more active form[47,48]. CYP2C9 is known to be involved in the metabolism of

the S enantiomer, with the CYP2C9*2 variant causing reduc-tions in warfarin metabolism by 30–50% and the CYP2C9*3allele leading to decreases in drug metabolism by 90% [52]. Inparticular, CYP2C9 PMs have been shown to be more likelyto develop major hemorrhagic complications with a five- tosixfold higher risk of elevated INR when warfarin treatmentis initiated [53].

Warfarin metabolism is also influenced by vitamin Kepoxide reductase complex (VKORC)1 polymorphism [54]

and it has been shown that serious overanticoagulation canresult from the combined effects of CYP2C9 plus theC1173T polymorphism of the VKORC1 gene [55–57].

In a decisive action, on August 16 2007, the US FDArevised the product label of warfarin to include CYP2C9 andVKORC1 polymorphisms among the clinical factors consid-ered for warfarin prescribing and dosage maintenance [203].Thus, CYP2C9 and VKORC1 genotyping prior to prescribingwarfarin represents an important clinical application of phar-macogenomics to reducing serious adverse drug events. Alle-les of CYP2C9 also play a role in the metabolism of the antie-pileptic drug phenytoin [58] where variance in drugconcentration can result in neurotoxicities, such as tremorand ataxia [59].

CYP2C19 & CYP3A4Two other CYP450 polymorphic variants that are worth men-tioning are CYP2C19 and CYP3A5. CYP2C19 is responsiblefor the metabolism of several widely used drugs, which includepsychiatric drugs (including many of the tricyclic antidepres-sants and several antipsychotics [60]) and certain gastrointestinalagents (e.g., proton pump inhibitors) [61–63].

Along with CYP3A4, CYP3A5 accounts for the drug metabo-lism of more than 50% of commonly used medications [201,202].An association between atorvastatin-induced myalagia and theCYP3A5*3 polymorphism has been reported [64].

Clinical implications of S-methyltransferaseOne of the earliest examples of product relabeling by the FDAintended to reduce ADRs is that of 6-mercaptopurine andazathiopurine to incorporate thiopurine S-methyltransferase

Box 1. Case study: a fatal adverse drug reaction in a breastfed neonate of a mother who is an ultrarapid metabolizer of CYP2D6.

A case of fatal neonatal morphine toxicity in a breastfed 13-day-old male infant was reported last year [100]. According to the case report, the mother had been prescribed codeine for postpartum-associated pain for 2 weeks postpartum, during which time, she continued to breastfeed. At 7 days after he was born, the male infant progressively developed lethargy and was examined by a pediatrician at 11 days owing to difficulty breastfeeding and changes in skin color. The pediatrician noted that the infant’s weight was normal for his age and reportedly advised the mother to wait [101]. The infant died on day 13, cyanotic and lacking vital signs. No anatomical explanation was found for this neonate’s death upon postmortem evaluation. Subsequent review of the mother’s medical record revealed she had been prescribed Tylenol #3 (30 mg codeine and 500 mg acetaminophen) and laboratory analysis of the mother’s frozen expressed breast milk showed a concentration of 87 ng/ml morphine [100]. Genotyping for CYP2D6 was performed, demonstrating that the mother was heterozygous for the CYP2D6*2A allele and CYP2D6*2x2 gene duplication. Furthermore, the mother and deceased infant were both homozygous for the UGT2B7*2 allele, which has also been shown to contribute to increased morphine metabolism. The authors suggested several possible strategies to avoid neonatal morphine toxicity, including genotyping of postpartum mothers prior to prescribing codeine [100]. This case illustrates the potential for pharmacogenomics to prevent serious and severe adverse drug reactions.



(TPMT) genetic testing as a means to adjust drug dosage toprevent toxicities and serious adverse events [65]. Initially dis-covered in the 1980s [66], the TPMT genetic polymorphismsare implicated in interindividual variability of response todrugs belonging to the thiopurine family, such as 6-mercaptop-urine, a routinely used chemotherapeutic for acute lym-phocytic leukemia (ALL), one of the most prevalent childhoodcancers [67].

