Pharmacogenetics

Dr. P.Naina Mohamed PhD

Pharmacologist

Introduction

Pharmacogenetics is the study of influences of a gene on therapeutic and adverse effects of drugs.

Pharmacogenetics is also defined as the study of inherited variation in drug-metabolizing enzymes and drug responses.

Pharmacogenetics

Pharmakon - Drug

Genetikos –Generative (Origin)

Primaquine induced hemolysis in patients with G6PD (Glucose-6-Phosphate Dehydrogenase ) deficiency, was the first pharmacogenetic discovery.

The term Pharmacogenetics was coined by Vogel in 1959.

Currently, there are over 120 drugs including voriconazole, warfarin, carbamazepine, atomoxetine, azathioprine, irinotecan, trastuzumab, and cetuximab whose labeling includes pharmacogenetic discoveries.

The Food and Drug Administration (FDA) published a guidance document to facilitate the use of pharmacogenomic discoveries in drug development.

http://www.ajhp.org/content/66/7/625.abstract

Introduction

The pharmacokinetics of a drug can be altered by sequence variations in drug-disposition genes.

The pharmacodynamics of a drug can be changed by sequence variations in drug-target genes.

http://www.ajhp.org/content/66/7/625.abstract

Divisions of Pharmacogenetics

Pharmacogenetics

Drug-dispositionPharmacogenetics

Drug-target Pharmacogenetics

A drug’s disposition includes its absorption, metabolism, distribution, and excretion (ADME).

The plasma concentrations of the parent drug or its active metabolites may be affected by a genetic polymorphism altering the function of a protein that is involved in the disposition of a drug.

For example, if a genetic polymorphism leads to lower activity of a metabolizing enzyme, the plasma concentrations of the parent drug may increase and plasma concentrations of metabolites may decrease. If only the parent drug exhibits pharmacologic activity, the genetic polymorphism will potentiate the drug response, including adverse drug reactions. If only the metabolites have pharmacologic activity, then the genetic polymorphism may reduce the drug response.

Examples:

Warfarin and CYP2C9 polymorphisms

Tamoxifen and CYP2D6 polymorphisms

Thiopurine drugs and Thiopurine S-methyltransferase (TPMT) polymorphisms

Drug-disposition Pharmacogenetics

CYP2C9*2 allele results in a 30-40% reduction in enzymatic activity for S-warfarin metabolism.

While CYP2C9*3 allele causes an almost complete loss of S-warfarin metabolism.

The patients carrying CYP2C9*2, CYP2C9*3 or both of these two alleles would have higher serum concentrations of S-warfarin at a given dosage.

A study in Caucasians found that patients carrying either CYP2C9*2 or CYP2C9*3 required significantly lower daily dosages of warfarin to maintain a therapeutic INR compared with patients carrying CYP2C9*1.

Warfarin and CYP2C9 Polymorphisms

Tamoxifen is commonly used for breast cancer treatment.

Endoxifen, a metabolite of tamoxifen, is 100 times more potent than the parent drug as a selective estrogen receptor modulator and exhibits about 7 times higher plasma concentrations than the other active metabolites at steady state.

CYP2D6 is involved in generating endoxifen from tamoxifen.

CYP2D6 genotype and phenotype have been associated with variability in plasma concentrations of endoxifen among individuals.

The CYP2D6 phenotype traditionally classified as

Ultraextensive metabolizer (CYP2D6*1/*1XN (gene duplication))

Extensive metabolizer (CYP2D6*1/*1 )

Intermediate metabolizer (CYP2D6*3/*17) or

Poor metabolizer (CYP2D6*3/*3)

Extensive or ultraextensive metabolizers would have significantly higher serum concentrations of endoxifen compared with intermediate and poor metabolizers.

Tamoxifen and CYP2D6Polymorphisms

Thiopurine S-Methyltransferase (TPMT) metabolizes thiopurine drugs such as mercaptopurine and azathioprine.

Reduced TPMT activity is associated with a higher frequency of mercaptopurine-associated adverse events, such as neutropenia.

Patients who do not carry TPMT*1, have extremely low TPMT enzyme activity and almost always develop neutropenia compared with patients with TPMT*1/*1.

FDA has recommended that clinicians consider a reduction in the dosage of a thiopurine in patients carrying a nonfunctional TPMT allele.

Thiopurines and Thiopurine S-Methyltransferase (TPMT) polymorphisms

Pharmacologic effects of drugs are exerted by modulating activities of enzymes or receptors.

Genetic polymorphisms of drug-target enzyme or receptor may alter the drug response.

Fewer genetic polymorphisms in pharmacodynamicgenes have been recognized by FDA, including… Vitamin K epoxide reductase complex subunit 1 gene

polymorphisms (VKORC1) and warfarin responseß1-adrenergic receptor gene polymorphisms (ADRB1)

and ß-blocker response

Drug-target Pharmacogenetics

VKORC1 encodes vitamin K epoxide reductase, which is inhibited by warfarin.

This inhibition interferes with carboxylation of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulation proteins C and S.

Two haplotypes (A and B) formed by five noncoding VKORC1SNPs in strong linkage disequilibrium.

The A haplotype has been shown to be associated with lower levels of VKORC1 mRNA expression compared with B haplotype.

Patients with A haplotype may produce smaller amounts of VKORC1 (the warfarin target protein) than do patients with B haplotype.

This finding is true in Asian patients who require smaller warfarin doses to maintain a therapeutic INR than other races since the majority of Asians carry VKORC1 haplotype A.

VKORC1 and warfarin response

Ser49Gly and Arg389Gly are two common SNPs in ADRB1.

