Pharmacogenomics in Primary Care

Applied PGx

To illustrate how PGx information can affect pharmaceutical management in clinical practice, an illustration drawn from a class of medications that are both commonly used and significantly affected by known biomarkers may be useful. HMG-coenzyme A reductase inhibitors (statins) are an excellent class of drugs to illustrate the value and limitations of PGx in everyday primary care. Cholesterol management is a pillar in primary care and statins are the most commonly prescribed pharmaceutical therapy in the US. They also display extensive inter patient variation in blood levels. Although generally safe, this variation undoubtedly leads to toxicity in some individuals or decreased efficacy in others. Table 3 shows some of the PGx biomarkers associated with variances in statin therapy. The significance of PK biomarkers is similar to PK drug interactions. For example, coadministration of grapefruit and statins is known to increase the blood levels of some statins and increase the risk of ADRs including myalgia and rhabdomyolysis. Coadministration of atorvastatin and grapefruit has resulted in up to a 50% increase in atorvastatin area under the curve (AUC). The mechanism for this interaction is intestinal inhibition of CYP3A4 by grapefruit. CYP3A4 is one of the enzymes that metabolizes atorvastatin into metabolites. The impaired metabolism of atorvastatin as a result of this inhibition results in increased bioavailability of the drug, therefore increasing the risk of ADRs. A loss-of-function allele for CYP3A4 may have similar effects. Indeed a clinical study observed a 78% decrease in atorvastatin dose requirements in CYP3A4*22 allele carriers compared to non-carriers. In these two scenarios, the clinician faces a similar mechanism potentially affected the therapeutic outcome of their prescribing decision. The obvious distinction is that while a patient can be advised not to consume grapefruit when atorvastatin is prescribed, a patient's CYP3A4 loss-of=function allele is inherent. However, the clinical may either opt to decrease the atorvastatin dose or choose an alternative statin that doesn't undergo significant metabolism by CYP3A4 such as rosuvastatin, pitavastatin, pravastatin, or fluvastatin. PD biomarkers can be more challenging to use clinically. When evidence is sufficient however they can help tp understand an individual's overall sensitivity to a medication. For example, one study found patients' response to atorvastatin 20mg daily x 14 days varied based on their HMG coenzyme A reductase (HMGCR) genotype. HMGCR expresses phenotypically as the protein that serves as a receptor for statins. Results showed a 15-23% greater LDL education in HMGCR rs3846662 AA homozygotes compared to GG homozygotes. While this information identifies patients who are most likely to respond to statin therapy, it doesn't strictly predict efficacy of treatment. Perhaps an alternative statin would work better, but due to the limited amount of evidence it is still up to the prescriber to undergo a process of trial and error to determine the optimal treatment strategy. As these brief examples illustrate, the clinical utility of PK biomarkers is much more straightforward since the routes of metabolism and transport of drugs are often well mapped. Simply adjusting dosage to compensate for the known effects or choosing a medication that ultilizes an alternative pathway for metabolism and/or transport may avoid interactions. PGx testing may in turn help a physician achieve optimal pharmacotherapy more efficiently and with less risk of ADRs. As physician knowledge expands, protocols may be developed that will enable PGx testing to become standard of care.

pharmacogenomics/genetics (slides) precision medicine initiative

"doctors have always recognized that every patient i unique, and doctors have always tried to tailor their treatments as best they can to individuals. you can match a blood transfusion to a blood type- that was an important discovery. what if matching a cancer cure to our genetic code was just as easy, just as standard? what if figuring out the right dose of medicine was as simple as taking our temperature?" -president Obama, January 30, 2015. ads are now directed towards the patients (commercial ads) no longer office to office pitching meds to MDs. in the past- scandal 100's million $ r/t bribes for drugs not necessarily the best meds but made the most money for the pharm sales people. MDs were bribed to Rx these meds.

pharmacogenomics/genetics (slides) pharmacogenomics ultimate promise

** goal: the possibility that knowledge of a person's DNA sequence might be used to enhance drug therapy to maximize efficient target drugs only to those people who are likely to respond and to avoid adverse drug responses (ADR). **increasing the number of patients who respond to therapeutic regimen with a concomitant decrease in the incidence of ADR is a much desired outcome. **the long term expected benefits are selective and potent drugs, more accurate drug dosages, advanced screening for disease, and a decrease in the overall cost of health care caused by ineffective therapy. Rx medication/Tx- does not work or have severe s/e before therapeutic effects, cannot use or pass on and give to others. can bring back to MD and have them use for others that cannot afford or waste the money for the drugs unable to use. pharmacogenetics/genomics might help in all of these 3 areas!!

intermediate metabolizer (article)

2 decreased-activity alleles OR one active allele and one inactive allele OR on decreased-activity allele and one inactive allele

extensive metabolizer (article)

2 functional alleles (wild type)

Poor metabolizer (article)

2 inactive alleles

Factor II

20210A allele carriers taking estrogen-containing oral contraceptive (OC) have been found to have a 400-800% increased risk of venous thromboembolism (VTE)

ABCB1 (P-glycoprotein)

2677TT/3435TT - Amlodipine - AUC decreased 33% in 2677TT/3435TT homozygotes compared to 2677GG/3435CC homozygotes

VKORC1

AA and GG homozygotes may have up to a 100% difference in warfarin dose requirements

ADEs and ADRs (article)

ADEs may be classified as any injury resulting from drug use. They contributed to an estimated 13.5 million outpatient visits between 2005 and 2007, including emergency depertment (ED) and physician office visits. The elderly are particular vulnerable in this regard. As estimated 100,000 ED visits related to ADEs among Americans 65 and older resulted in hospital admission between 2007 and 2009. Polypharmacy also increases the risk of ADEs. Older Americans have the highest rateof health care resource utilization in relation to ADEs, but the highest absolute number of such visits occured among 45- to 64-year-old patients. In fact, once data are adjusted for comorbidities and number of medications, the effect of age on this rate of visits related ADEs is greatly reduced. This indicates that the problem of medication management are not exlusive to the geriatric population. The increased utilization of health care resources associated with ADEs may contribute to up to 13% of the total spending on health care in the US. ADRs are a special type of ADE that occur at commonly prescribed doses making them of particular interest in pharmacogenomics and PGX. Reducing the incidence of ADRs may reduce burden on the health care system overall and produce cost savings by preventing a portion of drug related hospitalizations. Achieving this result will rely on PCPs understanding of pharcogenomics and applied PGx. Tables 1 and 3 show that three of GS's medications are associated with genetic variants that may affect the outcome of therapeutic changes. One of these, citalopram, is associated with a variant that carries and FDA-recommended dosage limitation for patients with a known genetic variant. This genetic variant is associated with increased risk of QTc prolongation and Torsades de Pointes, a potentially severe complication. Information like this is currently wide available and an understanding of how to use it will help PCPs make therapeutic decisions that are more likely to avoid ADRs and improve therapeutic outcomes.