A number of allelic variants of TPMT exist [68,69]; however,four variants in particular (TPMT*2, TPMT*3A, TPMT*3Band TPMT*3C) appear to account for the majority of cases ofTPMT enzyme deficiency [69,70]. This finding is significant tothe issue of ADRs, as decreases in TPMT enzyme activity areassociated with hepatoxicity and leukopenia [68,71].

Genotyping for TPMT variants is now offered routinely inthe USA as a Clinical Laboratory Improvement Amendments(CLIA)-certified test. With 98% sensitivity and 99% specifi-city in identifying patients with one or two enzyme deficientalleles, TPMT genotyping represents a successful applicationfor guiding thiopurine treatment [68,71].

A cost–effectiveness analysis conducted in Germany, TheNetherlands, Ireland and the UK found that genotyping ALLpatients for TPMT variants had a favorable cost–effectivenessratio, with a mean cost per life year gained of € 2100 (assuminga rate of genotyping at € 150 per patient) [72]. A study using adecision analytic model in the USA similarly concluded thatgenotyping ALL patients prior to prescribing might potentiallybe cost effective [73].

Uridine 5’-diphosphate glucuronosyl transferaseThe uridine 5´diphosphate glucuronosyl transferase (UGTs)are involved in phase II metabolism of substances that aremetabolized and excreted in the bile and urine, such asbilirubin, various drugs or carcinogens. Of the 16 knownUGTs, at least six (UGT1A1, UGT1A6, UGT1A7, UGT2B4,UGT2B7 and UGT2B15) have so far been shown to exhibitpolymorphic activity [74]. The most clinically significant poly-morphisms occur in UGT1A1. Of particular relevance to thefocus of this review is the association of UGT1A1 expressionand metabolism of the drug irinotecan (Camptosar®). Irinote-can is a widely used oncologic drug, notably for colorectal andlung cancers, but also for pediatric rhabdomyosarcoma andneuroblastoma. Irinotecan, a camptothecin analogue, is atopoisomerase inhibitor that is hydrolyzed to 7-ethyl-10-hydroxycampthothecin (SN-38) to form SN-38 glucuronide(SN-38G) [204].

The most frequently associated UGT1A1 variant that hasbeen demonstrated to be influential in defective SN-38 glu-curonidation is the UGT1A1*28 [74,75]. Approximately 5–15%of Caucasians and between 10 and 25% of Africans and Asiansare homozygous for UGT1A1*28 [76] and, therefore, atincreased risk for irinotecan-associated dose-limiting toxicityand severe ADRs, including myelosuppression (such as withleukopenia and neutropenia) and diarrhea.

Based primarily on cumulative evidence demonstrating theutility of UG1A1*28 as a valid biomarker for reduced UGT1A1enzyme activity and concomitant irinotecan toxicity [77], in2005 the FDA updated the label for irinotecan to include geno-typing information related to irinotecan dosing in UGT1A1*28homozygous individuals [205].

In August 2005, the FDA also approved the invader UTG1A1test [206], which should further facilitate the utility of UGT1A1pharmacogenetic testing for irinotecan prescribing [75].

Pharmacogenomics & PD considerationsPharmacodynamic factors are influenced by specific interactionsbetween the drug and a target, such as ion channels or receptors.PD also account for variability in drug response. Although thecontribution of polymorphisms in genes that encode receptors,drug transporters and ion channels has been less well studiedthan polymorphisms in genes encoding DMEs, there is increas-ing evidence that these genetic polymorphisms play an importantrole in drug response and drug toxicities.

Cardiac channelopathies & polymorphismsIn recent years, a number of prescription drugs have beenwithdrawn from the market following typical type A ADRsinvolving prolongation of the QT interval [12], including longQT syndrome (LQTS) and torsade de pointes (TdP). Thegenetics of voltage-gated potassium channels as drug targetsand particularly those relevant to LQTS events have beenstudied extensively [78]. Genetic variation in genes encodingthe potassium ion channel, notably KCNQ1 and KCNH2,appear to predispose certain individuals to drug-inducedarrhythmias and other QT prolongation-induced ADRs [78].

