Module 2

Explain the basic concepts of pharmacogenomics and be familiar with its terminology.
Discuss how genetics affect the activity of drug-metabolizing enzymes.
Consider how pharmacogenomics may play a role in drug therapy selection given a specific case.

Pharmacogenetics: refers to single or a few gene variations (called polymorphisms).
Pharmacogenomics: refers more broadly to the genome-wide (or an individual's entire deoxyribonucleic acid [DNA] sequence) effects on drug therapy.

It includes pharmacogenetics/pharmacogenomics.
It refers to "an emerging practice of medicine that uses an individual's genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of disease" (National Human Genome Research Institute, 2020).
This term is evolving to "precision medicine."
Much of the progress made in this field focused on pharmacogenomics.

The human genome is the underpinning to every human's individuality.
With the exception of identical twins, the genome is different for every individual, although there are only small differences among people's DNA that make them unique.
The human genome consists of approximately three billion base pairs, 99.9% of which are the same among all humans with only 0.1% variation among individuals.

The variations that occur with DNA (polymorphisms), along with environmental and dietary factors, create a patient's individuality, susceptibility to disease, and response to treatments.
Included in this individuality is a person's ability to absorb, distribute, metabolize, and excrete drugs.
Understanding the genetic components affecting these pharmacokinetic processes can help the clinician tailor treatment for a patient.

Each human has 23 pairs of chromosomes.
Twenty-two are autosomal and look the same in males and females, and one pair is the sex chromosome in which females have two X chromosomes and males have an X and a Y chromosome.
These chromosomes reside in the nucleus of a cell; each chromosome can have hundreds or thousands of genes.
Each chromosome is composed of DNA, which carries the genetic information for the individual.

Composition: Genes only make up about 1% of the total DNA found in humans.
Function: Genes function to produce proteins involved in the millions of biological processes that support the function of the body every day.
Malfunction of genes
Monogenic disease: Single gene malfunctions.
Polygenic disorders: Multiple genes cause disorder; they may have multiple biomarkers.

Two purines
Adenine (A)
Guanine (G)
Two pyrimidines
Thymine (T)
Cytosine (C)

Definition
Single nucleotide polymorphisms (SNPs) are variation in the DNA sequence that differs between members of a species or paired chromosomes in an individual.
Effect on drug activity and metabolism
Many of the genes responsible for drug activity and metabolism (e.g., cytochrome P-450 [CYP]) have different alleles on the same gene, producing different metabolic effects.

Which of the following is INCORRECT regarding the concept of SNPs and differing alleles?
A. SNPs can mutate or malfunction causing diseases.
B. SNPs have different alleles on the same gene producing different metabolic effects.
C. All SNPs in the human body are responsible for turning genes on or off.
D. SNPs can be indicators of future development of diseases.

All SNPs in the human body are responsible for turning genes on or off.
Rationale: Many of the genes responsible for drug activity and metabolism (e.g., cytochrome P-450 [CYP]) have different alleles on the same gene, producing different metabolic effects. Each person typically inherits two alleles of each gene: one from the mother and one from the father. There can be up to 10 million SNPs in humans, but only those SNPs on coding regions of the gene or the area of the DNA responsible for turning genes on or off have an effect on humans.

Patients can be given a therapy that inefficiently treats the underlying cause of the disease (lack of therapeutic effect).
Patients can be given a medication that can lead to adverse drug reactions (ADRs) that can be harmful or even fatal due to a difference in their genetic makeup.

The CYP2C19 gene has nine exons and is situated on chromosome 10.
To date, more than 30 different SNPs have been identified for this gene.
Clopidogrel is given as an inactive prodrug that is rapidly converted to its active metabolite via hepatic bioactivation through CYP2C19 enzymes.
Clopidogrel inhibits adenosine diphosphate-mediated platelet activation and aggregation by irreversibly binding to the platelet purinergic receptor P2RY12.

About 15% of clopidogrel is modified into an active compound and 85% is hydrolyzed to inactive forms to be excreted.
The metabolism of clopidogrel to its active metabolite is critical to successful treatment, and thus, inherited genetic polymorphisms associated with CYP2C19 have a high impact on the physiological responses to clopidogrel in patients.
Genetic variants of the CYP2C19 gene result in either normal, reduced, or absent enzyme activity or can directly lead to an overactive enzyme.

CYP2C19*1: wild-type allele (normal enzyme activity).
CYP2C19*2: most common loss-of-function variant allele inherited as an autosomal codominant trait that cosegregates mostly to Asian population.
CYP2C19*3: only detected in less than 10% of the Asian population.

Poor metabolizers (PM): 2% to 15% carry loss-of-function mutations (*2/*2,*2/*3,*3/*3) on both alleles resulting in significantly reduced or lack of CYP2C19 activity.
Ultrarapid metabolizers (URM): 5% to 30% have a gain-of-function mutation making CYP2C19 more active (*1/*17,*17/*17).
Extensive metabolizers (EM): 35% to 50% carry a normal CYP2C19 gene (*1/*1) without any mutations.
Intermediate metabolizers (IM): 18% to 45% have only one loss-of-function allele (*1/*2,*1/*3).