The Future: Pharmacogenetics in Primary Care (article)

Advancing technogology has always challanged physicians in their practice of medicine. New research techniques and treatments can improve the prevention and managmeent of disease, but not without confusion and occasional controversy. The addition of pharmacogentetic testing to the armamentarium of primary care providers prevents just such a challenge

Beta-2 adrenergic receptor (ADRB2)

Albuterol resistance was more likely in GLY allele carriers

Clinically Significant Statin Metabolism and Transport Pathways

Atorvasatin - CYP3A4, SLCP1B1 (OAT1B1) Fluvastatin - CYP2C9 Lovastatin - CyP3A4, ABCB1 (P-glycoprotein) Pitavastatin - SLCP1B1 (OAT1B1) Pravastatin - SLCP1B1 (OAT1B1) Rosuvastatin - SLCP1B1 (OAT1B1) Simvastatin - CYP3A4, SLCP1B1 (OAT1B1), ABCB1 (P-glycoprotein)

Intro to Case Study (article)

Bridging the gap in provider understanding of PGx is essential to the future of primary care. PCPs are ideally positioned to counsel patients in a manner that will make this technology most clinically meaningful. Not only are the vast marjority of prescription written in the primary care setting, but an estimated 60% of office visits related to adverse drug events (ADEs) take place in the primary care setting. Patients are also more likely to report ADEs in that environment. Further, patients have indiciated a preference for discussiong PGx test results with their PCP. Gs presents with a common constelation of issues. Cost concerns conflict with effors to reach therapeutic goals and reduce associated risks from known chronic conditions. She also presents with a psychological complaint common to primary care. The very familiarity of this scenario illustrates how PCPs are in an ideal position to use additional information from PGx testing to guide decision making to facilitate positive results, or avoid potential hazards. One of those hazards is the risk of adverse drug reactions to medication.

Serotonin transporter (5HTT/SLC6A4)

Caucasions with the 5HTT L/L or L/S genotypes had increased response to SSRI therapy compared to individuals with the S/S genotype

Case Vignette (article)

Consider the following hypothetical case: History of Present Illness: GS is a 46-year-old female office administrator who presents for follow-up on type 2 diabetes, depression, hypertension, and hyperlipidemia. Recent fasting lab work is avaiable for review. She is taking all medications as prescribed. She reports that her depression had recently worsened in conjunction with some stress at home and at work. She is taking citalopram, and her symptoms were previously well-controlled on that medication, but over the last few months, she has had increased dysphoria, anxiety and anhedonia. She is interested in an antidepressant dose increase to help control her symptoms. She is having some trouble affording Crestor as it is tier 3 on her insurance. She asks if a lower-cost generic would be appropriate for her. Past Medical History: hypertension, diabetes, hyperlipidemia, major depression, anxiety. Medications: Lisinopril 20mg daily, HCTZ 25mg daily, Metformin 500mg daily, Citalopram 20mg daily, Lorazepam 2 mg TID prn. Recent lab results: TSH and CBC WNL, CMP WNL except fasting glucose 127, LDL: 110mg/dl, CrCl: 80 ml/min. Framingham's Risk Score: 20% In the absence of additional information, a PCP might simply try an alternative statin and see if it was tolderated at a sufficent dose to achieve the desired result. The dosage of citalopram could be increased to see if she achieves better results. HOwever, the potential for both tolerance and effecitveness will not be known until after therapy is changed.

Developing Protocols

Developing Protocols Determining which patient populations to select as candidates for PGx testing will also be an important consideration. There are many proposed strategies with regard to this. Identifying risk due to factors like age, high-risk comorbid medical conditions and polypharmacy, or the presence of medications that are likely to be influenced by varying genotypes are all potential approaches. The association of both age and polypharmacy with ADRs is well established. Many medicaitons have been proposed as high-priority for the potential application of PGx testing. Examples include statins, opioids and anticoagulants. These medications are high priority because of the prevealence of their use and their importance as a class in the management of common high risk conditions. The known high frequency for ADRs, intolerance, and dependency are also important factors. The targeting of individual patients on the basis of known risk factors may be more reactive than truly proactive. Trials are underway to develop and test broader approaches to PGx testing. These studies seek to identify potential genetic factors that may impact future care, well before known risk factors are present. Some of these models may have a significant impact on the use of PGx testing in primary care, as they take a truly preventative approach to the use of this technology. Identifiying and utilizing patients individual genotyping for the purpose of collaborative communication with other members of the health care team will not be possible without consideration of how this information will be documented and shared. Consistent protocols will be of utmost importance in this effort. It would be preferable for genetic results to integrated into the EHR as structured data. This would allow HER systems to cross-reference other information in the medical record such as medication and problem lists. Tools within the HER system, such as computerized decision support (CDS) would then be able to flag certain medications or disease states that might be affected by particular genotypes. Indeed, development and testing of such CDS support tools for PGx information is already being done. Furthermore, this structured data could then be shared with members of the health care team. If PGx information were to become standard of care, we may even begin to see it incorporated into the continuity of care document (CCD) standards that currently form part of the interoperability criteria for the CMS meaningful use incentive program. Much of this could be accomplished by documenting testing through the use of ICD codes. These could be added to the patient record to reflect that genetic testing and counseling is being done and then added to the problem list if genetic variants potentially effecting medication management are identified. In current ICD-9 nomenclature, v82.79 which is "encounter for other screening for genetic and chromosomal anomlies." If a mutuation or clinically significant variant is didentified through testing, the ICD-9 code V83.89 "genetic carrier status" can be added which will transition to Z14.8 "genetic carrier of other disease." The implementation of ICD-10 may allow for more specific information to be directly coded into the patient record according to the needs of their care. This ubiquity and ease of access to clinically significant PGx information may prevent patients from experiencing ADRs thourgh the use of previously obtained genetic information. Also, as new information on pharmacgolically significant gentoypes becomes available, or if a patient develops a new condition that is affected by a known genetic factor, futher testing could be performed and new information could be added into the patient's individual record as needed. Several years later GS developed a fib requiring anticoagulation. Warfarin was chosen as the anticoagulant and the previously obtained PGx result specifically CYP2C9 and VKORC1 were utilized to assist with dose opitimization. Together these results individuated that a maintenance dose of approximately 3.5mg daily may be sufficient to achieve an INR of 2.5. This helped both the prescriber and patient treat with more confidence. While there is certainly debate about ordering phamacogenetic testing apecicially for dose opitimization of warfarin, there is also considerable evidence that CYP2C9 and VKORC1 can help to reduce ADRs related to warfarin. This case demonstrates and supports the ongoing utility of PGx results in the medical record. A positive value may not be obtained with the use of PGx results for one drug (warfarin) but over the lifetime of treatment with multiple drugs, the continued use of these results can contribute to imporved efficiency, efficacy and cost effectiveness in applied pharmacotherapy.

SNPs, Alleles, Genotypes and Phenotypes (article)

Different forms of genes that are passed on from parent to child are called alleles. The combination of alleles an individual inherits determines his or her gentoype, and the expression of these alleles determines his or her phenotype. Genetic variation arises from the introduction of mutations, or alterations in the DNA sequence, in these alleles. The most commonly identified mutations are single nucleotide polymorphisms, also called SNPs. A particular SNP may or may not result in changes in protein regulation, expression or activity. When an identified SNP negatively affects protein function it is termed a loss-of-function allele. Someone with one (heterozygote) or two (homozygote) loss-of-function alleles will have less overall protein expression and/or activity compared to someone with two normal-function alleles. When an SNP is identified that positively affects protein function, it is termed a gain-of-function allele. The preseence of a gain-of-function allele, or duplcation of a normal function allele, may result in increased protein expression and/or enhanced activity. These gentoypes can have a direct impact on numberous metabolic functions, including how individiuals respond to certain drugs at a cellular level. The effect that genetic variations have on drug metabolism is characterized by well-established phenotypes. A poor metabolizer is an indiviudal with two inactive or loss-of-function alleles. In patients with this phenotype, drugs may not be matbolized efficiently. This can result in increased drug concentrations that can reach toxic levels. Ultrarapid metabolizers have gene duplicates and therefore increased drug metabolism. This can result in subtherapeutic drug levels at doses that would likely be effective in normal metabolizers. Figure 1 illustrates the consequences that these genetic variations can have on drug metabolism and therefore effectivness and toxicity. Loss- and gain-of-function alleles may also result in altered response to medications due to abnormal binding at its site of action or receptor. Genetic testing for GS yields the following information: CYP2D6 (*1/*1) normal metabolizer, CYP2C9 (*1/*1) normal metabolizer, CYP2C19 (*2/*2) poor metabolizer, CYP3A4 (*1/*1) normal metabolizer, CYP3A5 (*3/*3) non-expressor, SLCO1B1/OAT1B1 (*1/*1) Normal transporter, VKORC1 (A/A) high sensitivity to warfarin