It is hypothesized that hypertensive patients carrying Ser49 or Arg389 would have greater reduction in blood pressure with ß-blocker therapy.

Several studies have found that hypertensive patients with Ser49Arg389/Ser49Arg389 haplotype had the greatest reduction in blood pressure with oral metoprolol.

Since the frequency of the Arg389 allele in ADRB1 is higher in Caucasians (73%) than in African Americans (58%), Caucasians are more likely to have a better blood pressure response to a ß-blocker than do African Americans.

ADRB1 and ß-blocker response

Both approaches can be used for gene-disease and gene-drug response association studies.

http://www.ajhp.org/content/66/7/625.abstract

Pharmacogenetic Studies

PharmacogeneticStudies

Candidate-gene studies

Genome-wide association study

(GWAS)

In patients who have a better (or worse) drug response, the candidate-gene approach tests how frequent an allele or a set of alleles.

Genes are selected based on their known physiological or pharmacologic effect on disease or drug response.

CYP2C9*2 and CYP2C9*3 polymorphisms had previously been shown to change the function of the CYP2C9 enzyme and were chosen to study the association with warfarin requirements.

The discovery of the association of VKORC1 haplotypes with warfarin dosage requirements shows how the candidate-gene approach is used.

The candidate-gene approach is a useful tool to study a genetic association with drug response if there is a plausible link between the gene and the drug response.

The candidate-gene approach is less expensive and requires a smaller sample size than GWAS.

A major disadvantage of the candidate-gene approach is that it requires prior knowledge of the function of the gene regarding the drug response.

Candidate-Gene Studies

The role of common genetic variations in disease or drug response surveyed by Genome-Wide Association Study (GWAS).

GWAS done by genotyping large sets of SNPs across the genome.

Most GWASs have been conducted as a case-control, cohort, or family study.

The goal is to determine whether a particular allele or a set of alleles is more common in patients with a certain disease or a better (worse) drug response.

GWAS is a great tool to discover new functions of a gene or to identify a new genetic biomarker used to evaluate drug response.

GWASs can be used to identify new biomarkers that could explain the underlying mechanisms of adverse drug reactions.

GWAS helps to understand the complex disease development and identify the factors that affect variable drug responses.

Genome-Wide Association Study

(GWAS)

Pharmacogenetics has a threefold role in the pharmaceutical industry including…

Studying drug metabolism and pharmacological effects

Predicting genetically determined adverse reactions (ADRs)

Drug discovery and development and as an aid to planning clinical trials

Role of Pharmacogenetics in Pharmaceutical Industry

Pharmacists may play a key role in applying pharmacogeneticdiscoveries to patient care.

Pharmacists can take a lead in application of pharmacogenetics in clinical practice, since they are experts in pharmacokinetics and pharmacodynamics.

Some experts have suggested that pharmacists need access to patients' genetic information in order to provide individualized pharmaceutical care before they fill prescriptions.

Pharmacists’ responsibilities for pharmacogenomics include…Promoting the optimal use and timing of pharmacogenomic

tests Interpreting clinical pharmacogenomic test resultsEducating other pharmacists, fellow health care professionals,

patients, and the public about the field of pharmacogenomics.

http://www.ashp.org/DocLibrary/Policy/HOD/StPharmacogenomicsPrepress.aspx

Roles of Pharmacists

The drug response is probably affected by multiple genes.

Drug response might be predicted from a certain pattern of polymorphisms rather than only a single polymorphism.

Holding sensitive information on someone’s genetic make up raises questions of privacy and security and ethical dilemmas in disease prognosis and treatment choices.

Limitations of Pharmacogenetics

•Focused on Patient variability

•One drug in different patients with inherited gene variants

•Predicts drug toxicity

•Useful in Patient/disease-specific healthcare

Pharmacogenetics

•Focused on drug variability

•Many drugs and one genome

•Predicts drug efficacy

•Useful in Drug discovery and development or drug selection

Pharmacogenomics

Pharmacogenetics Vs Pharmacogenomics

Pharmacogenetics plays an important role in drug development and drug safety.

Pharmacogenetics focuses on the effect of a single gene on drug response.

Pharmacogenomics deals with the effects of multiple genes on drug response.

Pharmacogenetic studies have provided strong evidence for the genetic basis of drug response and tolerability.

The translation of pharmacogenetic research into clinical practice is time consuming, labour intensive and expensive.

In future all pharmacists, not just those involved in a clinical or research setting, will probably need to understand pharmacogenetic information for better drug selection.

ASHP believes that pharmacists have a responsibility to take a prominent role in the clinical application of pharmacogenomics.

Health-care providers will increasingly need to take pharmacogenetics into consideration when prescribing medications.

Each patient’s history, physical condition, gender, and ethnicity must be considered when prescribing drugs.

Conclusion

Pharmacogenetics, 2eWendell W Weber

Pharmacogenetics and Individualized TherapyAnke-Hilse Maitland-van der Zee, Ann K. Daly

New Research on PharmacogeneticsLinda P. Barnes

Principles of Pharmacogenetics and PharmacogenomicsRuss B. Altman, David Flockhart, David B. Goldstein

Pharmacogenomics and Personalized MedicineNadine Cohen

References

http://apha.imirus.com/pdf/2008/Feb_CE_exam.pdf

http://www.ashp.org/DocLibrary/Policy/HOD/StPharmacogenomicsPrepress.aspx

http://www.medscape.com/viewarticle/590270

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1885075/

http://www.ashp.org/DocLibrary/Policy/HOD/StPharmacogenomicsPrepress.aspx

References