Pharmacogenetics and Pharmacogenomics

1. Biol 601 Seminar
May 10, 2012
Raul Soto
Adam Gainford
Greg Stanger
The Role of
Pharmacogenetics /
Pharmacogenomics in
Drug Development and
Regulatory Review
http://www.liv.ac.uk/pharmacogenetics/dna_and_pills.jpg

2.  “Different [drugs] to different patients, for the
sweet ones do not benefit everyone, nor do the
astringent ones, nor are all the patients able to
drink the same things.” – Diseases III
 Hippocrates, father ofWestern
Medicine, 2500 years ago
 We’ve known for a long time that not
all substances have the same effects
on all patients
 With the development of molecular
genetics, now we can begin to
explore WHY
http://www.sculpturegallery.com/two/hippocrates5.jpg

3.  How DNA-based differences
affect PK and PD of medications
 How pharmacogenomics info is
applied and reviewed in IND, and
NDA/BLA submissions
 Critical issues in regulatory
review
 Labeling implications
http://3.bp.blogspot.com/_9zrxRkzw1zg/R02H0bBqiDI/AAAAAAAAAA
M/Hj1YxWsZ3sg/S269/pharmacogenetics.jpg

4.  Pharmacogenetics: the convergence of
pharmacology and genetics, deals with genetically
determined responses to drugs… also concerned with
the differences in the metabolism of medications
among children, adults, and senior citizens; men and
women; and people with various medical conditions.
 Source: MedicineNet, www.medterms.com/script/main/art.asp?articlekey=4858
 Pharmacogenomics: biotechnological science
that combines techniques from medicine,
pharmacology, and genomics; and is concerned with
developing drug therapies to compensate for genetic
differences in patients which cause varied responses to
a single therapeutic regimen. Patient-drug interactions
is a complex trait influenced by many genes.
 Source: www.pharmainfo.net/reviews/role-pharmacogenomics-drug-development
http://www.cognigencorp.com/index.php/co
gnigen/our_services/

5.  Pharmacokinetics: The process by which a drug is Absorbed,
Distributed, Metabolized, and Eliminated (ADME) by the body.
 Source: http://medical-dictionary.thefreedictionary.com/pharmacokinetics
 Pharmacodynamics:The study of how a drug acts on a living
organism, including the pharmacologic response and the duration and
magnitude of response observed relative to the concentration of the drug
at an active site in the organism .
 Source: http://medical-dictionary.thefreedictionary.com/pharmacodynamics
 PK: what the organism does to the drug
 PD: what the drug does to the organism

6.  People’s responses to a drug substance may vary according to various
intrinsic and extrinsic factors
 Intrinsic:
 Age
 Gender
 Ethnicity
 Disease State (i.e. diabetes, heart disease)
 Organ dysfunctions (i.e. liver or kidney diseases)
 Physiological states (i.e. pregnancy, lactation)
 Genetics
 Extrinsic:
 Smoking
 Diet
 Medications a person is taking
 What do these have in common?
 Differences in the levels and patterns of gene expression
http://www.getfreeimage.com/pictures/different-people-groups-pic.jpg

7. Type Effects
Changes in a gene’s protein coding
region
Δ in translated amino acid sequence
=> Δ protein structure, conformation
=> Δ protein function
Changes in a gene’s promoter
/regulatory regions
Δ in protein expression levels
Changes in # of copies of a gene Δ in protein expression levels
If gene codes for a transcription factor Δ in protein expression for multiple genes
If gene codes for an intron/exon
splicing enzyme
Δ in protein structure/function for multiple
proteins
Deleted / inactivated gene No protein expression, protein is absent
If gene codes for metabolism-related
proteins
Δ in way drugs are absorbed, distributed,
metabolized, excreted; Δ in duration and
intensity of effect; Δ in toxicity …
 Polymorphisms in enzymes, receptors, transporters, signaling
proteins, etc. may affect a drug’s PK/ PD profile
 NOT limited to a drug’s target!