However, it should also be noted that some of the CYPenzymes have been demonstrated to be influential in drug-induced QT prolongation. Notable among these is CYP3A4,which plays an important role in drug–drug interactions (a sig-nificant clinical problem in QT-prolonging drugs) andCYP2D6 which, as previously mentioned, is known to mediatethe metabolism of several cardiovascular drugs, antipsychoticsand antidepressants [36–39,201,202].

β2-AR as a pharmacogenomic biomarkerSeveral therapeutic drugs target the β2-AR [79] and a number ofpolymorphisms have been shown to be associated with down-regulation, altered expression or coupling of the β2-AR [80]. Ofparticular clinical relevance is the fact that the β2-adrenergicagonistics, such as salbutamol, are among the most frequentlyprescribed asthma drugs [81].

The two most frequently described polymorphisms of the genethat encodes for the β2-AR involve amino acid substitutions atpositions 16 (Arg to Gly 16) and 27 (Gln to Glu 27) [79,81].There is some evidence that these two polymorphisms influ-ence treatment response to albuterol in asthmatics [82–84].Despite this fairly substantive evidence, however, genotypingof β2-AR polymorphisms is not yet routinely performed.


Review Issa

Current limitations of applying pharmacogenomics to ADRs

Although increasing evidence is accumulating regarding thepotential for pharmacogenomics to reduce ADRs [12,13], theuse of routine genotyping in clinical practice is hampered byvarious factors [11,85]. Chief among these is the requirement ofclinical studies with large numbers of human subjects inorder to detect valid associations of polymorphisms with par-ticular ADRs and unknown gene–gene interactions. Further-more, proper analysis and interpretation of such populationtoxicogenomic data is complex [86,87]. It should also be notedthat interindividual variation in drug effects is influenced byenvironmental factors, including drug–drug and food–druginteractions [85].

Concerns regarding cost–effectiveness constitute anothermajor factor contributing to the slow translation of genotyp-ing for ADRs into routine clinical practice. Criteria for thecost-effective utilization of pharmacogenomics, such as sever-ity of the clinical condition, the association between the geno-type and phenotype, and variant allele frequency have beenproposed [73]. However, to date, there are relatively fewcost–effectiveness studies of pharmacogenomics [88].

Expert commentary

Adverse drug reactions are a major public health problem. Theuse of genotyping to identify which patients may be predisposedto a potential ADR in order to better prescribe medications is animportant clinical application of pharmacogenomics.

However, the available data are presently limited to drugswhere a single nucleotide polymorphism is involved or witha well-established therapeutic index. Further clinical studiesare required to better understand the role of multiple poly-morphisms and multigenetic influence on ADRs, as well asthe role of drug–drug interactions and even food–drug (or

other environmental) interactions. Further studies are alsorequired to evaluate the possibility that pharmacogenomicsunderlies the differences in ADRs between males andfemales [89].

Additionally, high-quality validation studies are necessary toverify analytical and clinical validity of genotyping for specificpolymorphisms that might be linked to ADRs. Finally, morestudies of clinical utility and cost–effectiveness are needed inorder to better translate the data on pharmacogenomic appli-cations for ADRs into clinical recommendations and, in turn,into routine clinical practice and healthcare delivery.

Five-year view

Over the next 5–10 years, greater improvement in the technol-ogies and tools used for genotyping will lead to more precisionand cost–effectiveness in identifying patients who may be pre-disposed to be at risk for particular ADRs. A number ofgroups, including the FDA, Centers for Disease Control,EMEA and the International Conference on Harmonisation ofTechnical Requirements for Registration of Pharmaceuticalsfor Human Use, are working to develop consensus guidelinesregarding standards for use of ‘valid biomarkers’ [207–209].

One of the future tasks for pharmacogenomics is the devel-opment of pharmacogenomically guided algorithms that, inconjunction with clinical factors, are capable of integratingthe complex genetic and environmental information that isnecessary to improve clinical decision making regarding theappropriate drug dosages for improved patient outcomes.The development of algorithms is currently being pursuedon a small scale, as in the case of warfarin, for example [90].