Implementation Considerations

Even with increased education, providers and clinical groups will have to carefully consider strategites for the assimilation of PGx into clinical practice. While speciality providers like oncologists may deal with PGx routinely in their practice, there is debate over how PGx testing should be implemented in the primary care setting. The utilization of resources outside of the primary care setting may be beneficial in this regard. Clearly, pharmacology programs offer more education in the field, and phamacists are well positioned to partner in the clinical integration of PGx by assisting with phamcaceutical management. Models of PGx testing and information delivery have been proposed that center around pharmacists and genetic counselors, but this may not meet the needs of patients who would prefer working with their PCPs in assimilating PGx testing results. Some PCPs feel that pharmacists should take the primary responsibility for determining appropriate medication and dosing for patients dealing with significant PGx results. A collaborative approach, however, may be the most beneficial for the patient and serve to provide support for PCPs as they become more familiar with PGx testing and its implications in primary care. Previous studies have shown improved outcomes as the result of coordinated care between providers and pharmacists. This may suggest an ideally partnered approach to applied PGx. PCPs may want to consider developing streamlined communication with a cooperative, multispecialty care team that includes pharmacists as an integral rather than incidental part of care delivery. Genetic counselors can be consulted where they are available. Emerging models of care such as patient centered medical homes (PCMHs) and accountable care organizations (ACOs) may be well suited to this kind of collaborative and personalized approach. PCPs can then ensure that testing done either though the primary care office or ordered by another provider is entered into the HER and that the patient is appropriately counseled about available testing, his/her individual results, and the implications those results may have for health and treatement.

pharmacogenomics/genetics (slides) other uses

FDA genomic information on drug labels - over 50 drugs Pharmacogenomics can play an important role in identifying responders and non-responders to medications avoiding adverse effects and optimizing drug doses. drug labeling may contain information on genomic biomarkers and can describe: drug exposure and clinical response variability risk for adverse events genotype-specific dosing mechanisms of drug action polymorphic drug target and disposition genes labeling includes: actions to be taken based on biomarker biomakers include but are not limited to germ lines (23 - x and y) or somatic genes (1-22) germ line changes can affect future generations, don't want to mess with someones heredity and what someone can pass on functional deficiencies, expression changes, and chromosomal abnormalities

Summary

Increased knowledge in the area of genomic sciences is likely to have an expanding impact on medical care in the near future. PGx is already heavily influencing medication management in primary care, but much of this information is presented to physicians without an organized and proactive framework for applying it. It is critical the physicians, particularly, PCPs seek to assume a leadership role in the implementation of genomic science in patient care. Ongoing education will help them use this information to manage medications and high-risk conditions optimally. The development of coordinated care models like ACOs and PCMH will also leverage the skill sets of a broader segment of the health care team and greatly benefit the implementation of this technology. Despite significant barriers and pitfalls, creating solid protocols for implementation will yield optimal results for physicians and patients as genetic information takes a more prominent place in patient care. PCPs must become part of the development of these protocols for this technology to yield the greatest potential benefits.

Beta-1 adrenergic receptor (ADRB1)

Metaprolol-induced decrease in diastolic blood pressure was significantly greater in individuals with the 389ARg/Arg genotype compared to those with the Arg/Gly and Gly/Gly genotype

Biomarker Disease Association Examples

ORM1, CYP2D6 - addiction CYP2D6 - alzheimer's disease CYP3A4, ABCB1 (p-glycoprotein) - cancer risk Factor V Leiden and Factor II - DVT CYP2C19 - endometriosis susceptibility FMO3 - fish odor syndrome UGT1A1 - Gilbert's and Crigler-Najjar syndrome CYP2C8, CYP2C9, CYP2C19 - inflammatory related diseases such as coronary artery disease CYP3A4, CYP3A5 - salt-sensitive hypertension CYP1A2, SULT4A1 - schizophrenia

Factor V Leiden

Odds ration ranging from 11-41 have been reported for combination of Factor V Leiden allele and OC use

Pitfalls

Open access to genetic information is directly opposed to the majority of patient opinion when it comes to how they want their genetic information recorded and used. Most patients currently want their genetic information very closely held and shared only with express consent. Current legislation in the form of the Genetic Information Nondisclosure Act reflects this concern and limits how such information can be shared. It may be some time before PGx information may be freely used to benefit patient care. The association between genetic variation and the potential for phenotypic expression in known disease states is another concern. Indeed, some PGx variation are also associated with increased risk for certain disease states. This association presents an ideal opportunity to discuss the ethics of PGx testing with regard to informed consent. While the risks of many disease states as well the benefits of meeting treatment goals are well defined, the significance of some genetic variants are less clear. Informed constent becomes problematic when a patient is asked to make health care decisions weighting a known risk/benefit ratio against an unknown risk/benefit ratio. Patients may already be included to fear medication because of personal anxiety, somatization, anecdotal perception of personal or familial susceptibility to ADRs and/or frightening reports through media sources and peer interactions regarding the risk of pharmaceuticals. Conflicting information might sway patients in favor of declining treatment for known high-risk conditions based on the theoretical genetic risk of ADR. This may result in an ethical violation of non-maleficience (do no harm). While information regarding individual genotype should ideally provide patients with reassurance about which medications are safer and more efficacious for them, they have expressed reluctance to discuss information that did not result in clear and predictable advice. Developing a process for obtaining informed consent, preferable in writing, is highly advisable to optimally manage patient expectations, address potential concerns and engage them in the use of PGx. Patient engagement will be crucial as patients will need to participate actively information in their primary care setting as well as in other locations of care. Providing patients with a summary of their PGx results may be helpful if a patient is seeing providers not actively involved in cooperative health care teams. Surveys have indicated that patients may be willing to consider carrying results on a health alert card or some other device. This may provide a way to bypass patient concerns regarding the privacy of their genetic information, but relies on the patient to actively participate in their own care management. A strong informed consent process would also provide an opportunity for PCPs to be clear on the specific testing options, costs, reimbursement, and procedures for testing in their area when designing protocols for PGx testing and counseling patients. The economics of health care raise significant concerns with regard to accurate and consistent use of genetic information in primary care. As a relatively new technology, PGx testing may not be covered by all insurance. This may create financial barriers to care. Of additional concern is the potential for increased cost of medications if it is discovered that a person's genotype is not suitable for lower cost medications. It is not clear how responsive insurance carriers will be to authorizing preferred but more costly, medications to patients based on genomic data. The issue of insurance coverage raises a more direct concern in the management of PGx in primary care. Offices get communication throughout the course of the day from insurance carriers, pharmacies and patients with requests for medication changes based on cost and formulary coverage. The PCP often manages these requests without adequate time for in-depth consideration or access to the full patient record. Physicians may be able to make the decision if one medication can be substituted for a lower cost medication of the same class, but they cannot be expected to know if the alternative medications will be suitable for the patients genotype, unless the data are available and they are educated as to how to use it. Furthermore, changes to medications made outside the office visit, either by primary care or by other providers are not always consistently noted in the patient chart so that the new medications become part of their health record and can be considered in context of the patient's genotype. This may result in patients being asked to return to the office to discuss any changes to their medication, which could in turn erode any potential savings to the health care system from reduced ADRs.