8. http://www.pharmainfo.net/reviews/role-pharmacogenomics-drug-development

9. http://mostgene.org/2009_conference/personalized_meds_Gettig.pdf

10.  Women have better response to serotonin reuptake inhibitor antidepressants
(SSRIs) like Prozac and Paxil, than to tricyclic antidepressants like Elavil and
Tofranil; also more likely to develop depression due to low serotonin levels.
 Some anti-anxiety medications have better effect on men than women.
 Women have better response to narcotic pain relievers than to non-narcotics.
 Carvedilol (Coreg), a beta-adrenergic blocking agent used to lower blood
pressure, is more effective in Africans than Caucasians.
 Enalopril (Vasotec), an angiotensin II inhibitor to lower blood pressure, is more
effective in Caucasians than Africans.
 Heart failure combined treatment with hydralazine + isosorbine is more effective
in Africans than Caucasians.
 Expression of high levels of alcohol dehydrogenase enzyme in Asians (85%) vs
Caucasians (Swiss 20%, British 10%); alcohol is metabolized faster, causes slow
heartbeat, facial flushing.

11.  1980-1999 study of 354 drugs…
 21 % required dose changes …
 79 % of those changes were safety-related dose reductions
 Many changes based on new info obtained AFTER drug market
release
 Usually dose recommendations for specific populations, i.e.
 Renal / hepatic impairment
 Concomitant medications
 Pregnancy
 Drug manufacturers should have dosing recommendations
for individuals with intrinsic /extrinsic factors BEFORE market
release to AVOID risks of Adverse Drug Reactions (ADR).

12.  5 % hospital admissions
 10% hospitalized patients experience them
 106,000 deaths and 2.2 million serious events
caused by adverse drug reactions (ADRs) in
the US each year (Lazarou 1998)
 Jason Lazarou, MSc; Bruce H. Pomeranz, MD, PhD; Paul N. Corey, PhD. Incidence of Adverse Drug
Reactions in Hospitalized Patients: A Meta-analysis of Prospective Studies.
JAMA.1998;279(15):1200-1205
 4th – 6th leading cause of death in the US for
hospitalized patients
 May lead to drug being withdrawn from the
market
http://www.scientificamerican.com/article.cfm?id=a-biochemical-
way-to-reduce

14.  Many metabolic enzymes are
polymorphic
 => Evolutionary defense process
 7 – 22 % of a sample of randomly
selected drugs are substrates for
polymorphic enzymes
 59 % of drugs that cause ADRs are
metabolized by polymorphic
enzymes
http://media.rbi.com.au/AD_Media_Library/Fluvax.jpg

15. http://ridb.kanazawa-u.ac.jp/file/image_002253.jpg

16. Phase I metabolizing
enzymes
Cytochromes P450
Phase II metabolizing
enzymes
UGTs, GSTs, SULTs, MTs, EHs, NATs
Drug transporters Influx transporters: PGPs
Efflux transporters: OATPs (organic anion transport
proteins), OCTPs (organic cation transport proteins).
Drug receptors Class 1 receptors : ligand-controlled ion channels
Class 2 receptors : G-protein coupled receptors
Receptors regulating gene expression
G-proteins i.e. GNAS1, GNB3
 GeneticVariations can influence the activity of, or have an
effect on the expression of, the following types of proteins

17.  Body uses enzymes to modify drug substances
 Rate of this process is relevant to duration and intensity of a drug’s
pharmacological action
 Phase I: non-synthetic reactions
 Oxidation, reduction, hydrolisis, cyclization, decyclization
 Activate / deactivate substances
 Phase 2: conjugation reactions
 Typically detoxify / deactivate substances
 Methylation, sulphation, acetylation. glucuronidation, glutathione conjugation,
glycine conjugation
 Interference (induction, suppression, inhibition) with these
processes accounts for the most common and potentially severe
ADRs.

