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Abnormal Drug Response: Opportunities for Risk Reduction Through Pharmacogenetics

Posted on: Thursday, 16 June 2005, 03:00 CDT

An adverse drug reaction (ADR) can result from a variety of risk factors including variability in pharmacokinetics and pharmacodynamics of a drug due to the genetic make-up of an individual. Other important influences are external factors such as co-medications and co-morbidities, which give rise to drug-drug or drug-disease interactions. The net effect of these interactions is that the prescribed dose of a drug is an inappropriate one. Usually, clinically relevant drug interactions result when the plasma concentration of one of the interacting drugs increases to toxic levels.

With careful attention to prescribing information regarding dose, age-related adjustments and populations at risk for drug-drug and drug-disease interactions, the impact of ADRs can be greatly minimized. However, it is unlikely that any single approach will completely eliminate all ADRs. With available data suggesting that some ADRs might have a monogeneic or polygeneic basis, the application of pharmacogenetics provides an opportunity for further reductions in both the incidence and severity of ADRs.

The article below reviews some of the data on abnormal drug response related to polymorphisms in drug metabolizing enzymes, pharmacological targets and drug transporters. It illustrates how, at least in some areas, pharmacogenetics may offer the prospects of minimizing the risks of drug toxicity and therapeutic failures.

Pharmacogenetics and drug metabolizing enzymes

A number of drug metabolizing enzymes displays genetic polymorphisms. Candidate gene association studies, investigating the role of these polymorphic drug metabolizing enzymes such as CYP2D6, CYP2C9, CYP2C19, N acetyltransferase (NAT2), thiopurine S- methyltransferase (TPMT), UDP-glucuronosyltransferases (UGTs) and dihydropyrimidine dehydrogenase (DPD) have already shown that there is a genetic predisposition to a number of ADRs.

It is now generally assumed that because of this genetic predisposition, there may be a great potential for preventing ADRs and improving the safe and effective use of medicines through the increasing knowledge of genetic factors that determine drug response. Polymorphic genes and products of gene expression have been considered as markers for optimization of drug therapy, most especially in the field of oncology.

Table 1. Clinical consequences for PM and ultrarapid EM phenotypes of CYP2D6

Polymorphic variation in CYP2D6

Studies over the last two decades have shown that any given population may be divided into two phenotypes - extensive metabolizers (EMs) or poor metabolizers (PMs) - depending on their ability to mediate CYP2D6-dependent hydroxylation of the antihypertensive drug debrisoquine. Among the EM phenotype, there are two subgroups of particular interest at either extreme of the EM population distribution. One subgroup, termed the ultrarapid metabolizers (UMs), is comprised of individuals possessing multiple copies of the gene for normal metabolic capacity and the other group, termed the intermediate metabolizers (IMs), is comprised of a heterozygous genotype ("gene-dose effect"). UMs metabolize drugs so avidly that they attain very low concentrations of the parent drug and high concentrations of rapidly accumulating metabolites while IMs display a modest impairment in drug metabolizing capacity.

CYP2D6 is responsible for the metabolism of well over 60 drugs that include antiarrhythmics, b-adrenoreceptor antagonists, antihypertensives, antianginals, neuroleptics, antidepressants, analgesics as well as a number of other miscellaneous drugs. Candidate gene association studies have shown that a number of ADRs to CYP2D6 substrates are related to CYP2D6 genotype (Table 1).

One of the first reports on the clinical significance of CYP2D6 polymorphism and its association with serious toxicity was perhexiline-induced neuropathy in patients with impaired CYP2D6 metabolism. Although the recommended dose of perhexiline was 100 mg three times daily, a recent study of 23 patients has shown that to maintain the plasma concentrations of perhexiline within the therapeutic and non-toxic range, PMs required a dose of 10-25 mg/ day while EM and ultrarapid EM required 100-250 and 300-500 mg/day respectively [1]. Other clinical consequences for individuals with the PM or ultrarapid phenotypes of CYP2D6 are also shown in Table 1.

