INTRODUCTION

TO PHARMACOGENETICS

Genevieve Dable-Tupas, MD, FPPS, MMCE

Associate Professor
Chairperson, Dept. of Pharmacology
Director, Research and Publication
Davao Medical School Foundation Inc.
 Introduction
• Pharmacogenetics is the study of the genetic basis for
variation in drug response.

Pharmakon - Drug

Pharmacogenetics
Genetikos – Generative
(Origin)
 Pharmacogenetics vs
Pharmacogenomics
• Focused on Patient variability
• One drug in different patients with inherited
gene variants
Pharmacogenetics • Predicts drug toxicity
• Useful in Patient/disease-specific healthcare

• Focused on drug variability

• Many drugs and one genome
• Predicts drug efficacy
Pharmacogenomics • Useful in Drug discovery and development
or drug selection
 Case Study
4 patients came in for consult with diagnosis of Essential or
Primary Hypertension, Stage 2. You started all of them with
Metoprolol 100mg/tab, 1 tab once a day. You asked them to
come back after 2 weeks for a follow-up check up. These are the
findings:
Patient Initial BP BP after 2 weeks
A (42 yo male) 140/95 100/70
B (40 yo female) 140/95 110/75
C (43 yo female) 140/95 120/80
D (41 yo male) 140/95 140/90

Question: What can explain the different results of the patients ‘ BP readings after 2 weeks
of treatment?
 Importance of Pharmacogenetics to Variability
in Drug Response

• Interplay of environmental and genetic factors

• Inter-individual variation in response to drugs –
Serious problem
• Results in Lack of efficacy/Unexpected side
effects
• Variation:
– Pharmacokinetic (ADME)
– Pharmacodynamics (MOA, Drug Interactions)
– Idiosyncratic
 Pharmacogenetic Variations
May be due to :
A. Single mutant gene àGenetic polymorphism
B. Polygenic influences
• Polygenic influences & environmental factors
are responsible for normal biological
variations.
 Pharmacogenetic Variations
• Classical family studies provide information
on drug response & genetics
• Data limited
• Twin studies show that drug metabolism is
highly heritable, with genetic factors
accounting for variation
 Types of Genetic Variants
• Polymorphism – variation in the DNA sequence that
is present at an allele frequency of 1% or greater in a
population
• 1. single nucleotide polymorphism ( SNP)
– cSNP- coding region
– Nonsynonymous - or missense- if the base pair
change results in an amino acid substitution
– Synonymous – or sense – if the base pair
substitution within a codon does not alter the
encoded amino acid
 Types of Polymorphisms

1. Single Nucleotide Polymorphism (SNP)

-most common: substitution
 Types of Polymorphisms

2. Indels or SNP indels

GAAATTCCAAG

GAAA[ ]CCAAG
 Types of Polymorphisms

2. CNVs
 Case Study
4 patients came in for consult with diagnosis of Essential or
Primary Hypertension, Stage 2. You started all of them with
Metoprolol 100mg/tab, 1 tab once a day. You asked them to
come back after 2 weeks for a follow-up check up. These are the
findings:
Patient Initial BP BP after 2 weeks
A (42 yo male) 140/95 100/70
B (40 yo female) 140/95 110/75
C (43 yo female) 140/95 120/80
D (41 yo male) 140/95 140/90

Question: Is polymorphism involved in this case?

 CYP2D6 Polymorpism
Patient Initial BP BP after 2 Genotype
weeks
A (42 yo male) 140/95 100/70 Absent or very Poor
minimal gene metabolizer
expression (10%)
B (40 yo 140/95 110/75 Sub-optimal Intermediate
female) gene metabolizer
expression (10%)
C (43 yo 140/95 120/80 Genes are Normal
female) normally metabolizer
expressed (78%)
D (41 yo male) 140/95 140/90 Genes are Ultra rapid
overly metabolizer
expressed (2%)
 First Pharmacogenetic Discovery

• Primaquine induced hemolysis in patients

with G6PD deficiency
 Primaquine Pharmacogenetic
discovery
• Pharmacogenetics
– G6PD Deficiency as the genetic defect
– How this genetic defect is inherited (eg. Recessive,
dominant, x-linked, sporadic, etc)
– Distribution of defect in the population
– Drug response due to the genetic defect (eg. Hemolysis)
• Pharmacogenomics
– Explains how this genetic defect results to RBC hemolysis
when a patient takes Primaquine from transcription to
translation to expression (from genetics to transcriptomics
to proteomics to metabolomic changes) ---Omics
technologies
 Pharmacogenetic Discovery
• Currently, there are over 120 drugs whose labelling
includes pharmacogenetic discoveries: eg.
voriconazole, warfarin, carbamazepine, atomoxetine,
azathioprine, irinotecan, trastuzumab, and
cetuximab
• The Food and Drug Administration (FDA) published a guidance
document to facilitate the use of pharmacogenomic
discoveries in drug development.
Exogenous & Endogenous factors contribute to variation in drug response
(Worst case scenario)

(Best case scenario)

Fast vs. Slow Acetylators
 PERSONALIZED MEDICINE

Understanding human
genome

Simpler methods
identify genetic
information

Genetic information
specific to individual
No
toxicity No trial Preselect
& error effective drug
PHARMACOGENETICS IN CLINICAL PRACTICE

• 3 major types of evidence that should

accumulate in order to implicate a polymorphism
in clinical care.
A. Screens of tissues from multiple humans linking
the polymorphism to a trait;
B. Complementary preclinical functional studies
indicating that the polymorphism is plausibly
linked with the phenotype;
C. Multiple supportive clinical
phenotype/genotype studies
 Role of Pharmacogenetics in
Pharmaceutical Industry

• Pharmacogenetics has a threefold role in the

pharmaceutical industry including…
ØStudying drug metabolism and
pharmacological effects
ØPredicting genetically determined adverse
reactions (ADRs)
ØDrug discovery and development and as an
aid to planning clinical trials
 Limitations of Pharmacogenetics
• 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.
 Summary
• 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.
• 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.
 Thank You for your Attention!
Please study: Table 7–2. Examples Of Genetic Polymorphisms
Influencing Drug Response