Ultimately, using pharmacogenomics to improve our abilityto identify more precisely which patients will be predisposed tocertain ADRs will, by reducing patient morbidity and mortal-ity from ADRs, provide a positive public health, financial andsocietal impact.

Key issues

• Adverse drug reactions (ADRs) remain a significant public health problem.

• Genotyping to identify patients who might be predisposed to the risk of drug-induced adverse events holds valuable promise for minimizing ADRs.

• Currently available data suggest several potential applications of pharmacogenomics to reduce ADRs in a number of therapeutic areas, including cardiovascular, neuropsychiatric and oncological therapeutics.

• One role for pharmacogenomics will be the development of pharmacogenomically guided algorithms that can be used to aid clinicians in making decisions regarding drug dosages for improved patient outcomes.

• Several challenges remain before pharmacogenomics-based testing can be integrated into routine clinical practice, including issues related to analytical and clinical validity, clinical utility and feasibility, and cost–effectiveness.

• Pharmacogenomics-based testing and prescribing of drugs is poised to penetrate clinical practice and become a routine tool in the armamentarium of the clinician.

• Given the fact that ADRs are a major cause of morbidity and mortality worldwide, with significant concomitant use of medical care costs, pharmacogenomic applications for determining ADRs and better prescribing of drugs will no doubt significantly impact healthcare in the future.



Financial & competing interests disclosure

A Issa’s research program is partially supported by a grant from theGreenwall Foundation. Issa is also a member of the Agency forHealthcare Research and Quality’s DEcIDE Network. The author has

no other relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflictwith the subject matter or materials discussed in the manuscript apartfrom those disclosed.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:

• of interest

•• of considerable interest

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20 Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 356(9237), 1255–1259 (2000).

21 Evans WE, McLeod HL. Pharmacogenomics – drug disposition, drug targets, and side effects. NEJM 348(6), 538–549 (2003).

22 Weinshilboum RM, Wang L. Pharmacogenetics and pharmacogenomics: development, science, and translation. Annu. Rev. Genomics Hum. Genet. 7, 223–245 (2006).

23 Wilkinson GR. Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. In: The Pharmacological Basis of Therapeutics (10th Edition). Hardman JG, Limbird LE, Gilman AG (Eds). Goodman & Gilman’s, McGraw-Hill, NY, USA 31–43 (2001).

24 Pirmohamed M, Park BK. Cytochrome P450 enzyme polymorphisms and adverse drug reactions. Toxicology 192(1), 23–32 (2003).

25 Ingelman-Sundberg M. The human genome project and novel aspects of cytochrome P450 research. Toxicol. Appl. Pharmacol. 207(2 Suppl. 1), 52–56 (2005).

26 Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol. Ther. 116(3), 496–526 (2007).

27 Scordo MG, Caputi AP, D’Arrigo C, Fava G, Spina E. Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Pharmacol. Res. 50(2), 195–200 (2004).

28 Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M. Genetic polymorphism of cytochrome P450 2C9 in a caucasian and a black African population. Br. J. Clin. Pharmacol. 52(4), 447–450 (2001).


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29 Ozawa S, Soyama A, Saeki M et al. Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1. Drug Metab. Pharmacokinet. 19(2), 83–95 (2004).

30 Gaedigk A, Bhathena A, Ndjountché A. Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. Pharmacogenomics J. 5(3), 173–182 (2005).

31 Omari AA, Murray DJ. Pharmacogenetics of the cytochrome P450 enzyme system: review of current knowledge and clinical significance. J. Pharm. Practice 20(3), 206–218 (2007).

32 Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic hydroxylation of debrisoquine in man. Lancet 2(8038), 584–586 (1977).

33 Eichelbaum M, Spannbrucker N, Steincke B et al. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur. J. Clin. Pharmacol. 16(3), 183–187 (1979).

34 Weinshilboum R. Inheritance and drug response. N. Engl. J. Med. 348(6), 529–537 (2003).

35 Ingelman-Sundberg M, Evans WE. Unravelling the functional genomics of the human CYP2D6 gene locus. Pharmacogenetics 11(7), 553–554 (2001).