Application of pharmacogenetic principles may also improve efficacy. There are several examples where subjects carrying certain alleles suffer from a lack of drug efficacy because of ultrarapid metabolism caused by multiple genes or by induction of gene expression. As with perhexiline, some patients who are ultrarapid metabolizers fail to respond to conventional doses of nortriptyline and require 'megadoses' of this antidepressant. Similarly, poor metabolizers fail to respond to therapeutic effects mediated by metabolites. This is illustrated by the relative loss in PMs of analgesic effects following administration of codeine or tramadol or the loss of antiarrhythmic effects of encainide.

Polymorphic variation in CYP2C9

Retrospective case studies have shown that the presence of mutant CYP2C9 allele (especially CYP2C9*3 allele) confers a significantly increased risk of bleeding following treatment with warfarin. Available data, however, indicate that although the CYP2C9*3/ CYP2C9*3 genotype is associated with dramatic over anticoagulation soon after the introduction of oral anticoagulants, overdose during the maintenance period is mostly related to environmental factors [2, 3]. It is also recognised that inter-individual variability in warfarin sensitivity also originates from environmental factors. In one study, age and CYP2C9 genotype accounted for 12% and 10% of the variation in warfarin dose requirements, respectively [4]. Clearly, other pharmacodynamic (such as to an abnormality in the target enzyme vitamin K epoxide reductase) and dietary factors also play an important role. In a retrospective cohort study of patients on long- term warfarin, it was found that the mean maintenance dose varied significantly among the six genotypes of CYP2C9. Compared to patients with the wild type genotype, patients with at least one variant allele required longer time to achieve stable dosing and had a significantly increased risk of a serious or life-threatening bleeding event, although patient numbers were small for some genotypes in this study [5].

Similarly, to achieve a therapeutic serum concentration of phenytoin, patients carrying at least one mutant CYP2C9 allele required a mean phenytoin dose that was about 37% lower than that in patients with wild type genotype (199 mg/day versus 314 mg/day) [6]. Since phenytoin has a narrow therapeutic index and genotyping may be carried out rapidly and at a relatively low cost, dosage adjustment based on CYP2C9 genotype, especially at the induction of therapy, would be of value in order to lower the risk of concentration dependent phenytoin toxicity in the carriers of mutant alleles.

Polymorphic variation in CYP2C19

CYP2C19 mediates the major pathway responsible for metabolic elimination of proton pump inhibitors. Since therapeutic activity correlates with exposure to the parent compound, it is not surprising that a number of studies have shown that PMs of CYP2C19 respond better to H. pylori eradication therapy. These preliminary findings need to be confirmed in large prospective studies [7]. EMs of CYP2C19 require higher doses of these drugs.

Polymorphic variation in thiopurine S-methyltransferase

Azathioprine and 6-mercaptopurine are metabolised by thiopurine S- methyltransferase (TPMT). The activity of TPMT is inversely related to the risk of developing acute leucopenia associated with the use of these drugs. A number of studies have shown that the risk of azathioprine-induced acute leucopenia can be greatly reduced by basing the initial azathioprine dose on TPMT genotype or phenotype [8, 9]. Of course, not all azathioprine-induced toxicities have a genetic basis. In one study of 93 patients, it was noted that azathioprine-related gastrointestinal side effects are independent of TPMT polymorphism [10]. The value of genotyping for TPMT is illustrated by a report from Murphy and Atherton [11] that by initiating therapy at dose levels of 2.5-3.5 mg/kg in atopic eczema patients with a normal TPMT level, they felt confident in reducing the frequency with which tests of bone marrow and liver function had to be undertaken.

Polymorphic variation in UDP-glucuronosyltransferases

Conjugation reactions such as glucuronidation mediated by UDP- glucuronosyltransferases (UGTs) are now also attracting increasing attention, especially in the field of oncology. Glucuronidation is by far the most important conjugation pathway in man. A multigene family encodes the UGTs and a relatively small number of human UGT enzymes catalyse the glucuronidation of a wide range of structurally diverse endogenous (bilirubin, steroid hormones and biliary acids) and exogenous chemicals. Genetic variations and single nucleotide polymorphisms (SNPs) within the UGT genes are remarkably common, and lead to genetic polymorphisms [12, 13]. Some polymorphic UGTs have demonstrated a significant pharmacological impact in addition to being relevant to drug-induced ADRs. Two major isoforms of UDP- glucuronosyltransferase, UGT1A1 and UGT1A9, have been shown to display genetically determined wide inter-individual v\ariability in their activities. Studies investigating the role of UGT1A isoforms in the metabolism of diugs such as irinotecan [14, 15], flavopiridol [16, 17], tranilast [18] and atazanavir [19] have been most valuable in explaining the safety issues (myelosuppression, diarrhoea or hyperbilirubinaemia) associated with the use of these drugs.

