Genotype-guided Therapy Research Articles

Influence of CYP450 Enzymes, CES1, PON1, ABCB1, and P2RY12 Polymorphisms on Clopidogrel Response in Patients Subjected to a Percutaneous Neurointervention

PurposeClopidogrel is a thienopyridine prodrug that inhibits platelet aggregation. It is prescribed to prevent atherothrombotic and thromboembolic events in patients receiving a stent implant in carotid, vertebral, or cranial arteries. The influence of cytochrome P-450 (CYP) 2C19 on the response to clopidogrel has been widely studied; however, the effect of other genes involved in clopidogrel absorption and metabolism has not been established in this cohort of patients. MethodsThis observational retrospective study assessed the antiplatelet response and the prevalence of hemorrhagic or ischemic events after percutaneous neurointervention in clopidogrel-treated patients, related to 35 polymorphisms in the genes encoding the clopidogrel-metabolizing enzymes (CYP2C19, CYP1A2, CYP2B6, CYP2C9, CYP2C9, CYP3A4, CYP3A5, carboxylesterase-1 [CES1], and paraoxonase-1 [PON1]), P-glycoprotein transporter (ABCB1), and platelet receptor P2Y12. Polymorphisms were analyzed by quantitative real-time polymerase chain reaction and matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry. Antiplatelet response was documented with the VerifyNow system (Accriva, San Diego, California). FindingsWe confirmed that CYP2C19 is the most important enzyme involved in clopidogrel response. The carriage of the CYP2C19*2 allele was strongly associated with hyporesponse to clopidogrel, while the CYP2C19*17 allele was a protective factor for the development of ischemic events (odds ratio = 0.149; P = 0.002) but a risk factor for bleeding (odds ratio = 3.60; P = 0.038). Patients carrying ABCB1 mutated alleles showed lower aggregation values, suggesting that clopidogrel absorption is influenced by P-glycoprotein. In fact, the percentage of responders was significantly higher in the group carrying the mutated haplotype compared to the wild type (80.8% vs 43.3%; P = 0.009). Patients with the CES1 G143E C/T genotype showed a considerably lower, aggregation value versus wild-type patients, although the difference was not significant likely due to the small sample size (59.0 [21.2] vs 165.2 [86.0] PRU; P = 0.084), which suggests an increased active metabolite formation. No relationship was found between polymorphisms in other CYP genes, PON1, or P2RY12 and response to clopidogrel in patients subjected to neurointervention procedures. ImplicationsTherapeutic guidelines recommend that CYP2C19 intermediate and poor metabolizers with acute coronary syndromes undergoing percutaneous coronary intervention receive an alternative antiplatelet therapy; however, genotype-guided therapy is not a standard recommendation for neurovascular conditions. This is the first study to carry out a joint analysis of CYP2C19 and other genes involved in clopidogrel treatment in patients receiving percutaneous neurointervention. Our findings support routine genotyping in clopidogrel-treated patients. Moreover, we encourage considering an alternative antiplatelet therapy in CYP2C19 intermediate, poor and ultrarapid metabolizers. Additionally, ABCB1 polymorphisms could be considered for a better pharmacogenetic approach.

Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology

The Clinical Laboratory Improvement Amendments of 1988 require that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a Clinical Laboratory Improvement Amendments-accredited laboratory. Because no known reference materials were available, existing DNA samples were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other Clinical Laboratory Improvement Amendments-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays.

Genotype-guided therapy reduces toxicity, saves costs

Genotype-guided therapy reduces toxicity, saves costs

Genotype-guided therapy reduces toxicity, saves costs

Genotype-guided therapy reduces toxicity, saves costs

Prevalence of HIV-1 transmitted drug resistance and viral suppression among recently diagnosed adults in São Paulo, Brazil.