18.  LIVER : principal site of drug metabolism
 Smooth endoplasmic reticulum of liver cells
 OTHERS: most tissue has some metabolic capabilities
 Epithelial cells of gastrointestinal tract, skin, lung, kidneys
http://www.doctorfungus.org/thedrugs/images/antifung_1.jpg

19.  Cytochrome P450 superfamily of polymorphic enzymes
 Found all over the body
 Catalyze most Phase I oxidative reactions
 Major enzymatic activity occurs in hepatic CYPs (liver)
 Also expressed in the brain, lungs, kidneys, intestines, monocytes,
macrophages, lymphocytes…
 Relevant in the bioactivation and metabolism of 75% of drugs
http://www.p.chiba-u.ac.jp/lab/bukka/cyp2c9.png

20.  Families: 17 families in humans
 Subfamilies: 42 sub-families in humans
 Enzyme/gene: 55 genes and 29 pseudogenes in humans
http://www.doctorfungus.org/t
hedrugs/images/antifung_2.gif

21. Approximately 95% of all drug oxidation in humans is the action
of SIX CYP enzymes

22.  Member of a class of molecules called
statins
 Used to treat high cholesterol and related
conditions caused by dyslipidemia
(abnormal elevation of lipids in blood
 Approved by FDA in August 2003 in 10mg,
20mg, and 40mg presentations
 5 mg presentation was later developed for
Japan

23.  AUC : area under the plasma concentration curve
 AUC for Crestor ™ varies depending on several factors :
 Ethnicity (esp. Japanese, Singapore ethnic Chinese)
 Hepatic impairment
 Renal impairment
 Person taking cyclosporine, gemfibrozil, itraconazole

24.  “Because Asians appear to process the drug
differently, half the standard dose can have the
same cholesterol-lowering benefit in those
patients, though a full dose could increase the
risk of side-effects…”
http://articles.latimes.com/2005/mar/03/nation/na-crestor3

26.  Variability in drug response and factors that contribute to it
must be investigated during the drug development process
 Companies should submit to regulatory agencies data for key
PK/PD parameters as part of the drug IND, and NDA/BLA
reviews.
 AUC: Area under the plasma concentration curve
 Cmax: maximum plasma concentration
 Phase III clinical trials should include how these parameters
vary in various population groups
 This information should be included in the drug’s label

27. Changes in PK/PD
parameters
Efficacy / safety
Labeling of other drugs
in the same
pharmacological class
Intrinsic factors
Extrinsic factors
Drug R & D Patients
Drug labeling
recommendations

28. CYP2D6 is commonly used
polymorphic enzyme to test
drug metabolizing.
It is becoming increasingly more
common for submissions to use
genotyping vs. phenotyping
Distribution of submissions
from 1992-2001 evaluating
polymorphic enzymes

29. 1. PK differences in different phenotypes and
genotypes
2. Use genotypes as a covariant for PK/PD in clinical
trial analysis
3. Explain outliers in PK/PD in clinical trials
4. Sort subjects into genotypic categories by clinical
effectiveness
5. Determine if ADR is relative to certain genotypes

30.  More genotypic analysis and evaluations
 Investigation of multiple enzyme and
transporters and receptors
Genomic Analysis
examples

31. Alleles in different races and ethnic groups for
dose-response must be considered

32.  New FDA
guidelines based
on purpose of
evaluations and
the validity of
biomarkers used.
 Need to submit
new drug
applications when
using
metabolizing
enzyme
biomarkers.
Table 2.5

33.  Can be caused by dietary supplements or other
drugs.
 These interactions may be impacted by
genotypes
 Has begun to appear in product labels

34.  Regulations and guidelines
 Dictate what data needs to be
shared with the regulating agencies
and in what form
 Heavily regulated clinical trial
environment
 VGDS VXDS
 Voluntary Genomic Data
Submission
 IPRG review

35.  At any given time, there are thousands of clinical trials
underway. A standard must be set to ensure
consistency in the analysis of:
 Efficacy
 Variability
 Drug use and administration
 Patient screening
 Data quality
 Adverse Effects
 …and any other characteristic of
the drug development process
 Access to pharmacogenomic data (VGDS)
 May lead to a large database of genomic data
for research and optimization purposes