A meta-analysis by Phillips et al [20] identified 131 specific drugs, 55 drug classes, and 19 therapeutic drug categories as being associated with ADRs. All except three of these drugs were included among the top 200 selling drugs in the United States. The therapeutic categories associated with the most common ADRs were cardiovascular, analgesics, psychoactive drugs and antibiotics. This meta-analysis included 18 of 333 ADR studies and 22 of 61 variant allele review articles. It identified 27 drugs frequently cited in ADR studies. Among these drugs, 59% were metabolised by at least one enzyme with a variant allele known to cause poor metabolism. In contrast, only 7% to 22% of randomly selected drugs were metabolised by enzymes displaying genetic polymorphism (p = 0.006 - < 0.001). These data suggest that drug therapy based on the genotype of individual patients may result in a clinically important reduction in adverse outcomes.

Pharmacogenetics and transporters

For the vast majority of drugs, however, the reason for individual susceptibility to ADRs has remained unknown and there are hardly any data on genetic susceptibility. However, recent studies have shown that organ-specific organic anion and cation transporters play an important role in the transport of drugs into the cells. These transporters may account for drug-induced toxicity, hitherto termed "idiosyncratic".

Molecular studies have found evidence of genetic polymorphisms of these transporters in hepatocytes [21, 22]. Mutations in the genes coding for these transporters may lead to dysfunctional polypeptides, which affect not only the pharmacokinetics of the drugs concerned but also the potential hepatotoxic effects of some of these drugs [23, 24]. Furthermore, the variant alleles show inter- ethnic differences [22, 25] that may possibly explain inter-ethnic differences in the hepatotoxic potential of a drug (such as ibufenac). Studies investigating these transporters in patients with hepatotoxicity offer exciting prospects for exploring the potential role of pharmacogenetics in drug-induced hepatotoxicity.

These transporters and P-glycoproteins colocalize in organs of importance to drug disposition (intestine, liver and kidney). The expression of P-glycoprotein activity is under the control of the MDR1 gene [26] and is an important factor in the disposition of many drugs. In multidrug resistance (MDR), the processes involved show considerable interindividual and inter-ethnic variability. For example, a variant allele recently designated as MDR1*2 (resulting from three linked SNPs) occurred in 62% of European Americans and only 13% of African Americans [27].

The MDR1 gene and its variants have significant implications in terms of efficacy or development of resistance to anticonvulsants, antineoplastic therapy and anti-HIV drugs [28, 29].

Pharmacogenetics and pharmacological targets

In addition to pharmacogenetic effects on drug metabolism, therapeutically promising examples of genetic variations in pharmacological targets are also beginning to emerge. These targets include receptors, transporters, enzymes, channels and intracellular coupling processes that modulate pharmacodynamic responses. Among the most widely studied are the pharmacological targets related to cardiac arrhythmias, asthma, depression and the HLA antigen genotype in hypersensitivity reactions.

To date, the focus of pharmacogenetic studies in the context of ADRs has been on drug metabolising enzymes. It is now becoming evident that polymorphisms of pharmacological targets (pharmacodynamic polymorphisms) may in fact be even more important. In one study of 270 cancer patients given antiemetic therapy with 5- HTR^sub 3B^ receptor antagonists, approximately 30% suffered from nausea or vomiting despite these drugs. Ultrarapid metabolism of tropisetron (and to a lesser extent for ondansetron) was shown to predispose patients to poor efficacy [30]. In another study by the same group of investigators, patients homozygous for a deletion variant of the promotor region of 5-HTR^sub 3B^ gene were shown to experience vomiting more frequently than did all the other patients [31]. In a pharmacogenetic study that compared paroxetine and mirtazapine in 246 elderly patients with major depression, discontinuations due to paroxetine-induced side effects were strongly associated with the 5-HTR^sub 2A^ C/C, rather than CYP2D6, genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. The severity of side effects in paroxetine-treated patients with the C/ C genotype was also greater [32]. Thus, although paroxetine is metabolised by CYP2D6, polymorphism of 5-HTR^sub 2A^ is a more important determinant of paroxetine-induced ADRs.