HIV-1 transmitted drug resistance (TDR) mutations may reduce the efficacy of antiretroviral therapy (ART), but pre-treatment testing to determine the virus genotype can improve the efficacy of ART. Unfortunately, issues related to cost and logistics of pre-treatment testing limit its use in resource-limited settings. We studied 596 ART-naive individuals who were newly diagnosed from 2014 to 2016 in São Paulo, Brazil, to evaluate TDR and virological outcome after 48weeks of genotype-guided therapy. One or more TDR (based on the WHO surveillance list) was observed in 10.9% (CI 95%, 8.6-13.6) of the sequences, the most common of which was the K103N mutation, which confers resistance to first-generation drugs of the non-nucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral drug class. Dual-class (1%, 6/596) and triple-class (0.34%, 2/596) resistance were uncommon. After 48weeks of treatment with ART, infection was suppressed to below 200 copies/mL in most patients (95%), with full suppression (RNA target not detected) in 65%. The following characteristics at patient enrollment were independently associated with a lack of full suppression: CD4 T cell counts below 500 cells/µL, viremia above 100,000 copies/mL, older age, and TDR to NNRTI. The rates of resistance were intermediate, but genotype-guided therapy resulted in high rates of viral suppression. The observed resistance profile should not be an obstacle to the use of the dolutegravir-based regimen now recommended in Brazil, but genotype testing may be warranted before initiating first-generation NNRTI-based regimens.

CYP2C19 pharmacogenetics versus standard of care dosing for selecting antiplatelet therapy in patients with coronary artery disease: A meta-analysis of randomized clinical trials.

This study aimed to evaluate the efficacy and safety of personalized genotype-guided selection of antiplatelet therapy versus standard of care in patients undergoing percutaneous coronary intervention (PCI). Clopidogrel is the most frequently used P2Y12 receptor antagonist in patients with coronary artery disease. However, genetic variations of clopidogrel are associated with inter-individual response variability which could limit its efficacy. Electronic databases were searched for all randomized clinical trials (RCTs) evaluating genotype-guided therapy versus standard of care in patients undergoing stent implantation. Aggregated risk ratios (RRs) and 95% CIs were calculated using a random-effects model. We included 6 RCTs with a total of 2,371 patients. When compared with standard of care, the use of genotype-guided therapy did not significantly reduce major adverse cardiovascular events (MACE) (RR 0.67; 95% CI: 0.35-1.27; P = 0.22). However, MACE was significantly reduced in the subset of trials which enrolled only acute coronary syndromes (ACS) (P < 0.01). In addition, there was a significant reduction in myocardial infarction in the genotype-guided group (RR 0.44; 95% CI: 0.28-0.70; P < 0.01; I2 = 0%). Other clinical outcomes were not significantly different: cardiovascular mortality (RR 0.68; 95% CI: 0.27-1.74; P = 0.42), stroke (RR 0.62; 95% CI: 0.23-1.65; P = 0.34), stent thrombosis (RR 0.37; 95% CI: 0.13-1.06; P = 0.06), and bleeding (RR 0.68; 95% CI: 0.43-1.06; P = 0.09). In patients undergoing stent implantation, MACE with genotype-guided therapy was not significantly reduced; however, there was a signal towards reduction of MACE in ACS patients, as well as a lower rate of MI, though this will require further confirmation in adequately powered trials.

Cytochrome P450 genotype-guided drug therapies: An update on current states.

Over the past 2 decades, knowledge of the role and clinical value of pharmacogenetic markers has expanded so that individualized pre-emptive therapy based on genetic background of patients could be within reach for clinical implementation. This is evidenced from the frequent updating of drug labels that incorporates pharmacogenetic information (where compelling data become available) by the regulatory agencies (such as the US FDA), and the periodical publication of guidelines of specific therapeutic recommendations based on the results of pharmacogenetic tests by the pharmacogenetics working groups or consortiums of professional bodies. Clinical relevance of the cytochrome P450 (CYP) polymorphism related to dose, effectiveness and/or toxicity of key drugs are presented in this review, including that of warfarin, clopidogrel, tricyclic antidepressants, and proton pump inhibitors. Prospect for routine clinical application of CYP genotyping before prescribing drugs is still currently unclear due to challenges and barriers associated with availability of well-defined and validated pharmacogenetic studies, the interpretation, result reporting and potential error of genotype testing, involvement of non-genetic factors, and other patient's demographic and disease conditions. Further studies to provide additional supporting clinical data and acceleration of pharmacogenetic testing standards and techniques should help improve the evidence base needed for clinical utility and hence move the implementation of genotype-guided therapy in clinical practice a step closer to reality.

