Pharmacogenomics

Question 1

Introduction

Answer 1

Heterogeneity in genetic makeup contributes to many variations in pharmacokinetics

Various factors contribute to specific observable pharmacodynamic differences

Most drugs are metabolized through the cytochrome P450 enzyme system

Differences between poor metabolizers and extensive metabolizers impact provider management

Applying pharmacogenomics to clinical practice

Question 2

What is pharmacogenomics?

Answer 2

Branch of pharmacology that deals with the influence of genetic variations on drug response in patients by correlating gene expressions with a drug’s efficacy or toxicity.

Drugs and drug combinations are optimized for each individuals unique genetic makeup

Question 3

Genetics Review

Answer 3

Although humans share 99.8% of DNA sequence, the less that 0.1% difference is about 3 million nucleotides

Of the 0.1% difference, over 80% will be single nucleotide polymorphisms (SNPs). An SNP is a single base substitution of one nucleotide by another.

An example of an SNP is individual A has a sequence GAACCT, whereas individual B has a sequence GAGCCT, the polymorphism is a A/G.

Question 4

Genetic Differences in Drug Metabolism

Answer 4

Genetic polymorphism
The difference in the allele(s) responsible for the variation

Phase I and Phase II metabolism

Question 5

CYP450

Answer 5

CYP450 enzymes are involved in about 75% of drug metabolism and bioactivation in the liver

Some CYPs metabolize only one (or a very few) drug(s), whereas others may metabolize multiple drugs.

Genes provide the coding for CYP enzymes, and the enzymes themselves are designated by the abbreviation CYP, followed by an Arabic numeral indicating the gene family, a capital letter indicating the sub family, and another numeral for the individual gene.

Example: CYP2E1 is the gene that encodes the enzyme CYP2E1, one of the enzymes involved in acetaminophen metabolism

Question 6

Role of P Glycoprotein (P-gp)

Answer 6

P-gp membrane-bound transport systems responsible for drug transport across cell membranes

P-gp, an efflux pump expressed along the GI tract, limits the permeability of many drugs and thus affects their absorption and bioavailability

A number of drugs inhibit or activate both CYP450 and P-gp at the same time (e.g. grapefruit juice)

Question 7

Pharmacodynamic Differences

Answer 7

How does a person’s genetic makeup affect CYP enzyme function and pharmacodynamic differences?

What other factors besides genetic coding contribute to pharmacodynamic differences?

Question 8

CYP450 in Clinical Practice

Answer 8

Clinical knowledge of substrates, inhibitors, and inducers for each CYP450 family assists clinicians in predicting potential drug-drug interactions
They CYP3A subfamily is responsible for over 50% of drug metabolism

Race, gender, environmental factors, and drugs may alter the gene expression of individual CYP450 families and subfamilies
40% of Asians display drug polymorphism

There is no specific clinical test to estimate the sensitivity or activity of CYP450

CYP families 1 through 3 have the least affinity for substrates and have the widest genetic variability
They are responsible for 78-80% of phase I metabolism- drug interactions in clinically used drugs
Variations or polymorphisms in genetic codes for these CYP enzymes have tremendous clinical importance

Question 9

Inhibitors vs Inducers of CYP450

Answer 9

What are the clinical implications when substrates inhibit CYP450 enzymes?
An inhibitor may decrease the metabolism of substrates and generall lead to increased drug effect

What are the clinical implications when substrates induce CYP450 enzymes?
An inducer may increase the metabolism of substrates and generally lead to decreased drug effect

Question 10

Variations in Phenotypes Affect Speed of Metabolism

Answer 10

Poor metabolizers; homozygous for lack of a working enzyme.
Intermediate metabolizers; heterogenous for one working wild-type allele and one mutant-allele
Extensive metabolizers: homozygous
Ultra-rapid metabolizers; heterozygous for more than one functioning copy of a certain enzyme

Question 11

Clinical Implications of Pharmacogenomics

Answer 11

Pharmacogentic testing before prescribing

• Cetuximab
• Trastuzumab
• Maraviroc
• Dasatinib

Warfarin

• Variants in VCORC1 may lead to resistance
• Label updated by the US FDA to include recommended starting doses depending on the VKORC polymorphism profile

Carbamaepine
-FDA-labeled, recommending testing for the HLA-B*2503 allele in patients of Asian ancestry before initiating carbamazepine-induced Stevens-Johnson syndrome or toxic epidermal necrolysis