Polymorphisms of cardiac potassium channels

Drugs prolonging the QT interval of the surface electrocardiogram (ECG) have attracted considerable attention recently. Excessive prolongation of the QT interval, in the right setting, predisposes to torsade de pointes (TdP), a potentially fatal ventricular tachyarrhythmia [33]. The duration of this interval reflects the duration of ventricular action potential. The major determinant of the action potential duration is the potassium current mediated by the rapid component of the delayed rectifier potassium channels (IKr). Many drugs have been withdrawn as a result of their potential to prolong the QT interval and induce TdP.

Following advances in molecular biology, genetics and pharmacology of ion channels, it has become evident that there is a great diversity of genes that control the expression of these potassium channels. Mutations of the subunits that form these channels, including IKr, are common and give rise to congenital long QT syndromes.

Relatively large numbers of individuals carry variants of long QT syndrome genes that are clinically silent. While these individuals have a normal ECG phenotype, they nevertheless have a diminished repolarization reserve and are highly susceptible to drug-induced QT interval prolongation and/or TdP following normal therapeutic doses of drugs (such as cisapride, astemizole, terfenadine and halofantrine among others) even in the absence of inhibitors of their metabolism [34]. In an analysis of 341 reports of cisapride- induced ventricular arrhythmias, there were 38 (11%) cases in whom there were no identifiable risk factors or contraindications [35]. These individuals may well represent a population with a concealed genetic defect of their potassium channels.

Polymorphisms of b2-adrenoceptors and ALOX-5

Individuals who carry Arg16/Gly16 or Gly16/Gly16 mutations of b2- adrenoceptors have been shown to respond much less favourably to salbutamol-induced bronchodilatation, in contrast to those with wild type receptor characterised by Arg16/ Arg16 genotype - the difference in FEV1 response between Gly16/Gly16 and Arg16/Arg16 genotypes is 6.5-fold [36]. Similarly, asthmatic patients who carry mutations of the core promoter of 5-lipoxygenase (ALOX-5) respond poorly to ALOX-5 inhibitors such as zileuton [37].

Kaye et al [38] have recently shown that in individuals with cardiac failure, patients who were homozygous for the Gln27 allele of b2-adrenoceptor displayed a significantly lower proportion of good responders to carvedilol than did patients who were homozygous or heterozygous for the Glu27 polymorphism (26% versus 63%, p=0.003).

Polymorphisms of the serotonin transporter

Genetic polymorphism in the promoter region of the serotonin transporter (5-HTT) gene is reportedly a determinant of response to fluvoxamine, a selective serotonin re-uptake inhibitor. The insertion variant of this polymorphism (long allele) is associated with higher expression of brain 5-HTT compared to the deletion variant (short allele) [39]. Patients who have one or two copies of the long variant (homozygous I/I or heterozygous l/s) may show a better therapeutic response than patients who are homozygous for the short variant (s/s). The efficacy of fluvoxamine in the treatment of delusional depression has been shown to correlate with 5-HTT genotypes [40].

Abacavir-induced hypersensitivity reactions and HLA genotype

Hypersensitivity reactions (HSR) to abacavir occur in about 5% of patients who receive the drug for HIV-1 infection. Three independent research groups have identified an association between HLA-B*5701 and hypersensitivity to abacavir in patients of Caucasian ancestry [41-44]; the sensitivity of HLA-B*5701 ranged from 46-94%. While two groups suggest that there may be clinical value in prospectively screening Caucasian patients for HLA-B*5701 prior to the use of abacavir [43, 44], in the largest, and most ethnically diverse study, the association between HLA-B*5701 and hypersensitivity was much weaker in Hispanic patients and was absent in Black patients [45]. While this is an interesting example of the potential of pharmacogenetics, there is legitimate risk that HLA B*5701 screening could unintentionally compromise the highly successful risk management programme established for abacavir hypersensitivity. Specifically, physician vigilance might be reduced in patients who do not carry markers associated with hypersensitivity and marker- negative patients might be at increased risk for experiencing serious and/or life-threatening hypersensitivity reactions because symptoms associated with abacavir hypersensitivity are not promptly recognised and abacavir discontinued. Efforts to analyse thousands of SNPs across the genome for association to HSR are under way to identify additional gen\etic markers with sufficient predictive value to be clinically useful [46].