Opioid Receptor MU-1 (OPRM1)

Oxycodone induced pain attenuation was decreased in OPRM1 118G allele carriers. These individuals required increased oxycodone doses compared to 118AA homozygotes

Knowledge, Confidence and Attitudes Towards PGx (article)

PGx is an area where PCPs report a low index of confidence. In one national survey, the majority of PCPs reported that they do not feel well informed about PGx testing. Although more than half indicated that they recieved genetic training in medical school, most felt that the training was inadequate to prepare them to use PGx testing in their clininical decision making. The lack of confidence in using PGx test results may be a reason why many PCPs responding to the survey reported that they have never ordered PGx testing. A multi-speciality survey of US physicians shows that primary care is not unique in this regard. With the sole exception of oncology specialists, the vast majority of physicians surveyed did not regularly order genetic testing, citing lack of information. While PCPs indicate uncertainty about how to use PGx testing in clinical practice, there is broad acknowledgement of its potential utility. In the multi-speciality survey, 97.6% of respondents believed that genetics may influence a patient's response to drug therapies. In this PCP survey, almost two-thirds of respondents agreed that PGx testing represents a valuable potential tool to predict risk of ADRs or likelihood of efficacy. Among physicians who have utilized PGx testing, reducing drug toxicity and improving effectiveness were cited as significant observed benefits to patients. PCPs envision a strong role in the future of using PGx information in clinical practice. Most of the PCPs surveyed felt that informing patients of PGx testing availability and recording PGx testing results in patients records should be a responsibility of the PCP. More than half felt that PCPs should also be responsible for informing their patients of PGx testing results. Beyond that point, however, uncertainty again emerges. as less than half of surveyed PCPs felt that they should be primarily responsible for determining how PGx results should be used in medication management.

pharmacogenomics/genetics (slides) mental health disorders

Pharmacogenetics - may help to identify the right drug to treat mental health disorders. some people respond to the first antidepressant that they are given but some do not. takes weeks before antidepressant drugs take full effect. may take a month before see any change. patient is suffering for month, and then still doesn't work- poor patient outcome. genetic studies show that there are variants on how patients respond some drugs - celexa, celatopram are there any genetic tests that can predict SSRI outcomes - there is a genetic variant

Introduction (article)

Pharmacogenetics and pharmacogenomics are very similar terms that often are used interchangeabply. Authors tend to use pharmacogenomics when discussing broader research about the relationship between the genome and pharmacotherapy, such as in genome wide association studies (GWAS). Pharmacogenomics usually applies to a population. On the other hand, pharmacogenetics more often is used when talking about specific genes and their influence on specific drugs. An example of this would be the study of how cytocrome P450 2C9 (CYP2c9) and VKORC1 polymorphisms affect warfarin pharmacokinetics and pharmacodynamics. Pharmacogenetics deals with individuals. This article will distringuish the two terms and will focus on pharmacogeneitcs, which will hereafter be abbreviated, PGx. Pharmaceutical management is becoming the standard of care for many medical conditions. Many evidence based standards for quality in the treatment of certain disease states support the introduction of particular drug therapies in the precesnce of known diagnoses. Even if specific medications or classes of medications are not defined by quality standards, defined management goals may not be achieved without medicaton. The rationale for promoting evidence-based standards is clear to most physicians, although the benefit of such programs is debated. Research presents convincing evidence that the risks of many disease states are significantly reduced by the introduction of pharmaceutical agents and adherence to treatment goals. However, these drugs do not come without their own risks. Many management recommendations are drawn from well-designed studies, but these focus on results in broad populations rather than individuals. Medications shown to be effective in these studeies may be less effective in a particular patient, resulting in failure to reach desired treatment goals. Medications can also cause unindented effects. While most often inconveienent or uncomfortable, adverse drug reactions (ADRs) can be very dangerous. ADRs and/or treatment failure may erode patient confidence in their physician, or perhaps in the validity of the evidence used as a basis for their recommendation. This can lead to mistrust of pharmaceutical treatment as a whole and can reduce patient motivation to meet health management goals. This fear may contribute to the preference of some individuals for alternative therapies. Although many of these therapies have poor evidence of effectiveness, they often are embraced as an alternative to the anecdotal failures of recommended medications. The emergence of PGx testing offers promise in mitigating some risks associated with medication therapy. Testing for known genetic variants that affect drug metabolism can potentially enhance therapeutic response to medication, reduce ADRs, and optimize treatment of disease. While this can positively affect both disease-specific outcomes and patient satisfaction, PGx testing has its own complications. Testing may indicate that a commonly avaiable medication is less advisable for a particular patient, but alternatives may not be readily accessible. Also, the novelty of the technology may lead to patient uncertainty regarding the significance and implications of genetic testing results. Most health care professionals also feel uncertain about the utility of PGx testing and discussing it with their patients.

CYP2C9

Poor Metabolizer, Celecoxib, AUC increased up to 600% compared to normal metabolizers. Product insert recommends a 50% decreased maintenance dose and to avoid in individuals with juvenile rheumatoid arthritis.

SLC01B1 (OAT1B1)

Poor transporter (c.521CC genotype), Atorvastatin, AUC increased 145% compared to c.521TT homozygotes. Similar results have been observied in other studies. The maximum recommended dose is 20mg daily in individutals with this phenotype.

Potassium voltage-gated channel (KCNH2, hERG)

QTc interval is prolonged 14ms per KCN2 897lys allele in patients recieveing steady state methadone compared to non-allele carriers

Types of PGx Biomarkers (article)