Clinical Pharmacogenetics of Cytochrome P450-Associated Drugs in Children

Cytochrome P450 (CYP) enzymes are commonly involved in drug metabolism, and genetic variation in the genes encoding CYPs are associated with variable drug response. While genotype-guided therapy has been clinically implemented in adults, these associations are less well established for pediatric patients. In order to understand the frequency of pediatric exposures to drugs with known CYP interactions, we compiled all actionable drug–CYP interactions with a high level of evidence using Clinical Pharmacogenomic Implementation Consortium (CPIC) data and surveyed 10 years of electronic health records (EHR) data for the number of children exposed to CYP-associated drugs. Subsequently, we performed a focused literature review for drugs commonly used in pediatrics, defined as more than 5000 pediatric patients exposed in the decade-long EHR cohort. There were 48 drug–CYP interactions with a high level of evidence in the CPIC database. Of those, only 10 drugs were commonly used in children (ondansetron, oxycodone, codeine, omeprazole, lansoprazole, sertraline, amitriptyline, citalopram, escitalopram, and risperidone). For these drugs, reports of the drug–CYP interaction in cohorts including children were sparse. There are adequate data for implementation of genotype-guided therapy for children for three of the 10 commonly used drugs (codeine, omeprazole and lansoprazole). For the majority of commonly used drugs with known CYP interactions, more data are required to support pharmacogenomic implementation in children.

Genetics in the Clinical Decision of Antiplatelet Treatment.

Coronary artery disease remains the leading cause of death globally. Dual antiplatelet treatment with aspirin and aP2Y12 receptor significantly reduces thrombotic events. However, antiplatelet drug response displays considerable interindividual variability. Genetic factors account for up to 70% of impaired drug response. A number of genes encoding proteins involved in the pharmacokinetic pathway have been found to alter drug response. According to most studies, CYP2C19 gene is the strongest genetic determinant. The novel antiplatelet agents prasugrel and ticagrelor, seem to overcome genetic restrictions but in expense of increased bleeding rates. Achieving a balance between adequate platelet inhibition and bleeding complications is challenging. Genetic screening may provide valuable guidance towards an efficient antiplatelet treatment. However, the lack of randomized controls trials testing the effect of a genotype-guided therapy, forbids the implementation of genetic testing into clinical practice.

Institutional profile: University of Florida Health Personalized Medicine Program.

The University of Florida (UF) Health Personalized Medicine Program launched in 2012 with CYP2C19 genotyping for clopidogrel response at UF Health Shands Hospital. We have since expanded CYP2C19 genotyping to UF Health Jacksonville and established the infrastructure at UF Health to support clinical implementation for five additional gene-drug pairs: TPMT-thiopurines, IFNL3 (IL28B)-PEG IFN-α-based regimens, CYP2D6-opioids, CYP2D6/CYP2C19-antidepressants and CYP2C19-proton pump inhibitors. We are contributing to the evidence based on outcomes with genotype-guided therapy through pragmatic studies of our clinical implementations. In addition, we have developed a broad array of educational programs for providers, trainees and students that incorporate personal genotype evaluation to enhance participant learning.

Implementation of inpatient models of pharmacogenetics programs.

The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided drug therapy in pharmacogenetics programs at three institutions is highlighted. Pharmacists are well positioned to assume important roles in facilitating the clinical use of genetic information to optimize drug therapy given their expertise in clinical pharmacology and therapeutics. Pharmacists have assumed important roles in implementing inpatient pharmacogenetics programs. This includes programs designed to incorporate genetic test results to optimize antiplatelet drug selection after percutaneous coronary intervention and personalize warfarin dosing. Pharmacist involvement occurs on many levels, including championing and leading pharmacogenetics implementation efforts, establishing clinical processes to support genotype-guided therapy, assisting the clinical staff with interpreting genetic test results and applying them to prescribing decisions, and educating other healthcare providers and patients on genomic medicine. The three inpatient pharmacogenetics programs described use reactive versus preemptive genotyping, the most feasible approach under the current third-party payment structure. All three sites also follow Clinical Pharmacogenetics Implementation Consortium guidelines for drug therapy recommendations based on genetic test results. With the clinical emergence of pharmacogenetics into the inpatient setting, it is important that pharmacists caring for hospitalized patients are well prepared to serve as experts in interpreting and applying genetic test results to guide drug therapy decisions. Since genetic test results may not be available until after patient discharge, pharmacists practicing in the ambulatory care setting should also be prepared to assist with genotype-guided drug therapy as part of transitions in care.