A patient mutation of CYP2C19 is documented as (*1/*17). What is the term for a person with this function mutation?
A. Poor metabolizer
B. Intermediate metabolizer
C. Extensive metabolizer
D. Ultrarapid metabolizer

D. Ultrarapid metabolizer
Rationale: URM have a gain-of-function mutation making CYP2C19 more active (*1/*17,*17/*17). PM carry loss-of-function mutations (*2/*2,*2/*3,*3/*3) on both alleles resulting in significantly reduced or lack of CYP2C19 activity. IM have only one loss-of-function allele (*1/*2,*1/*3). EM: 35% to 50% carry a normal CYP2C19 gene (*1/*1) without any mutations.

The PMs are those who could benefit the most from genetic testing prior to therapy, as stated on package inserts and as suggested by the Food and Drug Administration.
These PMs are incapable of producing the active metabolite of clopidogrel and would suffer from an unsuccessful treatment of their coronary blockage.
Clinical Pharmacogenetics Implementation Consortium (CPIC) also recommends special attention be given to ultrarapid metabolizers and that alternative therapies be used in poor metabolizers to treat their coronary obstruction.

IM are also challenging to treat with clopidogrel as these patients have a higher number of residual platelets, which could lead to adverse cardiovascular outcomes and therefore might also benefit from other forms of therapy.

Warfarin is a commonly prescribed blood thinner used to prevent atrial fibrillation-induced strokes, as well as permanent damage following the onset of venous thromboembolism or pulmonary embolism.
It exists as a racemic mixture of R-warfarin and S-warfarin.
S-warfarin possesses the most anticoagulant properties through its action as a vitamin K antagonist.
Vitamin K plays a crucial role in the coagulation cascade as its reduced form acts as a cofactor of -glutamyl carboxylase.

This is accomplished by an upstream enzyme called vitamin K epoxide reductase complex, subunit 1 (VKORC1).
VKORC1 is the therapeutic target of warfarin and its inhibition results in decreased amounts of reduced vitamin K preventing coagulation factors from being activated.
Once its therapeutic window is achieved, S-warfarin is rapidly metabolized through the P-450 liver enzyme CYP2C9 to its inactive oxidized form (7-hydroxy warfarin).

The rate at which S-warfarin is metabolized is highly dependent on the enzymatic activity of CYP2C9.
A less efficient metabolism and clearance of warfarin could lead to accumulation of its active form systemically leading to sustained anticoagulation effects.
Deaths have occurred due to excessive bleeding following warfarin treatment. It was later discovered that some patients do not have a fully functional CYP2C9 enzyme due to alleles containing mutations, preventing the proper inactivation of the potent S-warfarin.

CYP2C9*1: Individuals possess normal enzyme activity.
CYP2C9*2: Carriers exhibit a 30% decrease in activity.
CYP2C9*3: Patients have as much as 90% decrease in their enzymatic activity.
Patients can carry two normal copies *1/*1 or a normal copy and a polymorphic *1/*2, or could have both copies with polymorphism *2/*3.
The target enzyme VKORC1 has also shown the presence of inactivating mutation -1639G>A.

For patients receiving warfarin treatment, genetic testing is recommended in order to predict which patients are carrying these mutations who would be at higher risk of bleeding.
A haplotype individual would require less warfarin to inhibit VKORC1 to produce similar anticoagulant effects.
The same is true for patients that carry CYP2C9*2 and *3 where the active form of warfarin does not go through clearance normally leading to immediate excessive bleeding.

NGS: next-generation sequencing
WGS: whole genome sequencing
Exome sequencing
Targeted ribonucleic acid sequencing
Genetic Information Nondiscrimination Act (GINA 2008)
Ethical, legal, and social issues (ELSIs)

Another area that is broadly presenting policy challenges involves ethical, legal, and social issues (ELSI) such as patient privacy and protection of data and genetic samples, return of results obtained within the context of research studies to patients, and decisions related to the use of genomic information and insurance coverage.
To date, the implementation of pharmacogenomics into clinical practice has presented with various ELSI and policy challenges.

Pharmacogenomics and personalized medicine provide both economic opportunities and challenges. The cost of different pharmacogenomic tests continues to decline, and there is increasing evidence for cost-effectiveness of pharmacogenomics, particularly its potential to reduce ADRs.
It is also important to consider how pharmacogenomics might increase costs, including the storage of genetic samples, resources for computational analysis, and interpretation of the findings.

Describe the historical origins and evolution of health insurance and managed care organizations in the United States.
Compare and contrast the common types of prescription drug formularies and corresponding prescription copayment strategies.
Explain the responsibilities of a pharmacy and therapeutics (P&T) committee and describe the factors that P&T committees consider in their decision-making processes.
Discuss how formulary management tools (generic substitution, therapeutic interchange, prior authorization, and step therapy programs) can influence prescribing patterns.
Explain how emerging health technologies (electronic prescribing, electronic medical records, and telehealth) have influenced the delivery of care.