The FDA refers to alleles that influence drug effectiveness and toxicity as "pharmacogenetic and biomarkers." PGx biomarkers are further classified as either pharmacokinetic (PK) or pharmacodynamic (PD). PK biomarkers affect how the body absorbs, distributes, metabolizes and excretes drugs. Their effects on drug bioavailability, blood concentrations, and distrubition into tissues are easy to measure and therefore they are well understood and studied. This class of biomarkers includes genes that code for drug-metabolizing enzymes such as CYP2D6, CYP2C9, and CYP2c19. Also included are genes that code for transporter proteins like OAT1B1 and P-glycoprotein. Drug-metabolizing enzymes like the cytochrome P450s biotransofrm drugs into metabolites more readily eliminated by the body or modified by other enzymes. Transporters function to move drugs in and out of cells and across barriers like the small intesting, liver, kidney, and brain. For this reason they are somtimes referred to as "gatekeepers." They are also involved in directly eliminating drugs via biliary and urinary excretion. Two important biomarkers involved in drug transport include SLCo1B1, which codes for the OAT1B1 transporter, and ABCB1, sometimes called the multidrug resistance gene which codes for p-glycoprotein. OAT1B1 is an influx transporter meaning it moves drugs into cells and p-glycoprotein is an efflux transporter meaning it moves drugs out of cells and into the intestinal tract, bile, blood or urine. PD biomarkers are less well understood. These biomarkers affect the action of drugs at the molecular level. Thier effects are harder to isolate and measure, and uncertainty of the exact mechanism of action for many drugs further limits research in this area. Just as there are different subtypes of PK biomarkers, there are also subtypes of PD biomarkers. Some impact drug response directly wheras others may play a more indirect role as a result of a genetic variance that affects the underlying disease process. Indirect PD biomarkers may still significatnly influecne the efficacy, toxicity and/or laboratory values of treatments. An example of a direct effect would be opioid binding to the mu-opioid receptor. Genetic variations of the OPRM1 gene, which codes for the mu-opioid receptor, may affect the amount of pain attenuation achieved with opioid or laboratory values of treatment. An example of a direct effect would be opioid binding to the mu-opioid receptor. Genetic variations of OPRM1 gene, which code for the mu-opioid receptor,may affect the amount of pain attenuation achieved with opioids. An example of an indirect PD biomarker would be HLA-B*1502, which is strongly associated with carbamazepine use and the risk of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), despite it not being involvedin the drug's known mechanism of action. APOE is an example of a PD biomarker that is associated with laboratory values. Certain variations in APOE are associated with greater LDL reductions in patients being treated for high cholesterol. While PGx biomarkers can increase physician knowledge of how patients will potentially respond to medications, some PK biomarkers may affect the metabolism fo a drug in a manner that does not result in a PD difference, either good or bad. A list of significant PGx biomarkers may be found on the FDA website. Tables 1 and 2 describe some of the important PK and PD biomarkers. GS Treatment plans: Plan 1 prescribe simvastatin 40mg daily, #2 diet and exercise recommendations, #3 change citalopram to paraxetine, #4 increased psycologist sessions GS's PGx results reveal important aspects with regard to current and future medication management. CYP2D6, CYP2C9, and CYP2C19 are all highly polymorphic. Together they metabolize approximately 75% of all hepatically metabolized medications. Currently, citalopram is the only medication GS is receiving that goes through one of these pathways, namely CYP2C19. Being normal at the CYP2D6 and CYP2C9 pathways means that choosing medications that go through these pathways can be administered at standard doses. Being a CYP2C19 poor metabolizer limits the dose or therapeutic option of medications that are substrates for this pathway. At 20mg daily, citalopram was at a maximum daily dose per the product insert. therefore, choosing paroxetine, an SSRI metabolized by the CYP2D6 pathway, creates therapeutic options for management of this patient's depression. CYP3A4 has many substrates, including several of the statins. Individuals with decreased expression/activity of CYP3A4 may require decreased doses to achieve similar therapeutic effects and acceptable risk compared to normal metabolizers. Because GS is a CYP3A4 normal metabolizer, standard doses of a statin metabolized by this pathway may be appropriate. SLC01B1 results allow for the prescriber to more condiently initiate therapy with a SLC01B1 transported statin that might otherwise result in statin intolerance due to inadvertent increased exposure of the drug. This information leads to the use of simvastatin 40mg daily for cholesterol managment.

Getting Educated

To begin incorporating PGx testing into practice, the first step is education for physician and the health caare team. Medical schools in the US and canada are beginning to incorporated pharmacogenomics into their curriculum, but do not sufficiently prepare students to confidently utilize PGx in practice. A recent study determined that 82% of US and Canadian medical schools incoporated pharmacogenomics into their curriculum, yet only 28% had more than 4 hours of didactic coursework on the subject and only 29% had plans to expand the curriculum within the next 3 years. Students feel that this is not adequate to prepare them; 57% considered pharmacogenomics instruction at their own school as "poor" or "not at all adequate" while 76% considered it "poor" or "not at all adequate" at most medical schools. There is more pharmacogenomics training available in schools of pharmacology. A study from 2010 determined that approximately 90% of schools included pharmacogenomics in their PharmD curricula compared to 39% as reported in 2005. Topic coverage was <10 hours for 40.6% 10-30 hours for 42.0% and 31-60 hours for 14.5% of colleges and schools of pharmacy. Fewer than half were planning to increase course work over the next 3 years. Although the need for ongoing education for future PCPs in pharmacogenomics is significant, PCPs already in practice must rely on resources outside of the classroom for information. Again the need for suitable sources of professional education is largely unmet. While some physicians report learning of PGx testing and its clinical implications through organized CME such as professional meetings, grand rounds, and professional journals, some physicians also report less formal educational resouces such as drug labeling information, communication with professional colleages and the Internet as primary sources of information. Through organized CME such as professional meetings, grand rounds, and professional journals, some physicians also report less formal educational resources such as drug labeling information, communication with professional colleagues and the Internet as primary sources of information.

CYP2D6 a. Poor metabolizer b. ultrarapid metabolizer

a. Atomoxetine - AUC (area under the curve) increased up to 900% compared to normal metabolizers. Product insert specifies a more conservative dosing regiment for this phenotype. Metoprolol - plasma concentrations increased up to 390% and heart rate and blood pressure significantly decreased compared to other phenotypes b. nortriptyline - AUC decreased by 35% in patients with three active alleles and 80% in patients with 13 active alleles compared to normal metabolizers. A dose increase of up to 150% has been recommended.

CYP2C19 a. Poor metabolizer b. Ultrarapid metabolizer

a. Clopidogrel - AUC of active metabolite decreased 65% compared to normal metabolizers. A meta-analysis showed a 55% increase in cardiovascular events, MI, or stroke in individuals with this phenotype compared to normal metabolizers undergoing percutaneous coronary intervention for ACS. Product insert recommends using an alternative platelet inhibitor. Citalopram - AUC increased 107% compared to normal metabolizers. Product insert recommends 20mg maximum daily dose in indivuduals with this phentotype. b. Omeprazole - AUC decreased 52% compared to normal metabolizers. Dose increase up to 300% have ben recommended.

Biomarkers Specific to Statins: Pharmacodynamic a. Apolipoprotein E (APOE) b. Cholestoral ester transfer protein (CETP) c. CYP7A1 d. HMG CoA reducatase (HMGCR) e. Kinesin-like protein 6 (KIF6) f. Parahydroxy-benzoate-polyprenyl-transferase (COQ2)

a. Hepatic uptake of lipoproteins. Epsilon-2 allele carriers had greater reduction in LDL and a larger proportion achieved an LDL goal of <70 mg/dL when treated with atorvastatin or pravastatin compared to epsilon-4 carriers b. Lipid transfer. Atorvastatin-induced LDL reduction and HDL elevation was greater in CC homozygotes compared to A allele carriers. LDL levels decreased 43.5% in CC homozygotes, 25.5% in CA heterozygotes, and 11.7% in AA homozygotes. However, there was no difference in long-term clinical prognosis. c. Bile acid synthesis. Atorvastatin-induced LDL reducation was 35% in rs8192870 AA homozygotes and 28% in G allele carriers. d. Statin receptor. Atorvastatin-induced LDL reducation was 15-23% greater in HMGCR rs3846662 AA homozygotes compared to GG homozygotes. e. Intracellar transport. Carriers of the KIF6 719Arg allele who received high-dose atrovastin had a 41% decreased risk of death or major cardiovascular events compared to individuals who received standard-dose pravastatin. This difference was not seen in non-carriers of the 719Arg allele. f. Homozygotes for SNP1, SNP2, and the 2-SNP haplotype had significantly increased risk of statin intolerance defined as muscle weakness, tenderness and/or pain with at least one of the following: 1) medically advised discontinuation of statin medication on at least two occasions; 2) serum CK elevated to >3-fold of the upper limit of normal while on a statin on at least one occasion; and 3) medically diagnosed rhabdomyolysis.