The feasibility of molecular testing on cell blocks created from brush tip washings in the assessment of peripheral lung lesions.

With the rapid development of genotype-guided therapies, molecular testing is becoming important in the management of lung cancer. Bronchoscopy is one of the most common investigations performed to diagnose and investigate lung cancer. Given the limited samples often produced by bronchoscopy, this study aims to evaluate the feasibility of performing molecular testing on cell blocks created from bronchoscope cytology brush tip washings (BTW). Patients with positive brush cytology for tumour cells had cell blocks created from the BTW. Mutations were detected using amplicon-based massively parallel sequencing of targeted regions of EGFR, KRAS, and BRAF genes. A total of 45 patients were included in this study. Of those, 91% had adequate specimens for molecular analysis and 66% of patients with adenocarcinoma had mutations detected. Bronchial brush tip wash cell blocks were the sole specimen available for molecular testing in 27 (60%) patients. The findings of this study demonstrate that molecular testing can be performed on cell blocks created from BTW and this technique may allow for an increase in bronchoscope specimens amenable to molecular testing without further increasing morbidity and mortality.

Abstract P3-07-23: CYP2D6 genotype and breast cancer recurrence in tamoxifen treated patients: An evaluation of the importance of loss-of-heterozygosity

Abstract Background: Tamoxifen therapy for estrogen receptor positive (ER+) breast cancer reduces recurrence risk by about half. Steady-state concentrations of endoxifen, a potent anti-estrogenic tamoxifen metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Many studies have measured associations between genetically impaired CYP2D6 function and tamoxifen resistance. It has been suggested that the subset of studies using DNA extracted from tumor-infiltrated tissue may have been susceptible to genotyping error induced by loss of heterozygosity (LOH); the putative non-differential genotype misclassification may have biased these studies' estimates toward the null. We reviewed the clinical epidemiology studies conducted to date to assess the importance of loss-of-heterozygosity (LOH) at the CYP2D6 locus and its implications for assessing tamoxifen effectiveness. Methods: We searched for the terms "tamoxifen" and "CYP2D6" in PubMed, including all papers and abstracts through 31 May 2015 on the association of CYP2D6 gene variants and the risk of breast cancer recurrence or mortality. We used a quantitative bias analysis (QBA) to evaluate the importance of genotype misclassification in studies that extracted DNA from tumor-infiltrated tissue. We conducted a random effects meta-analysis to evaluate all studies simultaneously, and within groups according to whether DNA was derived from tumor-infiltrated tissue or non-neoplastic tissue. Results: Thirty-one studies investigated CYP2D6 genotype and breast cancer recurrence, yielding relative effect estimates ranging from 0.08 to 14. DNA was extracted from blood or non-neoplastic tissue in 21 of these 31 studies (68%), and from tumor-infiltrated tissue in the remaining 10 (32%). Our analysis of the association between variant/variant genotype compared with wildtype/wildtype genotype included 21 of the 31 studies. Sixteen (76%) of these 21 studies extracted DNA from blood or non-neoplastic tissue and five (24%) extracted DNA from tumor-infiltrated tissue. Genotype misclassification parameters for the QBA were estimated from six concordance studies. There was little difference between the effect estimates (EE) and 95% confidence/simulation intervals (95% CI/SI) before and after QBA (EE=1.71, 95%CI=1.24, 2.36, and 1.80 95%SI=1.28, 2.54, respectively). Studies using non-neoplastic DNA had higher variance than those based on tumor-infiltrated tissue DNA, half reported implausibly high EE, and many were susceptible to design and analysis errors that would bias estimates of association away from the null. Conclusions: We found little relative bias in the summary estimates of association, either overall or when limited to the tumor-infiltrated tissue DNA studies. Three guideline panels, based on robust evidence, recommend against CYP2D6 genotype-guided tamoxifen therapy. Alternatives for optimizing the effectiveness of tamoxifen therapy, such as assuring adherence and persistence, are more likely to achieve clinically important benefits. Citation Format: Ahern TP, Hertz DL, Damkier P, Ejlertsen B, Hamilton-Dutoit SJ, Rae JM, Regan MM, Thompson AM, Lash TL, Cronin-Fenton DP. CYP2D6 genotype and breast cancer recurrence in tamoxifen treated patients: An evaluation of the importance of loss-of-heterozygosity. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-23.