36 Sikka R, Magauran B, Ulrich A, Shannon M. Bench to bedside: pharmacogenomics, adverse drug interaction, and the cytochrome P450 system. Acad. Emerg. Med. 12(12), 1227–1235 (2005).

37 Bertilson L. Dahl ML, Dalen P et al. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br. J. Clin. Pharmacol. 53(2), 111–122 (2002).

38 Lessard E, Yessine MA, Hamelin BA, O’Hara G, LeBlanc J, Turgeon J. Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics 9(4), 435–443 (1999).

39 Scordo MG, Spina E, Romeo P et al. CYP2D6 genotype and antipsychotic- induced extrapyramidal side effects in schizophrenic patients. Eur. J. Clin. Pharmacol. 56(9–10), 679–683 (2000).

40 Charlier C, Broly F, Lhermitte M, Pinto E, Ansseau M, Plomteux G. Polymorphisms in the CYP2D6 gene: association with plasma concentrations of fluoxetine and paroxetine. Ther. Drug Monit. 25(6), 738–742 (2003).

41 Mihara K, Kondo T, Yasui-Fakurukori N et al. Effects of various CYP2D6 genotypes on the steady-state plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, in Japanese patients with schizophrenia. Ther. Drug Monit. 25(3), 287–293 (2003).

42 Romkes M, Faletto MB, Blaisdell JA, Rawey JL, Goldstein JA. Cloning and expression of complementary DNAs for multiple members of the cytochrome P450 II C subfamily. Biochemistry 30(13), 3247–3255 (1991).

43 Voora D, Eby C, Linder MW et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb. Haemost. 93(4), 700–705 (2005).

44 Yuan HY, Chen JJ, Michael Lee MT et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum. Mol. Genet. 14(13), 1745–1751 (2005).

45 Herman J, Peternel P, Stegnar M, Breskvar K, Dolzan V. The influence of sequence variations in factor VII, γ-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb. Haemost. 95(5), 782–787 (2006).

46 Wadelius M, Chen LY, Eriksson N et al. Association of warfarin dose with genes involved in its action and metabolism. Hum. Genet. 121(1), 23–34 (2007).

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48 Hirsch J, Dalen JE, Anderson DR et al. Oral anticoagulants: mechanisms of action, clinical effectiveness and optimal therapeutic range. Chest 114(5 Suppl.) S445–S469 (1998).

49 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann. Intern. Med. 139(11), 893–900 (2003).

50 Boulanger L, Kim J, Friedman M, Hauch O, Foster T, Menzin J. Patterns of use antithrombotic therapy and quality of anticoagulation among patients with non-valvular atrial fibrillation in clinical practice. Int. J. Clin. Pract. 60(3), 258–264 (2006).

51 Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with

non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 91(4), 472–477 (2005).

52 Visser LE, van Schaik RH, van Vliet M et al. The risk of bleeding complications in patients with cytochrome P 450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Thromb. Haemost. 92(1), 61–66 (2004).

53 Higashi MK, Veenstra DL, Kondo LM et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287(13), 1690–1698 (2002).

54 Rost S, Fregin A, Ivaskevicius V et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427(6974), 537–541 (2004).

55 Schalekamp T, Brasse BP, Roijers JF et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin. Pharmacol. Ther. 80(1), 13–22 (2006).

56 Sconce EA, Khan TI, Wynne HA et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106(7), 2329–2333 (2005).

57 Carlquist JF, Horne BD, Muhlestein JB et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J. Thromb. Thrombolysis 22(3), 191–197 (2006).

58 Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol. Rev. 58(3), 521–590 (2006).

59 Hung CC, Lin CJ, Chang CJ, Liou HH. Dosage recommendation of phenytoin for patients with epilepsy with different CYP2C9/CYP2C19 polymorphisms. Ther. Drug Monit. 26(5), 534–540 (2004).

60 de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics 47(1), 75–85 (2006).

61 Furata T, Shirai N, Sugimoto M, Nakamura A, Hishida A, Ishizaki T. Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies. Drug Metab. Pharmacokinet. 20(3), 153–167 (2005).



62 Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin. Pharmacokinet. 41(12), 913–958 (2002).