Biomarkers Specific to Statins: Pharmacokinetic a. CYP3A4 b. CYP2C9 c. ABCB1 (p-glycoprotein) d. SLC01B1 (OAT1B1)

a. Metabolism, Dose requirements of atorvastatin, simvastatin, and lovastatin were decreased 73% in CYP3A4*22 allele carriers compared to normal metabolizers. When analyzed alone, the simvastatin and atorvastatin dose requirements were decreased 40% and 78% respectively b. Metabolism - The AUC of fluvastatin increased 200% in poor metabolizers. However, no differences were observed in LDL or total cholesterol levels. c. Transport - Total cholesterol decreased 29% in 1236T allele carriers recieving simvastatin and only 24% in 1236CC homozygotes. Likewise, LDL decreased 40% in 1236T allele carriers compared to 34% in 1236CC homozygotes d. Transport In poor transporters (c.521CC homozygotes), the AUC of simvastatin acid increased 21% pitavastatin 162-191%, atorvastatin 144%, pravastatin 57-130%, rosuvastatin 62-117%, and fluvastatin 19%. For every c.521C allele presents the odds of myopathy increase 4.5%

HLA-B*1052

associated with increased risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Asians taking carbamazepine.

pharmacogenomics/genetics (slides) changes in kids and adolescents

body changes. newborn - slow metabolizers, eventually require phenotype that is more consistence with their genotype. teenagers - hormonal changes, change effects that drugs have on their bodies, once hormonal swings take place go back to things as normal

pharmacogenomics/genetics (slides) pharmacogenomic research

chemotherapy drugs - very active area, immunotherapy or antibody, certain chemotherapy drugs work better who's tumor have certain genetic changes, some drugs don't work well in 40% of patients with colon cancer who has a specific gene. depression - citalopram (Celexa) development of new drugs - screening for chemicals, now using genomic information.

pharmacogenomics/genetics (slides)

disciplines that combine pharmacology with genomic capabilities. concerned with using DNA and amino acid sequence data to guide drug development and testing. an important application is correlating individual genetic variation with drug responses. future advances will enable HCPs to select drugs and drug doses that are likely to work best for a particular person and have the least side effects. *consider when Rx medications for different patients.

pharmacogenomics/genetics (slides) why do people react differently to the same drugs?

drugs are excreted in chemically altered forms relative to those in which they were administered. enzymes are involved. disproportionate responses result from deficiency or excess of the required enzyme. certain ADRs result from inherited variation in enzyme activity. * some can take huge doses- others cannot (drinking alcohol/drugs).

pharmacogenomics/genetics (slides) genomic research

enables more personal approaches to using and developing drugs. HCPs will be able to routinely use information about a person's genetic makeup to select drugs and doses that offer the greatest chance of helping you. May also save time and money by selecting the best fit drug from the beginning. no longer have one size fits all approach, don't have to give ampicillin to everyone or gentamicin to everyone. depending on genetic makeup some drugs will work differently in person or act differently, people can tolerate certain drugs and others cannot, some have adrs' and some don't. by shortening or abandoning the trial approach, better for patients going to get right dose or right drug in a shorter time.

pharmacogenomics/genetics (slides) national institutes of health

funded research to study the effect of genes on medications relevant to a wide range of conditions (asthma, heart disease, cancer, depression). findings collected in online resource of pharmacogenomic knowledge. diabetes work with researchers, clinicians and patient advocates to ensure privacy of research participants and to maximize the benefits of pharmacogenomics research for individuals and society. people are afraid this will effect their insurance coverage.

ultrarapid metabolizer (article)

gene duplication in the absence of inactive or decreased alleles

pharmacogenomics/genetics (slides) is this in use today?

genetic data is in use but only for a few health problems. HIV - abacavir (Ziagen) - test genetic variant to make sure they don't have bad reaction to drug. some people are allergic to this drug, ill stay in room first 15 minutes, back pain, most likely going to happen in first 15 minutes, but SOB and dizzy, MD left room, coded - severe anaphylactic reaction and was allergic to drug, would have been nice to know before hand. Breast Cancer - Herceptin (trastuzumab) - only works if tumor has a genetic profile that leads to over production of Her2, Her2 must be positive. FDA recommendation - (1) ALL - mercaptopurine (Purinethol) - acute lymphoblastic leukemia - genetic variant that interferes with processing drug, leads to severe side effects and infection, dose should be adjusted depending on genetic profile; (2) colon cancer - irinotecan (Camptosar) - may not be able to clear drug as quickly as others can develop diarrhea or risk of infection. pharmacogenetics predicted to develop better drugs for heart disease, cancer, asthma, depression, and other common diseases.

pharmacogenomics/genetics (slides) benefits

genetic research: 1- has changed the "one six=ze fits all" approach. 2- avoids the "trial and error" approach" (lets keep trying different things until something works). 3- allows selection of the "best fit" drug. * going to use information about a persons genetic make up (genome/genotype) to figured out the best medication, dosage/duration/etc. to use for each specific make up.

pharmacogenomics/genetics (slides) definitions

genetics: study of hereditary and its variations genetic makeup (genotype): derived as a result of genetic recombination (mixing) of genes from nose's parents. genome: all the DNA contained in any individual cell; represents all the genes an individual can express. genomics: study of the complete set of genetic information present in a cell, an organism, or a species. genotype is used several times throughout this lecture. **a picture/recording of a persons genetic makeup**. show how many genes they have- 46x female, 46y male. kariotype- test shows how many genes the pt has. this is the genotype of the person. phenotype how genes are expressed/is what the person looks like. the phenotype should be typical of the genotype. ex. varitype- 45x0, this genotypes phenotype is expressed as a person with turner syndrome, will have traits typical of turner syndrome or genotype trisome 21, 47xx- phenotype is expressed as traits of downs.

pharmacogenomics/genetics (slides) how it works

just as genes determine hair and eye color, they are partially responsible for how our bodies respond to medications. genes are instructions, written in DNA, for building protein molecules. different people can have different versions- slightly different DNA sequences- of the same gene. some variations are common and some are rare. same are relevant for health, such as those associated with a tendency to develop certain diseases. Examine genes for variations in proteins that influence drug responses - can't look at all, pick certain ones we want to look at Some proteins include a number of liver enzymes that convert medications into active or inactive forms CYP2D6 - liver enzyme acting on25% of all Rx drugs - not on exam - includes codeine converts to active form morphine, CYP2D^ exists in more than 160 different versions, only by a single difference in a nucleotide, some have larger differences, variations don't effect drug response, people with extra copies manufacture an over abundance of enzyme, metabolize very rapidly - standard dose might be overdose for them Slow metabolizers - metabolize codeine very slowly or don't metabolize it at all, don't get pain relief, give higher dose or different drug - drug seekers might have genetic variation. **at risk for developing adverse effects for some drugs - procainamide, isoniazid, sulfonamides. north america - 50% of caucasians and african americans - slow metabolizers 90% in some mediterranean 20%- canada all infants are slow acetalizers of caffeine instead of glucorinatdation they use actelation pathway - diff substances or longer half life than adults do % of slow metabolizers in newborns is going to change as the infant grows older difference between genotype and phenotype, since slow acetylation of caffeine is not genetically determined but is a developmental process, not genotypically determined

pharmacogenomics/genetics (slides) genetics revisited

nucleotides: sequence determines genes. join together in a specific way. adenine, guanine, cytosine, taurine- make up DNA adenine- taurine (specific bond) cytosine- guanine (specific bond) when genes are mapped/studied- study how these occur. (GATC blah blah blah) DNA structure- double helix. bonded by hydrogen bonds. unrelated people share about 99.9% of the same nucleotide sequencing. there is less than 0.1% of DNA (phenotype) difference btw us- blonde instead of brunette. this translates into about 1 million nucleotides. *3 billion pairs translates to 1 million nucleotides that makes each of us different. different sequence of pairs. may not be expressed but difference exists. variations in single nucleotides are called SNPs (snips). surprisingly the genomic variations account for nearly all of the phenotypic difference we see in each other. genetic polymorphisms- multiple difference of DNA sequence found in at least 1% of the population.