Differential Response to Risperidone in Schizophrenia Patients by KCNH2 Genotype and Drug Metabolizer Status.

Antipsychotic drugs target dopamine and serotonin receptors as well as Kv11.1 potassium channels encoded by KCNH2. Variable patient responses and a wide range of side effects, however, limit their efficacy. Slow metabolizer status and gene variants in KCNH2 associated with increased expression of Kv11.1-3.1, an alternatively spliced isoform of Kv11.1, are correlated with improved responses to antipsychotic medications. Here, the authors test the hypothesis that these effects may be influenced by differential drug binding to Kv11.1 channel isoforms. Drug block of Kv11.1 isoforms was tested in cellular electrophysiology assays. The effects of drug metabolism and KCNH2 genotypes on clinical responses were assessed in patients enrolled in the multicenter Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Risperidone caused greater in vitro block of the alternatively spliced Kv11.1-3.1 isoform than full-length Kv11.1-1A channels, whereas its metabolite paliperidone and other atypical antipsychotics have similar potencies for the two isoforms. In the CATIE study (N=362), patients with genotypes associated with increased Kv11.1-3.1 expression (N=52) showed a better treatment response to risperidone compared with other drugs, but this association was dependent on metabolism status. Patients with KCNH2 risk genotypes and slow metabolizer status (approximately 7% of patients) showed marked improvement in symptoms when treated with risperidone compared with patients with fast metabolizer status or without the KCNH2 risk genotypes. These data support the hypothesis that Kv11.1 channels play a role in the therapeutic action of antipsychotic drugs, particularly risperidone, and further highlight the promise of optimizing response with genotype-guided therapy for schizophrenia patients.

PCV76 - Systematic Review of Recent Pharmacoeconomic Evaluations Related to Genotype-Guided Therapy In Patients at High Risk for Thrombotic Event

PCV76 - Systematic Review of Recent Pharmacoeconomic Evaluations Related to Genotype-Guided Therapy In Patients at High Risk for Thrombotic Event

Abstract P1-03-02: CYP2D6 intermediate metabolizers includes patient groups with distinct metabolic activity

