PHM360 Pharmacogenetics and Personalized Medicine Exam Questions

Personalized medicine

Involves tailoring medical treatment to individual patient characteristics, including genetic, physiological, and environmental factors.

Primary goal of personalized medicine

Optimize therapeutic efficacy and minimize adverse effects by prescribing the right drug, at the right dose, to the right patient.

Environmental factors influencing drug absorption

Diet (e.g., high-fat meals), drugs (e.g., antacids), toxins/pollutants (e.g., tobacco smoke).

Genetic factors influencing drug absorption

CYP enzyme polymorphisms (e.g., CYP3A5), transporter polymorphisms (e.g., PGP variants), receptor polymorphisms (e.g., HTR2A).

Adverse drug reactions (ADRs)

ADRs are the 4th leading cause of hospitalization and 5th leading cause of death.

Impact of ADRs

ADRs significantly increase healthcare costs and patient morbidity/mortality.

Personalized medicine and ADRs

Aims to predict and prevent ADRs by accounting for individual genetic and environmental differences.

Pharmacogenetics

Studies how single-gene variations affect drug response (e.g., CYP2D6 polymorphisms affecting antidepressant metabolism).

Pharmacogenomics

Examines multiple genes and genome-wide variations affecting drug behavior (e.g., genome-wide studies identifying multiple SNPs affecting warfarin dosing).

Commercially available pharmacogenetic tests

23andMe, OneOme.

Limitation of pharmacogenetic tests

Limited testing of gene variants, potential for misinterpretation due to lack of comprehensive clinical guidelines.

Intermediate metabolizer (IM)

Reduced enzyme activity; may require dosage adjustments.

Poor metabolizer (PM)

Minimal/no enzyme activity; risk of drug accumulation/toxicity, requires alternative drugs or major dose reductions.

Single nucleotide polymorphisms (SNPs)

Represent the most common genetic variation affecting drug response.

SNPs and drug response

SNPs can alter protein function or expression, influencing drug efficacy, dosing, and risk of ADRs.

CYP3A5 polymorphism

*1 allele increases metabolism, reducing tacrolimus levels.

OATP2B1 polymorphisms

Affect uptake of statins.

PGP polymorphisms

Reduced function alleles increase digoxin bioavailability.

High-fat meals

Enhance lipophilic drug absorption (e.g., saquinavir).

Antacids

Raise gastric pH, reducing absorption of weak bases (e.g., ketoconazole).

Grapefruit juice

Inhibits CYP3A, increasing bioavailability (e.g., felodipine).

Importance of ADRs in personalized medicine

ADRs significantly burden healthcare (costly hospitalizations and deaths).

Healthcare expenses due to ADRs

ADRs account for millions in healthcare expenses annually.

Personalized medicine

Identifies risk factors (genetic and environmental), improving safety by customizing treatments.

Barrier 1

Lack of clinical guidelines.

Solution to Barrier 1

Develop comprehensive CPIC guidelines.

Barrier 2

Cost and accessibility of genetic testing.

Solution to Barrier 2

Increase insurance coverage, partnerships with pharmacies for affordability.

Barrier 3

Limited clinician education.

Solution to Barrier 3

Incorporate pharmacogenetics training into medical curricula.

VKORC1

Polymorphisms alter sensitivity to warfarin, requiring dosing adjustments to prevent bleeding complications.

KRAS G12C

Mutation leads to constitutive activation promoting cancer growth; targeted inhibitors like Adagrasib selectively inhibit mutated KRAS.

CYP2D6 poor metabolizers

Increased paroxetine toxicity (sedation, weight gain, serotonin syndrome).

Alternatives for CYP2D6 poor metabolizers

Use CYP2C19-metabolized drugs (citalopram 20mg or escitalopram 10mg) due to normal CYP2C19 metabolism.

Targeted therapy concept

Therapy targets specific genetic mutations (KRAS G12C) responsible for disease (NSCLC).

Adagrasib

Irreversibly inhibits KRAS G12C, keeping it inactive, reducing uncontrolled cell proliferation.

Importance of genotyping

Ensures only patients with G12C mutation receive treatment, avoiding ineffective therapy and adverse effects.

OATP2B1 polymorphisms

Reduced function variants decrease uptake and bioavailability (e.g., statins, fexofenadine).

PGP polymorphisms

Reduced function increases absorption and CNS distribution (e.g., digoxin), increasing efficacy but also toxicity risk.

CPIC guidelines

Tools translating genetic test results into actionable prescribing decisions.

Purpose of CPIC guidelines

Guide clinicians on using pharmacogenetic results to optimize drug therapy.

Key assumption of CPIC guidelines

Genotype results already available (proactive genotyping).

Evidence level A

Strong evidence, clear clinical actions.

Evidence level B

Moderate evidence, optional actions.

Evidence levels C/D

Limited evidence, unclear actions, no clinical recommendations.

Genetic factors affecting drug metabolism

Polymorphisms like CYP3A51 (increased metabolism) or CYP2D64 (poor metabolism).

Environmental factors affecting drug metabolism

Grapefruit juice inhibits CYP3A4, smoking induces CYP1A2, affecting CYP substrates.

Interaction example in drug metabolism

CYP3A5 expressers need higher tacrolimus dose; grapefruit juice inhibition can increase tacrolimus levels, risking toxicity.

Interpatient variability in drug response

Differences in drug response between individuals receiving the same medication and dose.

Reasons for interpatient variability

Variations in genetic makeup, age, sex, disease states, and environmental factors (diet, drug interactions), all of which affect drug pharmacokinetics and pharmacodynamics.

Diet

High-fat meals can influence drug absorption.

Concurrent medications

Medications like antacids and PPIs can affect drug absorption.