Pharmacogenetics and hepatotoxicity

Hepatotoxicity is of serious concern not only because of the morbidity and mortality associated with it but also because it is the leading reason for withdrawal of drugs from the market [47]. Apart from the role of transporters at the hepatocytes-biliary canalicular interface, there is conclusive evidence for the role of polymorphic drug metabolism in hepatotoxicity associated with some drugs.

For isoniazid, the genetic basis for this toxicity is well known. Individuals who have a low activity of N-acetyltransferase (NAT2 slow acetylators) are at a much greater risk of developing isoniazid- induced hepatotoxicity. Slow acetylators produce a low level of an intermediate metabolite that is also eliminated by acetylation. Failure to eliminate this effectively results in production of an alternative metabolite that is hepatotoxic [48, 49].

Perhexiline-induced hepatotoxicity, a major factor in the drug's withdrawal from the market, is associated with impaired CYP2D6 status [50]. The involvement of genetic factors in drug-induced hepatotoxicity generally is strongly suggested by the susceptibility of the female gender. In addition, there are reports of familial or ethnic susceptibility to hepatotoxicity associated with some drugs such as phenytoin [51] or ibufenac [52] respectively.

Pharmacogenetics and drug interactions

Drug-drug interactions can be dramatically influenced by genotypic differences. A number of studies have shown that CYP2D6 PMs (with alleles expressing no functional enzyme) do not show the drug-drug interactions predicted from in vitro studies. This is hardly surprising since there is no functional CYP2D6 activity to inhibit or induce. Likewise, UMs too may fail to exhibit the expected drug-drug interaction unless the dose of the inhibitor is (toxic) high enough. The individuals most likely to display a drug interaction are those who have an intermediate drug metabolising capacity or those who have inherited CYP2D6 alleles with reduced or altered affinity for CYP2D6 substrates. At the level of CYP2D6, the dependence of drug interactions on the metabolic phenotype has already been shown for a number of its substrates, for example codeine [53], propafenone [54, 55], mexilqtine [56], encainide [57], metoprolol [58] and desipramine [59]. The organic ion transporters and P-glycoproteins referred to earlier are additional sites of important drug interactions and pharmacogenetic factors are also likely to be important here.

Predictive genotyping: improving drug response and minimizing ADRs

It has been estimated that predictive genotyping (for candidate genes) will lead to benefit in 10-20% of drug treatment by allowing prevention of ADRs [60, 61].

If genetic markers of a greater number of ADRs (candidate genes, SNPs or haplotypes) can be identified and if cheap and rapid genotyping of patients can be done routinely, then the impact of ADRs on morbidity and mortality can be considerably reduced. Veenstra et al [62] have reviewed cost-effectiveness of genetic tests and have identified five primary characteristics that will enhance the cost-effectiveness of the application of pharmacogenetics. These are:

1. A well-established association between the genotype and drug response.

2. The variant gene is relatively common.

3. Relatively cheap and rapid genetic test.

4. Difficulties in monitoring drug response.

5. Severe clinical or economic consequences from not using the pharmacogenetic information.

Similar conclusions have been reached by Rioux [63] who has also emphasised the importance of the frequency of the variant allele in determining the cost-effectiveness of the application of pharmacogenetics in therapeutics.

Other workers who have evaluated the potential impact of pharmacogenetics have concluded that its application in therapeutics will be costeffective "sometimes" and that it would be effective primarily for chronic diseases where unnecessary long-term therapy with an ineffective drug for many years could be avoided in some patients [64].