Abstract Background: Tamoxifen is a selective estrogen receptor modulator that is the most commonly used and cost effective hormonal agent for pre-menopausal hormone-receptor positive breast cancer patients. CYP2D6 activity phenotype, which is classified by genotype, predicts the extent of metabolic activation of tamoxifen to endoxifen. We previously reported that increasing the daily dose to 40 mg/day in intermediate metabolizers (IMs), but not poor metabolizers (PMs), achieves target endoxifen concentrations, defined as that of extensive metabolizers (EMs) on 20 mg/day. There was substantial endoxifen variability in the IM phenotype group, which is composed of several discrete diplophenotypes (EM/IM, EM/PM, IM/IM, IM/PM). We enrolled a second, larger cohort of patients in order to determine whether these diplophenotypes should be combined into a single IM phenotype or segregated. Methods: 380 patients on tamoxifen ≥ 4 months and not on potent CYP2D6 inhibiting medications enrolled in Lineberger Comprehensive Cancer Center (LCCC) trial 0801. Genotyping was performed using the Amplichip® CYP450 test (Roche Diagnostics) for CYP2D6, followed by systematic assignment of phenotype based on diplophenotype. Tamoxifen was increased from 20 to 40 mg/day in PMs and IMs. Endoxifen concentrations in IM diplophenotypes were compared with EM/EMs and PM/PMs at baseline and at 4 months (after dose increase in patients with IM and PM phenotypes). Results: After exclusion of UM patients and patients missing endoxifen data at baseline and/or 4 months, 295 patients were included in this analysis. At baseline the EM/IM patients had similar endoxifen level to the EM/EM patients while the IM/IM and IM/PM patients had similar levels to the PM/PMs. After 4 months on 40 mg/day the endoxifen concentrations in EM/IM patients were significantly greater than EM/EMs; EM/PM and IM/IM patients were similar to EM/EMs; but IM/PM patients remained significantly lower than EM/EMs and similar to PM/PMs (See Table 1 for results). Conclusions: The large group of patients currently defined as CYP2D6 intermediate metabolizers is comprised of four distinct CYP2D6 diplophentoypes. The most metabolically active diplophenotype (EM/IM) are very similar to EM/EMs while the least active diplophenotype (IM/PM) are similar to PM/PMs. A more accurate CYP2D6 activity classification system may be necessary if genetic association testing and genotype-guided therapy are pursued. Endoxifen Level at Baseline and 4 Months by CYP2D6 Diplophenotype Baseline Endoxifen 4-Month Endoxifen DiplophenotypenMedian (SD)P-val vs. EM/EMP-val vs. PM/PMMedian (SD)P-val vs. EM/EMP-val vs. PM/PMEM/EM11038.67 (6.01)NAp=0.00018.23 (5.09)NAp=0.007EM/IM2568.02 (4.75)p=0.09p=0.00213.11 (9.38)p&amp;lt;0.0001p&amp;lt;0.0001EM/PM2745.72 (4.45)p=0.0001p=0.028.91 (5.28)p=0.42p=0.003IM/IM2174.29 (4.10)p=0.001p=0.266.52 (5.53)p=0.27p=0.24IM/PM2323.90 (3.17)p&amp;lt;0.0001p=0.485.82 (3.47)p=0.0009p=0.77PM/PM3133.33 (2.89)p=0.0001NA6.08 (2.57)p=0.007NA1Diplophenotype classified as extensive metabolizer phenotype, continued on 20 mg/day. 2Diplophenotypes classified as intermediate metabolizer phenotype, changed to 40 mg/day. 3Diplophenotype classified as poor metabolizer phenotype, changed to 40 mg/day. Citation Format: Daniel L Hertz, Anna C Snavely, Howard L McLeod, Christine M Walko, Joseph G Ibrahim, Steven Anderson, Karen E Weck, Peter Rubin, Oludamilola Olajide, Susan Moore, Rachel Raab, Daniel R Carrizosa, Steven Corso, Gary Schwartz, Jeffrey M Peppercorn, James P Evans, Zeruesenay Desta, David A Flockhart, Lisa A Carey, William J Irvin Jr. CYP2D6 intermediate metabolizers includes patient groups with distinct metabolic activity [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-03-02.

Pharmacogenomics: personalizing pediatric heart transplantation.

In recent years, outcomes for pediatric cardiac transplantation (PCTx) have steadily improved, with current 5-year overall survival rates estimated at 83%.1 This progress may be attributed to improvements in pretransplantation management, selection of donor hearts, surgical technique, prevention and treatment of rejection, and minimization of treatment-related adverse events. Despite these advances, children who receive cardiac transplants experience significant morbidity and mortality, and there is considerable variability in outcomes, much of which cannot be explained by known clinical risk factors. One source of interindividual variability is genetic variation in the host. There is growing evidence that genomic variation leads to differences in immune response, response to therapies, and susceptibility to adverse outcomes such as malignancy and infection.2–4 This review will focus on the effect of variation in genes that encode enzymes, transporters, and drug target molecules that influence drug response. After review of the foundational principles of pharmacogenomics, evidence for the pharmacogenomic effects on cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil (MMF), and the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus will be reviewed and clinical implications of these findings discussed. Given the limited nature of evidence from studies of PCTx patients, support will also be drawn from non-PCTx research and pediatric renal transplantation. Genetic studies of nonpharmacogenes such as those in immunomodulatory pathways and variation in the donor genotype may contribute to risk prediction but are beyond the scope of this review. ### Genetic Variation DNA variation can alter biological function through several mechanisms (Figure 1). Variation within the coding sequence or in intron/exon borders can change the protein product through changes in start codons, stop codons, splice sites, or within the coding sequence, leading to nonsense-mediated decay or altered protein function. Other variants associated with pharmacogenomic outcomes are not predicted to change the encoded protein. These synonymous and …