63 Sapone A, Vaira D, Trespidi S et al. The clinical role of cytochrome P450 genotypes in Helicobacter pylori management. Am. J. Gastroenterol. 98(5), 1010–1015 (2003).

64 Wilke RA, Moore JH, Burmester JK. Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage. Pharmacogenet. Gen. 15(6), 415–421 (2005).

•• Interesting retrospective cohort study investigating the association of cytochrome P450 (CYP)3A variants with atorvastatin-induced muscle damage.

65 Haga SB, Thummel KE, Burke W. Adding pharmacogenetics information to drug labels: lessons learned. Pharmacogenet. Genomics 16(12), 847–854 (2006).

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67 Relling MV, Pui CH, Cheng C, Evans WE. Thiopurine methyltransferase in acute lymphoblastic leukemia. Blood 107(2), 843–844 (2006).

68 Schaeffeler E, Fischer C, Brockmeier D et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German–Caucasians and identification of novel TPMT variants. Pharmacogenetics 14(7), 1407–1417 (2004).

69 Krynetski EY, Evans WE. Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 6(4), 279–290 (1996).

70 Sirot EJ, van der Velden JW, Rentsch K, Eap CB, Baumann P. Therapeutic drug monitoring and pharmacogenetic tests as tools in pharmacovigilance. Drug Saf. 29(9), 735–768 (2006).

•• Interesting article describing the use of pharmacogenomics for the purposes of therapeutic drug monitoring (TDM); a good resource for readers wanting to learn more about the possibilities of pharmacogenomics for TDM.

71 Rocha JC, Cheng C, Liu W et al. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood 105(12), 4752–4758 (2005).

72 van den Akker-van Marle ME, Gurwitz D, Detmar SB et al. Cost–effectiveness of pharmacogenomics in clinical practice: a case study of thiopurine methyltransferase genotyping in acute lymphoblastic leukemia in Europe. Pharmacogenomics 7(5), 783–792 (2006).

73 Veenstra DL, Higashi MK, Phillips KA. Assessing the cost–effectiveness of pharmacogenomics. AAPS PharmSci 2(3), E29 (2000).

74 Burchell B. Genetic variation of human UDP-glucoronosyl-transferase: implications in disease and drug glucuronidation. Am. J. Pharmacogenomics 3(1), 37–52 (2003).

75 Van Bebber S, Phillips KA, Issa AM. Novel personalized medicine technology: UGT1A1 testing for irinotecan as a case study. Pers. Med. 3(4), 415–419 (2006).

76 Premawardhena A, Fisher CA, Liu YT et al. The global distribution length polymorphisms of the promoters of the glucuronosyl-transferase 1 gene (UGT1A1): hematologic and evolutionary implications. Blood Cells Mol. Dis. 31(1), 98–101 (2003).

77 Andersson T, Flockhart DA, Goldstein DB et al. Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin. Pharmacol. Ther. 78(6), 559–581 (2005).

• Balanced discussion of the evidence regarding the promise and limitations of using pharmacogenomics.

78 Shah RR. Pharmacogenetic aspects of drug-induced torsade de pointes: potential tool for improving clinical drug development and prescribing. Drug Saf. 27(3), 145–172 (2004).

79 Liggett SB. β2-adrenergic receptor pharmacogenetics. Am. J. Respir. Crit. Care Med. 161(2 Pt 3), S197–S201 (2000).

80 Johnson JA, Lima JL. Drug receptor/effector polymorphisms and pharmacogenetics: current status and challenges. Pharmacogenetics 13(9), 525–34 (2003).

81 Wechsler ME, Israel E. How pharmacogenomics will play a role in the management of asthma. Am. J. Respir. Crit. Care Med. 172(1), 12–18 (2005).

82 Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the β2-adrenoreceptor and response to albuterol in children with and without a history of wheezing. J. Clin. Invest. 100(12), 3184–3188 (1997).

83 Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term β-agonist use: influence of β2 adrenoreceptor polymorphism. Thorax 55(9), 762–767 (2000).

84 Israel E, Chincilli VM, Ford JG et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomized, placebo-controlled cross-over trial. Lancet 364(9444), 1505–1512 (2004).