Limitations

It is not intended to suggest that the application of pharmacogenetics will totally eliminate the problems of ADRs. Recently, Kirchheiner et al have provided a preliminary guidance for a number of drugs metabolised by CYP2D6 and CYP2C19 with a view to introducing genotype/ phenotype-specific dose schedules [65]. Recommending inappropriately high dose can easily offset the potential benefits of pharmacogenetics. Co-administration of a metabolic inhibitor converts an extensive metabolizer into a poor metabolizer. It is therefore not surprising that drug interactions feature prominently among the causes that lead to withdrawal of drugs from the market.

One unpublished report analysed 17 studies (with a total of about 1,350 patients) published between 1995-2000 on antipsychotic drug therapy, investigating an association between CYP2D6 genotype and both plasma levels of the drug(s) and response to these drugs [66]. There was a relationship between genotype and plasma concentrations of drugs that were predominantly, metabolised by CYP2D6 but a large intra-genotypic variability obscured clinical utility of concentration measurements.

However, there was no relationship evident between genotype and drug response (i.e. failure to respond beneficially). There was only a modest positive trend between the genotype, especially the presence of CYP2D6*10 allele in the Japanese, and severity of tardive dyskinesia and extrapyramidal syndrome. This may not altogether be surprising since many neuroleptics have active metabolites. When applying pharmacogenetic testing in routine clinical practice, it is important to take note of the pharmacology of the metabolites relative to that of the parent drug, the fraction of the drug cleared by the polymorphic pathway and the therapeutic index of the drug concerned [67].

In humans, diclofenac is metabolised to 4'-hydroxy (OH), 3'-OH and 5-OH metabolites. The polymorphic CYP2C9 is involved in the metabolism of diclofenac to 4'-OH diclofenac and 3'-OH diclofenac. However, the CYP2C9 genotype does not correlate with diclofenac- induced hepatotoxicity or COX-1 and COX-2 inhibition [68, 69]. Similarly, in asthma, patients who are deficient in 5-lipoxygenase due to a genotypic variant in the ALOX-5 gene are non-responsive to 5-lipoxygenase inhibitors. However, most of the 5-lipoxygenase inhibitor non-responders have ALOX-5 genes, and the basis of their nonresponsiveness lies in other factors, probably related to the nature of their asthma.

However, if a genotype/phenotype relationship can be shown, pharmacogenetics offers another important strategy by which to reduce ADRs. The dose schedules recommended need to be carefully chosen and the clinical awareness of the consequences of co- administration of interacting drugs need to be heightened. Prior genotyping of patients can be used to improve safe and more effective use of specific and carefully chosen medicines by identifying patients most likely to respond beneficially and those most likely to develop an ADR. This strategy would immediately translate into great reductions in healthcare and economic resources that are currently expended in managing the consequences of ADRs.

Even if a correlation between genotype and phenotype can be established, it is worth remembering that drug-related problem(s) may not be completely eliminated. This is because a number of non- genetic external factors interact with genotype or modulate the response to a drug. In addition, there are a number of other factors that complicate what may appear to be a simple relationship.

Conclusions

This article highlights the potential contribution of pharmacogenetics in reducing the incidence of dose-related and idiosyncratic ADRs. In relation to ADRs, the research aim of pharmacogenetics is to identify a genetic profile that characterises patients who are more likely to suffer an ADR compared with those in whom the risk is unlikely. Using this knowledge in the clinic, the choice of medicine and dose can be targeted for an individual and the overall result may be an improvement in the safety profile of the drug. Moreover, as a result of improved safety following application of pharmacogenetic principles, improved efficacy may also accrue. Many dosing schedules are limited by appearance of side effects. By eliminating the use of high doses in those genotypes most at risk, it may become possible to evaluate the additional benefits of higher doses in the remaining genotypes.

Advances in biotechnology promise the prospects of characterising genetic variations in individual patients rapidly and cheaply with a view to individualisation of therapy. Exploration of the role of pharmacogenetics should be undertaken during drug development and continued well into the post-marketing period to include the study of rare and delayed adverse reactions. This will make the application of pharmacogenetics in minimising morbidity and mortality from ADRs a realistic and worthwhile proposition.

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Source: WHO Drug Information

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