Cost-utility analysis of genotype-guided antiplatelet therapy in patients with moderate-to-high risk acute coronary syndrome and planned percutaneous coronary intervention.

Prasugrel is recommended over clopidogrel in poor/intermediate CYP2C19 metabolizers with acute coronary syndrome (ACS) and planned percutaneous coronary intervention (PCI), reducing the risk of ischemic events. CYP2C19 genetic testing can guide antiplatelet therapy in ACS patients. The purpose of this study was to evaluate the cost-utility of genotype-guided treatment, compared with prasugrel or generic clopidogrel treatment without genotyping, from the US healthcare provider's perspective. A decision model was developed to project lifetime economic and humanistic burden associated with clinical outcomes (myocardial infarction [MI], stroke and major bleeding) for the three strategies in patients with ACS. Probabilities, costs and age-adjusted quality of life were identified through systematic literature review. Incremental cost-utility ratios (ICURs) were calculated for the treatment strategies, with quality-adjusted life years (QALYs) as the primary effectiveness outcome. Relative risk of developing myocardial infarction and stroke between patients with and without variant CYP2C19 when receiving clopidogrel were estimated to be 1.34 and 3.66, respectively. One-way and probabilistic sensitivity analyses were performed. Clopidogrel cost USD19,147 and provided 10.03 QALYs versus prasugrel (USD21,425, 10.04 QALYs) and genotype-guided therapy (USD19,231, 10.05 QALYs). The ICUR of genotype-guided therapy compared with clopidogrel was USD4,200. Genotype-guided therapy provided more QALYs at lower costs compared with prasugrel. Results were sensitive to the cost of clopidogrel and relative risk of myocardial infarction and stroke between CYP2C19 variant vs. non-variant. Net monetary benefit curves showed that genotype-guided therapy had at least 70% likelihood of being the most cost-effective alternative at a willingness-to-pay of USD100,000/QALY. In comparison with clopidogrel, prasugrel therapy was more cost-effective with <21% certainty at willingness-to-pay of >USD170,000/QALY. Our modeling analyses suggest that genotype-guided therapy is a cost-effective strategy in patients with acute coronary syndrome undergoing planned percutaneous coronary intervention.

Cost-Effectiveness of IL-28 Genotype-guided Protease Inhibitor Therapy in Hepatitis C-infected Patients

Cost-Effectiveness of IL-28 Genotype-guided Protease Inhibitor Therapy in Hepatitis C-infected Patients

A Pharmacogenetics Service Experience for Pharmacy Students, Residents, and Fellows

To utilize a comprehensive, pharmacist-led warfarin pharmacogenetics service to provide pharmacy students, residents, and fellows with clinical and research experiences involving genotype-guided therapy. First-year (P1) through fourth-year (P4) pharmacy students, pharmacy residents, and pharmacy fellows participated in a newly implemented warfarin pharmacogenetics service in a hospital setting. Students, residents, and fellows provided genotype-guided dosing recommendations as part of clinical care, or analyzed samples and data collected from patients on the service for research purposes. Students', residents', and fellows' achievement of learning objectives was assessed using a checklist based on established core competencies in pharmacogenetics. The mean competency score of the students, residents, and fellows who completed a clinical and/or research experience with the service was 97% ±3%. A comprehensive warfarin pharmacogenetics service provided unique experiential and research opportunities for pharmacy students, residents, and fellows and sufficiently addressed a number of core competencies in pharmacogenetics.