pharmacogenomics/genetics (slides) what about babies

pediatrics tract- developmental and pediatric pharmacogenomics- consider the dynamic changes in gene expressions that accompany maturation from embryo to fetus, from neonate to infant, infant to child, and child through adolescent, the patterns in gene expression and the nature of gene interactions contributing to the pathogenesis in pediatric disease may only be discernible of relevant at specific critical points in development. variability in drug disposition and action which effect drug response in pediatrics can also be expected to change as growth and development occur. *either genetics can influence or developmental changes can effect the way pediatrics respond to drugs. may not be idiosyncratic- may be a normal pattern of development. doses may be completely different from adult doses. ampicillin- not based on per kg in adult. babies have different amount of body fluid, extracellular- wider volume of distributing, little 3% body at pre-me have less that 1%- don't give drugs distributed in fat. drugs/doses/intervals are different. changes through development. HL determined by how liver metabolizes drug- babies use different metabolic path ways. talks about theophylline metabolism- confusing... i dunno. **read the whole drug monograph for safety when prescribing!!

UGT1A1

poor metabolizer, ezetimibe, AUC increased 177% compared to normal metabolizers

UgT2B15

poor metabolizer, lorazepam, AUC increased 72% compared to normal metabolizers

Platelet endothelial aggregation receptor-1 (PEAR1)

rs12041331 A allele carries receiving aspirin had significantly increased risk of MI compared with GG homozygotes

pharmacogenomics/genetics (slides) pharmacogenomics

similar terms used interchangeably; but NOT the same. pharmacogenomics- study of the effects of genetic difference among people and the impact of these difference have on the uptake, effectiveness, toxicity, and metabolism of drugs; usually applied to a population. study of genome- wide response to compounds administered with therapeutic intent. the goal of pharmacogenomics is to find the right drug for the right disease.- here we are talking about populations.

pharmacogenomics/genetics (slides) patient population r/t treatment

standard approach = use drug A to treat toe nail fungus and now... all these people are going to react in a different way. standard approach- only 20% of these people will react favorable (toxic reaction/adverse reaction/no reaction at all). tailored approach- all different patients in different classes with different meds (drug A, B, C, D) these people had genomic/genetic testing and found out these drugs are better for each group. **the goal is to move to a tailored approach vs. what we do now.

pharmacogenomics/genetics (slides) pharmacogenetics

study of the influence of hereditary factors on the response of individuals to drugs; study of the role of genetic factors in drug disposition, response and toxicity. drup disposition= absorption, distribution, metabolism (biotransformation), and excretion. environmental factors (diet, smoking, toxin exposure), physiologic variables (age,gender, disease state), and patient compliance also play important roles in variations (effect) in drug response. (women have less of a tolerance for alcohol/elderly- drank more at 21 than 35) **more often used when talking about specific genes/specific people and their influence of specific drugs.