36.  The possible outcomes for data submission:
 Full Study Reports
 Contains all clinical and pharmacological data
that may contribute to the evaluation of
effectiveness for the proposed indication along
with any information stated in the label
 Abbreviated Report
 Does not involve the effectiveness or
pharmacology. Contains all of the safety
information that would be found in the full
study report
 Synopsis
 Format allowing the reviewer to
successfully evaluate the safety data

37. Is the data used
for clinical or
preclinical
decisions?
Used to support
the drug
description?
Was the data
collected
through the
detection of a
known valid
biomarker?* Known valid biomarker – one that is accepted by the
scientific community at-large to predict a clinical outcome

38. Will the data
be used
towards
approval or
labeling
justification?
Was the data
collected
through the
detection of
a known or
probable
biomarker?
* Probable valid biomarker – Appears to have predictive value but not yet
replicated or widely accepted

39. (Book gives four)
1 2
3 4
Stage: IND
Situation: The NME is metabolized by
CYP2C19.The patients genotypes are
screened for CYP2C19 to determine drug
dosing.
Data submission format: Full Report
Reasoning: Data used to support scientific
arguments based on drug dosing selection
Stage: Phase III
Situation: The NME is metabolized by
CYP2D6. After the testing occurred, a subset
of patients were screened genotypically for
CYP2D6 to analyze any genotype and dosing
association.
Data submission format: Full Report
Reasoning: This data will be used for proposed
labeling.
Stage: Phase III
Situation: The NME is metabolized by
CYP2D6. After trial completion, a subset of
patients were screened genotypically for
CYP2D6 to find an association between
plasma clearance values and genotype. Not
used for labeling.
Data submission format: Abbreviated Report
Reasoning: Not used for label or drug
description
Stage: Drug Interaction Study
Situation: The NME is metabolized by CYP3A.
The patients genotypes are screened for
CYP3A5, a polymorphism to determine its
effect on inter-individual variability.
Data submission format: Synopsis only
required for NDA/BLA. AVGDS is
recommended for NDA/BLA/IND.
Reasoning: Data used to support scientific
arguments based on drug dosing selection

40. * Regardless of data influence on drug efficacy, safety or labeling, a
VGDS is recommended for all pharmacogenomic data
Goal:
-Better collaboration
between sponsors and
FDA for PG data
-The education of
physicians, healthcare
management and the
patient
* IPRG – Agency wide
review group that
reviewsVGDS and works
on providing public and
industry knowledge

41. * Regulated by 21 CFR 201.56
• PG data can be included in the following label sections:
• Indications and Usage
• Dosage and Administration
• Contraindications
•Warnings and Precautions
• Adverse Reactions
• Drug Interactions
• Use in Specific Populations

42. Drug Label Section Description
Herceptin Indications and
Usage
Should be used in
patients whose tumors
were evaluated with a
HER2 predicting assay.
Purinethol Warnings / Dosage
and Administration
Those homozygous
forTPMT defect gene
may be sensitive to
myelosuppressive
effects and rapid bone
marrow suppression.
Mellaril Contraindications 7% of the normal
population have a
genetic defect leading
to reduced activity of
P450 2D6.This leads
to contraindication.
Depending on the
risk/benefit, the
information can be
placed in multiple
label sections.

43. IF:
1. Genomic testing must
occur prior to dosing
2. Dose is dependent on
the genotype
3. Serious Adverse Events
due to PG profile
THEN:
1. The information goes to the Indications
and Usage sections
2. The information goes to the Dosage and
Administration /Warnings sections
3. The information goes to the
Contraindications section

44. • Pharmacogenomic data can greatly help us to understand the
variability in drug response from person to person
•This will in turn lead to improved safety and efficacy during
the drug development process
•The FDA is taking an
active role for the
integration of
pharmacogenomic data
in the drug development
process.
•TheVGDS (nowVXDS)
allows for an industry
wide compilation for the
association between
genomics and drug
response.
Drug ResponseVariation
- Genetic differences

45. •There has been a consistent rise in the
amount of pharmacogenomic data labeling
and the trend will increase as we further
understand our genome and the many
factors that effect PK and PD of drug
substances
•The continuous creation of assays
allowing for biomarker detection presents
a greater possibility for personalized
medicine based on genome