85 Wilkinson GR. Drug metabolism and variability among patients in drug response; N. Engl. J. Med. 352(21), 2211–2221 (2005).

86 Wilke RA, Reif DM, Moore JH. Combinatorial pharmacogenetics. Nat. Rev. Drug Discov. 4(11), 911–918 (2005).

87 Wilke RA, Carrillo MW, Ritchie MD. Pacific symposium on biocomputing: computational approaches for pharmacogenomics. Pharmacogenomics 6(2), 111–113 (2005).

88 Phillips KA, Van Bebber SL. A systematic review of cost–effectiveness analysis of pharmacogenomic interventions. Pharmacogenomics 5(8), 1139–1149 (2004).

89 Wang J, Huang Y. Pharmacogenomics of sex difference in chemotherapeutic toxicity. Curr. Drug Discov. Technol. 4(1), 59–68 (2007).

90 Anderson JL, Horne BD, Stevens SM et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 116, 2563–2570 (2007).

91 Gross AS, Phillips AC, Rieutord A, Shenfield GM. The influence of the sparteine/debrisoquine genetic polymorphism on the disposition of dexfenfluramine. Br. J. Clin. Pharmacol. 41(4), 311–317 (1996).

92 Ni W, Li MW, Thakali K, Fink GD, Watts SW. The fenfluramine metabolite (+) norfenfluramine is vasoactive. J. Pharmacol. Exp. Ther. 309(2), 845–852 (2004).

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94 Ishikawa C, Ozaki H, Nakajima T et al. A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin. J. Hum. Genet. 49(10), 582–585 (2004).


Review Issa

95 Napolitano C, Schwartz PJ, Brown AM et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J. Cardiovasc. Electrophysiol. 11(6), 691–696 (2000).

96 Makita N, Horie M, Nakamura T et al. Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation. Circulation 106(10), 1269–1274 (2002).

97 Watanabe I, Tomita A, Shimizu M et al. A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus. Clin. Pharmacol. Ther. 73(5), 435–455 (2003).

98 Acuna G, Foernzler D, Leong D et al. Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity. Pharmacogenomics J. 2(5), 327–334 (2002).

99 Ford GA, Wood SM, Daly AK. CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system. Br. J. Clin. Pharmacol. 50(1), 77–80 (2000).

100 Madadi P, Koren G, Cairns J et al. Safety of codeine during breastfeeding: fetal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can. Fam. Physician 53(1), 33–35 (2007).

• Describes an interesting case report of CYP2D6 variants resulting in a fatal ADR.

101 Priest L. Codeine can turn toxic in nursing mothers. The Toronto Globe and Mail. May 10, 2006.

Websites

201 The cytochrome P450 systemwww.edhayes.com/startp450.html

202 Drug interactions: defining genetic influences on pharmacologic responseshttp://medicine.iupui.edu/flockhart

203 FDA. Questions and answers on new labeling for warfarin (marketed as Coumadin)www.fda.gov/cder/drug/infopage/warfarin/qa.htm

204 Thorn CF, Carrillo MW, Ramirez J et al. Irinotecan pathwaywww.pharmgkb.org/do/serve?objId=PA2001&objCls=Pathway

205 Drugs at US FDAwww.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

206 FDA News. FDA clears genetic test that advances personalized medicine test helps determine safety of drug therapywww.fda.gov/bbs/topics/NEWS/2005/NEW01220.html

207 Table of valid genomic biomarkers in the context of approved drug labelswww.fda.gov/cder/genomics/genomic_biomarkers_table.htm

208 Guidance for Industry: pharmacogenomic data submissionswww.fda.gov/cber/gdlns/pharmdtasub.pdf

209 Vamvaka S, Cavaleri M. Report on the EMEA/CHMP biomarkers workshopwww.emea.europa.eu/pdfs/human/biomarkers/02report.pdf

Affiliation

• Amalia M IssaProgram in Personalized Medicine & Targeted Therapeutics, The University of Houston, 300 Technology Building, Houston, TX 77204, [email protected]

Documents

Clinical applications of pharmacogenomics to adverse drug reactions