nicole's notes from lecture

the difference of pharmacogenomics and pharmacogenetics the goals of pharmacogenomics are the goals of pharmacogenetics are infants and children drugs that are targets of studies poor metabolizer vs rapid metabolizer definitions genetics - study of hereditary and its variations genetic makeup (genotype) - derived as a result of genetic recombination (mixing) of genes from one's parents, picture or recording of a person's genetic makeup, genome - all the DNA contained in any individual cell; represents all the genes an individual can express, my genes, yours, a group of people, or the entire human race genomics - study of the complete set of genetic information present in a cell, an organism, or a species send patient for genetic test karyotype - shows person how many genes they have, 46xx female, 46 xy male - genotype of the person phenotype - how genes are expressed what a person looks like, hopefully typical of genotype if patient has karyotype - 45x0 - genotype expressed a person with Turner's syndrome, will have all of the traits typical of Turner Syndrome, same with trisomy 21, down syndrome genotype - 47xx (have extra chromosome), phenotype all of the traits displayed by a person with down syndrome DNA structure double helix, bars in the helix, nucleotides bonded by hydrogen bonds, sequence of nucleotides determine genes, join together specific why Adenine - Taurine A-T Cytosine - Guanine C-G genes studies or mapped, how these occur unrelated share about 99.9% of the same nucleotide sequencing. There is less than 0.1% of DNA difference between us. This translates into about a million nucleotides. variation in a single nucleotides are called SNPs (snips). not tested on this part. Surprisingly the genomic variations account for nearly all of the phenotypic differences we see in each other. (blue brown eyes, color hair, cystic fibrosis, or no observable differences) genetic polymorphisms - multiple differences of a DNA sequence, found 1% of populations Why do people react differently to the same drug? some can take little some can take a lot - alcohol is good example -drugs are excreted in chemically altered forms relative to those in which they were administered. enzymes are involved - drug metabolism disproportionate response result from deficiency or excess of the required enzyme -certain ADRs result from inherited varition in enzyme activity ***pharmacogenonmics/pharmacogenetics -similar terms used interchange -genomics - study of the effects of genetic differences among people and the impact these difference shave on the uptake, effectiveness, toxicity, and metabolism, usually applied to population -sutdy of the genome wide response to compounds administered with therapeutic intent. the goal is to find the right drug for the right disease genetics study of influence of hereditary factors on the response of individuals to drugs; study of the role of genetic factors in drug dispositions, response and toxicity -drug dispassion =absopriotpin, distortion, metabolism, (biotransofmration), and excretion -environmental factors (diet smoking toxin exposures) physiological variables (age, gender, disease state) & patient compliance also play important roles in variations in drug response -more often used when talking about specific genes & their influence specific drugs gene influence the genes that control drug disposition in the body determine the pharmacokinetic properties of that drug (time, half life, elimination constants) long half life - therapeutic drug monitoring drug metabolizing enzymes and transporters play significant roles in this process - genetically determined factors -pharmacogenetics related variations in human genes to variability in drug responses at the level of the individual patient -goal is to identify the right drug for the right patient fast, rapid, extensive metabolizer to a very poor or slow metabolizer at the other end, could be intermediate group depending on enzyme or drug that is involved pharmacogenicocs/pharmacogenetics disciplines that combines pharmacology with genomic capabilities concerned with using DNA and amino acid sequence data to guide drug development & testing an important application is correlating individual genetic variation with drug response future advances will enable us to select drugs and doses that are likely to work best for a person and have least side effects obama - precision medicint initiantive drs have always recognized that every patient is unique, and doctors have always tried to tailor their txs to individuals. you can match a blood transfusion to a blood type - that was an important discovery. what if matching a cancer cure to our genetic code was just as easy, just as standard? what is figuring out the right dose of medicine was as simple as taking our temp? pharmacogenomics ultimate promise the possibility that knowledge of a person's dan sequence might be used to enhance drug therapy to maximize efficacy target drugs only to those people who are likely to respond and to avoid adverse drug response. increasing the number of patients who respond to therapeutic regimen with a concomitant decrease in the incidence of ADRs the long term expected benefits are selective and potent drugs more accurate drug dosages and advances screening for disease and a decrease in the overall cost of health care caused by ineffective therapy now - drug A everyone gets to treat toenail fungus, only 20% react favorably, effective in 20% in target population, 80% is waste tailored approach - 4 diff drugs for 4 different groups - this the goal benefits genomic research: has changed the one size fits all approach avoid the trial and error approach allows selection of the best fit drug **infants developmental and pediatric pharmacogenomics - consider dynamic changes in gene expression that accompany muturation from embryo to fetus, neonate to infant, infant to child, child trough adolescence. contributing to pediatric disease. variability in drug disposition and action. changes as growth and development occur. genetics can influence the way children respond to drugs, developmental changes can change the way children respond to drugs too newborns have different amount of body fluid, instead of being intracellular its extracellular, wider volume of distribution, very little body fat, don't give them drugs that are distributed in fat. drugs doses and intervals are different doses and intervals change at end of one month theophylline is metabolized to caffeine in a newborn - double wammy in babies. careful when we give particular drugs to babeies neofax is a book that we use read the whole drug monograph Kids newborn - slow metabolizers, eventually require phenotype that is more consistence with their genotype teenagers - hormonal changes, change effects that drugs have on their bodies, once hormonal swings take place go back to things as normal Pharmacogenetics - may help to identify the right drug to treat mental health disorders. some people respond to the first antidepressant that they are given but some do not. takes weeks before antidepressant drugs take full effect. may take a month before see any change. patient is suffering for month, and then still doesn't work- poor patient outcome. genetic studies show that there are variants on how patients respond some drugs - celexa, celatopram are there any genetic tests that can predict SSRI outcomes - there is a genetic variant How it works just as genes determine hair and eye color, they are partially responsible for how our bodies respond to medications. genes are instruction written in DNA for building protein molecules Different people can have different versions - slightly different DNA of the same gene, some variation are common and some are rare some are relevant for health such as those associated with a tendency to develop certain disease (azheimers, cancer, asthma, hunting don's dz) Examine genes for variations in proteins that influence drug responses - can't look at all, pick certain ones we want to look at Some proteins include a number of liver enzymes that convert medications into active or inactive forms CYP2D6 - liver enzyme acting on25% of all Rx drugs - not on exam - includes codeine converts to active form morphine, CYP2D^ exists in more than 160 different versions, only by a single difference in a nucleotide, some have larger differences, variations don't effect drug response, people with extra copies manufacture an over abundance of enzyme, metabolize very rapidly - standard dose might be overdose for them Slow metabolizers - metabolize codeine very slowly or don't metabolize it at all, don't get pain relief, give higher dose or different drug - drug seekers might have genetic variation at risk for developing adverse effects for some drugs - procainamide, isoniazid, sulfonamides, north america - 50% of caucasians and african americans - slow metabolizers 90% in some mediterranean 20%- canada all infants are slow acetalizers of caffeine instead of glucorinatdation they use actelation pathway - diff substances or longer half life than adults do % of slow metabolizers in newborns is going to change as the infant grows older difference between genotype and phenotype, since slow acetylation of caffeine is not genetically determined but is a developmental process, no genotypically determined genomic research enables more personal approaches to using and developing drugs. HCPs will be able to routinely use information about a person's genetic makeup to select drugs and doses that offer the greatest chance of helping you May also save time and money by selecting the best fit drug from the beginning no longer have one size fits all approach, don't have to give ampicillin to everyone or gentamicin to everyone depending on genetic makeup some drugs will work differently in person or act differently, people can tolerate certain drugs and others cannot, some have adrs and some don't by shortening or abadoning the trial approach, better for patients going to get right dose or right drug in a shorter time is this in use today? genetic data is in use but only for a few health problems HIV - abacavir (Ziagen) - test genetic variant to make sure they don't have bad reaction to drug some people are allergic to this drug, ill stay in room first 15 minutes, back pain, most likely going to happen in first 15 minutes, but SOB and dizzy, MD left room, coded - severe anaphylactic reaction and was allergic to drug, would have been nice to know before hand Breast Cancer - Herceptin (trastuzumab) - only works if tumor has a genetic profile that leads to over production of Her2, Her2 must be positive FDA recommendation - (1) ALL - mercaptopurine (Purinethol) - acute lymphoblastic leukemia - genetic variant that interferes with processing drug, leads to severe side effects and infection, dose should be adjusted depending on genetic profile; (2) colon cancer - irinotecan (Camptosar) - may not be able to clear drug as quickly as others can develop diarrhea or risk in infection pharmacogenetics predicted to develop better drugs for heart disease, cancer, asthma, depression, and other common diseases other uses FDA genomic information on drug labels - over 50 drugs Pharmacogenomics can play an important role in identifying responders and non-responders to medications avoiding adverse effects and optimizing drug doses. drug labeling may contain information on genomic biomarkers and can describe: drug exposure and clinical response variability risk for adverse events genotype-sepcific dosing mechanisms of drug action polymorphic drug target and disposition genes labeling inclues: actions to be taken based on biomarker biomakers include but are not limited to germ lines (23 - x and y) or somatic genes (1-22) germ line changes can affect future generations, don't want to mess with someones heredity and what someone can pass on functional deficiencies, expression changes, and chromosomal abnormalities pharmacogenomic research chemotherapy drugs - very active area, immunotherapy or antibody, certain chemotherapy drugs work better who's tumor have certain genetic changes, some drugs don't work well in 40% of patients with colon cancer who has a specific gene depression - citalopram (Celexa) development of new drugs - screening for chemicals, now using genomic information national institutes of health funded research to study the effect of genes on medications relevant to a wide range of conditions (asthma, heart disease, cancer, depression) findings collected in online resource of pharmacogenomic knowledge diabetes work with researchers, clinicians and patient advocates to ensure privacy of research participants and to maximize the benefits of pharmacogenomics research for individuals and society

pharmacogenomics/genetics (slides) genetic influences

the genes that control drug dispositions in the body determine the pharmacokinetic properties of that drug. drug metabolizing enzymes and transporters play significant roles in this process. *genetically determined factors- transported from blood stream to hepatocytes, r/t genes. pharmacogenetics relates variations in human genes to variability in drug responses at the level of the individual patient. **goal is to identify the right drug for the right patient** *half life of a drug- what ever number of hours/min, important to know when deciding how to give a drug- short half life= continuous infusion, one half life= therapeutic monitoring levels- controlled by genes. which patient will treat drug x a certain way- very long HL/short HL, study genetics, look at enzymes and figure out whether this drug/dose is appropriate for this patient. fast/poor/intermediate metabolism differs btw patients.

Executive Summary (article)

with the rapidly increasing number of drugs available to the primary care physician's armamentarium, the rational and judicious use of pharmacogenetics (PGx) can improve drug selection by increaseing the likelihood of effectiveness and reduce harmful side effects. -Adverse drug events contributed to 13.5 million, outpatient and ED visits over a recent 3-year period, with the elderly particularly vulnerable. -The increased utilization of health care resources may be contributing up to 13% of the total spending on healthcare in the U.S. -The FDA refers to alleles that influence drug effectiveness and toxicity as "pharmogenetic biomarkers." PGx biomarkers are further classified as either pharmokinetic (PK) or pharmacodynamic (PD). PK biomarkers affect how the body absorbs, distributes, metabolized, and excreted drugs. These biomarkers affect the action of drugs at the molecular level. -Clinical scenarios commonly targeted for pharmacogenomic investigation includes statin, warfarin anticoagulation, clopidogrel, pain manamgment, and a host of psychotropic medications.