Exposure to pollutants/toxins

Tobacco smoke is an example of a pollutant that can influence drug absorption.

CYP enzyme polymorphisms

Genetic variations in enzymes such as CYP3A5 and CYP2D6 can affect drug metabolism.

Transporter polymorphisms

Variations in transporters like P-glycoprotein and OATP2B1 can influence drug absorption.

Gastrointestinal metabolic enzymes

Variations in intestinal CYP3A4 expression can impact drug metabolism.

High-fat meals (Environmental Factor)

A specific environmental factor that influences drug absorption.

Drugs affecting gastric pH (Environmental Factor)

Antacids are an example of drugs that can alter gastric pH and affect drug absorption.

Grapefruit juice (Environmental Factor)

Acts as a CYP3A inhibitor, influencing the absorption of certain drugs.

CYP3A5 variants (Genetic Factor)

Genetic variations that can affect drug metabolism.

PGP transporter polymorphisms (Genetic Factor)

Genetic variations in P-glycoprotein that can influence drug absorption.

OATP transporter polymorphisms (Genetic Factor)

Genetic variations in OATP transporters that can affect drug absorption.

Intestinal permeability

Can be altered by inflammation, leading to increased drug absorption initially.

Gastric motility

Decreased gastric motility increases drug absorption; increased motility decreases absorption.

Colitis-induced diarrhea (Disease example)

Increases gastric motility, leading to reduced drug absorption.

Opioids (Drug example)

Decrease gastric motility, resulting in increased drug absorption due to prolonged exposure.

Achlorhydria

Absence or reduction of gastric acid secretion, causing increased stomach pH.

Ketoconazole (Drug example)

Shows reduced absorption in achlorhydric patients.

Atazanavir (Drug example)

Absorption is decreased in achlorhydria, reducing therapeutic efficacy.

Intermediate metabolizer (IM)

Characterized by reduced enzyme activity with one functional and one non-functional allele.

Poor metabolizer (PM)

Characterized by no functional enzyme activity, leading to minimal drug metabolism and higher toxicity risk.

Single nucleotide polymorphisms (SNPs)

Single base variations that significantly alter protein function or expression, affecting drug efficacy and toxicity.

Plasma protein binding

Drugs bound to plasma proteins are pharmacologically inactive; changes in plasma proteins alter free drug availability.

Hypoalbuminemia

Low albumin levels that increase free drug fraction, potentially causing toxicity.

Tiaprofenic acid (Drug example)

Increased volume of distribution and prolonged half-life due to hypoalbuminemia.

Efflux transporter (PGP)

Polymorphisms like C3435T and G2677T/A reduce function, increasing bioavailability of certain drugs.

Uptake transporter (OATP2B1)

Variants like SLCO2B1*3 reduce function, altering absorption of drugs like fexofenadine.

Achlorhydria (Physiological factor)

High gastric pH that reduces absorption of weak bases.

Environmental factor

High-fat meals enhance solubility/absorption of lipophilic drugs (saquinavir).

Genetic factor

CYP enzyme polymorphisms (CYP3A5*1 increases intestinal metabolism, reducing tacrolimus bioavailability, requiring higher doses).

Impact of inflammation on drug metabolism

Inflammation decreases CYP3A and PGP activity → increased oral bioavailability (e.g., tacrolimus, midazolam).

Inflammatory conditions

Decrease CYP enzyme activity (e.g., propranolol higher AUC in RA patients).

Clinical implication of inflammation

Adjust dosing in inflammatory states to avoid toxicity.

Plasma protein binding

Hypoalbuminemia (e.g., renal disease) increases free drug (e.g., tiaprofenic acid), increasing distribution (Vd) and prolonging half-life.

Membrane permeability

Tumor-induced permeability increases drug entry (useful in oncology).

Blood flow/tissue perfusion

Reduced cardiac output (heart failure) decreases drug delivery, requiring dose adjustment.

Pediatrics and renal drug clearance

Immature renal function, reduced GFR and renal transport activity; requires lower or adjusted dosing to avoid toxicity.

Geriatrics and renal drug clearance

Decreased renal mass and blood flow cause a gradual decline in renal function, necessitating dose reductions or increased dosing intervals (e.g., gentamicin).

Inflammatory bowel disease (IBD)

IBD increases intestinal permeability (leaky gut), enhancing drug absorption and potential toxicity.

Chronic inflammation effects

Can reduce CYP3A and PGP activity, increasing systemic drug exposure (e.g., tacrolimus).

Clinical recommendations for IBD

Monitor drug levels closely, consider dose reduction or alternative medications, frequent therapeutic monitoring to avoid toxicity or therapeutic failure.

Drug-drug interactions

Grapefruit juice inhibits CYP3A (intestinal), increasing plasma levels and toxicity risk (e.g., felodipine).

Ketoconazole interaction

Inhibits intestinal CYP3A and PGP, significantly increasing plasma levels of orally administered drugs (e.g., midazolam, budesonide).

Clinical outcomes of drug interactions

Potential for increased side effects/toxicity; avoid grapefruit juice/ketoconazole co-administration or adjust drug dose accordingly.

Chronic kidney disease (CKD) effects

CKD reduces renal blood flow, glomerular filtration, active secretion, and drug clearance, increasing half-life and drug accumulation risk.

Medication adjustments in CKD

Adjust dosing by reducing dose or frequency based on renal function (CrCl/eGFR).

Examples of medications in CKD

Aminoglycosides, digoxin, enoxaparin require dosage reduction in CKD patients to prevent toxicity.

Genome

Complete set of DNA containing all genetic information for an organism.

Chromosome

Structure of tightly coiled DNA around histone proteins, humans have 23 pairs (46 total).

Gene

Segment of DNA that codes for a specific protein.