**4.1 Warfarin and CYP2C9/VKCOR**

The most commonly prescribed medication for which a pharmacogenetic test has been proposed is warfarin [63]. The adoption of such testing as a standard of care has had to overcome three major challenges: (i) the presence of an alternative biomarker, the international normalized ratio, which is widely used and trusted by the practice community [64]; (ii) the need for specific dosing guidelines resulting from testing; and (iii) the need to demonstrate improvements not only in short-term toxicity but also in long-term toxicity [65]. Several dosage algorithms have been presented, and an international collaboration of researchers led by the PharmGKB (Pharmacogenomics Knowledge Base) has developed a clear, generalizable dosing methodology. Only the VKORC1 (P = 6.2 10–13) and CYP2C9 (P = 5 10–4) polymorphisms were found to be significant in a genome-wide association investigation of about 550,000 polymorphisms, suggesting that extensive and expensive trials would be necessary to find other relevant genetic variations [66]. The United States Food and Drug Administration (FDA) has revised the labeling to include genetic information, recognizing the importance of the relationship between the CYP2C9 genotype and the risk of severe bleeding episodes as well as a number of effectiveness surrogates [67]. Additional studies on the specificity and sensitivity of testing for both effectiveness and toxicity will likely be required before existing practice guidelines are amended to incorporate CYP2C9 9 and VKORC1 testing as clinical recommendations [68].

#### **4.2 Tamoxifen and CYP2D6**

Numerous studies across the world have investigated correlations between genotype and clinical outcome since the Consortium on Breast Cancer Pharmacogenomics identified a substantial relationship between the active metabolite endoxifen concentrations and the CYP2D6 genotype [69, 70]. Although more than 10 studies have been published on the subject, they are all small, and none of the large prospective trials comparing tamoxifen to aromatase inhibitors have been opened for analysis [71]. This is important, since the publishing of small studies might lead to selection bias and underpowered results in the research. Given that complex CYP genotypes can now be determined from paraffin sections [72], these data should be critical to the long-term clinical utility of CYP2D6 testing for tamoxifen efficacy in the many practice settings where it is used.

#### **4.3 (5-fluorouracil) and dihydropyrimidine dehydrogenase deficiency**

5-Fluorouracil is a chemotherapeutic medication commonly used to treat solid tumors, but its inconsistent effectiveness is exacerbated by its equally variable and often severe mucocutaneous toxicity [73]. The main metabolic enzyme in the target of 5-fluorouracil, dihydropyrimidine dehydrogenase, has a significant number of functional genetic variations [74]. Because testing for these variations cannot identify all cases of toxicity, their specificity and sensitivity are limited. This might be due to contributions from unknown genetic variations or nongenetic variables, such as age and gender, which have been shown to impact 5-fluorouracil clearance and toxicity [75]. Genome-wide association studies and the development of predictive scores integrating both clinical and genetic variables may be useful in this regard.

#### **4.4 Irinotecan and UGT1A1**

Variable effectiveness and possibly life-threatening toxicity limit the use of irinotecan as an effective therapy for colorectal and lung cancer [76]. Irinotecan is metabolized to the active metabolite SN-38, which is then removed by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1)-catalyzed phase II glucuronidation [77]. It was immediately realized that this enzyme is also the primary cause of Gilbert's syndrome's benign, congenital hyperbilirubinemia. UGT1A1 polymorphisms are also predictive of irinotecan pharmacokinetics and treatment results, according to a number of studies [78, 79]. Irinotecan's FDA-approved label has been updated to contain a reference to UGT1A1 genetic testing but no precise dosage recommendations. This, along with evidence that UGT1A1 testing may not be predictive for all irinotecan dosage regimens, has limited the test's utility [58]. FDA labeling has not resulted in widespread usage of this test. This might be due to the absence of wellestablished alternative therapy options for patients with certain UGT1A1 genotypes as well as the unknown effects of testing.

#### **4.5 Azathioprine, 6-mercaptopurine, and thiopurine methyltransferase**

Granulocytopenia is a rare but life-threatening complication caused by giving standard dosages of azathioprine or 6-mercaptopurine to those who have homozygous thiopurine methyltransferase gene variations (TPMT) [80]. Although these medicines are approved for the treatment of leukemia in children, most of their

*Interplay between Pharmacokinetics and Pharmacogenomics DOI: http://dx.doi.org/10.5772/intechopen.108407*

clinical usage is in the treatment of inflammatory bowel disease in adults, where there have been fewer studies evaluating their efficacy. The perception that alternative indicators, such as a simple measurement of white blood cell count, may be used in place of the genetic test has limited its usage [81]. Furthermore, the availability of an equally predictive alternative—the test for phenotypic enzyme activity—has led to the increased adoption of this phenotypic test in some situations. The TPMT genotyping test is now included on the FDA labels for the medicines in question, but neither the criteria for testing nor the ramifications of the test's results are specified [82]. Overall, the rarity of the variant phenotype, the availability of alternative predictors, and an FDA label that is neither specific nor proscriptive restrict the widespread utility of testing for the TPMT genotype.

#### **4.6 Abacavir and HLA\*B5701**

Abacavir's usage in the treatment of HIV/AIDS is linked to severe skin sensitivity, which has severely restricted its use [83]. Fortunately, significant skin responses are strongly linked to a germline HLA variation, and HLA\*B5701 testing has been routinely utilized to prevent these reactions all over the world [84]. As a result, the medication is now used more effectively, and genetic testing is now the standard of care when abacavir is administered. The release of large prospective clinical trials demonstrating decreases in the incidence of skin sensitivity responses with clinically acceptable specificity and sensitivity has contributed to this accomplishment [85]. These studies were linked to a significant rise in the usage of testing [86]. However, abacavir is not extensively utilized in all clinical settings, and a single pharmacoeconomic analysis found that HLA-B\*5701 testing would remain the favored approach only if abacavir-based treatment was as effective as tenofovir-based treatment and if the cost was lower per month.

#### **4.7 Carbamazepine and HLA-B\*1502**

Carbamazepine can induce severe skin responses, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, similar to abacavir. These negative occurrences have been linked to a specific HLA allele, HLA-B\*1502,18, which is found nearly exclusively in Asian people [87]. HLA-B\*1502 genetic testing is available, and the FDA has determined that Asian individuals should be tested before commencing carbamazepine medication [88]. Unless the predicted benefit clearly justifies a higher risk of severe skin responses, carbamazepine should not be initiated if they test positive. Even if a pharmacogenetic impact is limited to a particular ethnic group, rapid FDA action is conceivable when the link is convincing and a therapeutic change may be achieved, as in the instance of carbamazepine. It is worth noting that the identical genetic variation has recently been linked to phenytoin hypersensitivity responses.

#### **4.8 Clozapine and HLA-DQB1**

Agranulocytosis, the most serious side effect of clozapine, has been linked to the HLA locus, limiting the use of this essential and effective medicine [89]. An association between the incidence of clozapine-related agranulocytosis and HLA-DQB1\*0201 in schizophrenia patients has been reported [90]. This assumption is based on short trials with a small number of 50 patients, making it less powerful and specific than in the instances of abacavir and carbamazepine. As a result, the test has a lower acceptance rate, and recommendations have yet to be developed.