Overturned restrictive state laws regulating health providers.
Defined a basic package of services that HMOs were required to offer.
Established procedures by which HMOs could become federally qualified.
Health Maintenance Organization Act of 1973

Because they evaluate both cost and human data, studies on pharmacoeconomics are important tools for managed care organizations (MCOs) in making drug therapy decisions.
Overview of Pharmaeconomics

Used to determine the overall cost of a particular intervention or protocol by evaluating all pertinent data and converting the data to a monetary end point.
Cost-minimization analysis
Evaluates the cost of two or more interventions with equivalent components or end points and determines which intervention is least costly.
Types of Analyses #1

May help determine the best program or intervention, where the desired outcome is a combination of both a monetary end point and a nonmonetary end point relative to an improvement in health.
Cost-utility analysis
Measures data in terms of quality of life.
These analyses predominantly use quality-adjusted life-years (QALYs) gained as a major outcome.
Types of Analyses #2

Usually organized by therapeutic area and medication class, with the formulary status and reimbursement category listed for each medication.
Encourage the use of medications considered to be safer, more clinically effective, or more cost-effective than other medications within the same therapeutic category.
Formularies and Pharmacy and Therapeutics Committees

The drugs are most often categorized within their respective therapeutic classes with the therapeutic classes listed in alphabetical order.
Additional information usually detailed for each drug includes the brand/generic status; the drug's relative cost.
A "formulary medication" is a drug that is covered (reimbursed) by the health plan.
Structure of Formularies

Open: usually do not involve a preferred group of agents; instead, they allow the prescriber to select any covered medication.
Tiered: are open formularies that set different copay tiers for generic, preferred, and nonpreferred medications.
Categories of Formularies

A. It is based on the patient's ability to pay.
B. It sets different copays for medications.
C. It allows the prescriber to select any covered medication at the same copay.
D. It limits prescribers to a limited list of preferred agents.
Question #1

Rationale: Tiered formularies are open formularies that set different copay tiers for generic, preferred, and nonpreferred medications. Closed formularies limit clinicians to prescribing from a limited list of preferred agents. Open formularies usually do not involve a preferred group of agents; instead, they allow the prescriber to select any covered medication.
Answer to Question #1

Can differ from plan to plan and by geographic region.
Closed and open formularies usually have two copays; one for generics and one for brand drugs.
Tiered formularies have more than two copays, and each tier is related to a copay amount.
Tiered formularies usually have three tiers: generic drugs, preferred brand drugs, and nonpreferred brand drugs.
Copay

Promote the use of less costly and equally efficacious medications (which are most often generic medications).
Financially incentivize the use of preferred brand drugs over nonpreferred brand drugs, or place barriers that prevent nonpreferred branded medications from being covered by the MCO.
Function of Formularies #1

Function of Formularies #2

Therapeutic interchange
Drug-dispensing limitations
Prior authorization and step-therapy programs
Medical necessity
Formulary Policies to Promote Appropriate Drug Utilization

Composed primarily of physicians and pharmacists and may also include nurses, nurse practitioners, physicians' assistants, and members of the organization's administration.
Formulary management
Develop and revise the formulary, create and implement medication-use policies, and provide education for practitioners.
Pharmacy and Therapeutics (P&T) Committee #1

These programs and protocols provide useful recommendations for practitioners treating various diseases.
Pharmacy and Therapeutics (P&T) Committee #2

A. It is composed of pharmacists and insurance company Chief Financial Officers (CFOs).
B. It licenses pharmacists to practice in hospital settings.
C. It helps to develop and manufacture safe, effective generic medications.
D. It creates and implements medication-use policies.
Question #2

Rationale: The main responsibilities of a P&T committee are to develop and revise the formulary, create and implement medication-use policies, and provide education for practitioners. The committee is composed primarily of physicians and pharmacists and may also include nurses, nurse practitioners, physicians' assistants, and members of the organization's administration. The P&T promotes the use of effective generic products but does not develop or manufacture them nor does it license any practitioners.
Answer to Question #2

Evaluating compliance: percentage formulary compliance
Health care trend reporting
Improving formulary compliance
Pharmacist reimbursement
Patient prescription copayment
Ensuring Formulary and Practice Guideline Compliance

The ability of prescribers to directly transmit prescriptions from the office to the pharmacy eliminates the need for the patient to take it to the pharmacy to be filled.
E-prescribing has been shown to reduce prescribing errors.
Electronic Prescribing and Electronic Health Records

Affordable Care Act Premises
Ensure accountability of MCOs.
Lower health care costs.
Improve quality of care.
Provide improved consumer choice for health care services.
Current Issues in Managed Care

It is imperative for practitioners and MCOs to understand each other's role in health care.
Although practitioners and MCOs have quite different responsibilities in health care, both groups share a common goal: the delivery of high-quality care to patients.
Summary