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Transcript
Pharmacogenomics: The Future
of Personalized Medicine
Kimberly Dunbar, PA-S2
South University
Khalil Khlifi, Pharm D. Candidate
University of Georgia
Objectives
 Provide an overview of genomics and
its implications in medicine
 Discuss the challenges of genomics
 Discuss examples of “Hot Topic”
genomic finds
 Discuss examples of drug targeted
therapeutics
Case Study
 You are rounding on a 65 yr old
Caucasian female who presented to the
ER yesterday with a recent h/o loss of
consciousness and fall





She is still complaining of pain and right sided weakness
She is stable at this time
Xray reveals right hip fracture
CT and MRI reveals CVA
EKG shows Atrial Fibrillation
What’s going on?
 Proper emergency treatment was
completed but she is still complaining
of severe pain despite morphine
 The ER physician started her on
Coumadin 3mg daily and her INR is
4.0
What is Genomics??
 Newer branch of medicine that deals with the
influence of genetic variation on drug response in
patients by correlating their gene expression with a
drug’s efficacy and toxicity3
Science of Genomics
 Although the genomes of individuals are 99.9% identical,
the small 0.1% accounts for a possibility of 3 million
polymorphisms
 These polymorphisms can account for variations in protein
expression and function, resulting in phenotypes affected for
disease or drug response
 Mechanism of action for drug therapy depend on the
molecular interaction of the drug with the specific protein
target: receptors, transporters, or cell-signaling pathways
 Polymorphisms in each individual’s genome accounts for
the variation in drug response due to differences in the
coding of their individual protein expression
Science of Genomics
 Possible causes of polymorphisms are:
 Insertion/Deletion Polymorphisms
 Gene Duplications
 Gene Deletions
 Consequences of polymorphisms
 May result in different amino acid sequences or a
stop codon
 May result in a change to protein function, quantity,
or expression
 May alter stability of mRNA
 Benign
Pharmacogenetics vs.
Pharmacogenomics
 Pharmacogenetics is the study of
how genetic differences in a single
gene influence variability in drug
response
 Pharmacogenomics is the study of
how genetic differences in multiple
genes influence variability in drug
response
What does it mean for patients?
 Ideally, genomics would optimize drug therapy for
patients based on prescribing medication that
would deliver the best results based on the
patient’s genotype, while minimizing the adverse
effects
 The theory involves better pharmaceutical
outcomes for patients and possibly finding the right
mix of medications for that patient, thereby
reducing the need for polypharmacy in some cases
What does this mean to healthcare
providers?
 As healthcare providers, we are given the task of
using the scope of genomics to tailor medication
therapy to a patient that would maximize the
efficacy and decrease the adverse events
 Patient’s genomes would give us clues into what
drug classes would work best for them and which
ones would have minimal effect on their therapeutic
goal outcomes
Polymorphisms in the ReninAngiotensin System and Cognitive
Improvement
 Currently there is research being conducted to
determine the efficacy on ACE inhibitors and their
effect on cognition
 Two polymorphisms exist within the angiotensinogen
gene and ACE gene
 The Perindopril Protection Against Recurrent Stroke
Study (PROGRESS) revealed that he use of ACE-I
reduced the risk of cognitive impairment in those
with previous history of a stroke
 The Hypertension in the Very Elderly Trial revealed
that there was no improvement in cognition or
dementia in those treated with ACE-I
Angiotensin Converting Enzyme
(ACE) Gene
 The DD polymorphism leads to elevated levels of
plasma ACE
 There is only one defined polymorphism currently
with this gene:
 ACE-ID (Genotypes: D/D, I/D, I/I)
Angiotensinogen (AGT) Gene
 Codes the angiotensinogen protein which is
involved in the production of angiotensin II
 There are two different polymorphisms present in
this gene
 AGTM235T (Genotypes: C/C, C/T, T/T)
 AGT6 (Genotypes: A/A, A/G, G/G)
 M235T polymorphism is associated with higher
angiotensinogen levels and possibly higher renin
angiotensin system activity
Results of Current Research
 There seems to be some protective property
against cognitive decline only in individuals who
have the AA genotype of the 6AGT or CC genotype
of M235T when treated with an ACE-I
 Polymorphisms in the ACE-ID showed no
improvement in cognition decline with treatment
with ACE-I
“Hot Topics”
 Warfarin and CYP2C9
 Genetic polymorphisms have been found that
decrease the activity of the CYP2C9 metabolizing
enzyme
 Patients with the polymorphism require a smaller
dose than those without the polymorphism because
warfarin is not metabolized at the same rate for the
deficient patients
 Patients were at higher risk for serious or lifethreatening bleeds if the polymorphism was present
(Hazard Ratio of 3.94 during first e months of follow
up)
“Hot Topics”
 CYP2D6 Polymorphisms


Responsible for the metabolism of antidepressants,
antipsychotics, analgesics, acetylcholinesterase inhibitors,
etc
Polymorphism are classified as follows:






Ultrarapid metabolizers (UM)
Extensive Metabolizers (EM)
Intermediate Metabolizers (IM)
Poor Metabolizers (PM)
Most people are EMs (>80%)
PMs and UMs tend to show higher transaminase activity
than EMs and IMs
“Hot Topics”
 CYP2D6 Polymorphisms and antidepressants

There was an increase rate of adverse effects in the patient
population of poor metabolizers
 Prozac death in child attributed to CYP2D6 poor
metabolizer genotype
 CYP2D6 poor metabolizers with severe mental illness had
more adverse drug reactions, increased cost of care, and
longer hospital stays
“Hot Topics”
 CYP2D6 Polymorphisms and Acetylcholinesterase
Inhibitors



Poor metabolizers and Ultrarapid metabolizers responded
poorly to Donepezil for treatment of Alzheimer’s disease
Extensive metabolizers and intermediate metabolizers
improved their cognitive function by 10% and 5% of their
MMSE score, respectively
While poor metabolizers and Ultrarapid metabolizers
declined 13% and 6%, respectively
“Hot Topics”
 CYP2C19 and Proton Pump Inhibitors (PPI’s)
 Patients being treated with PPI’s for ulceration had
variation in cure rate based on their genotype
 RM- 28.6%
 EM- 60%
 PM- 100%
 Patients with rapid or extensive metabolism were
more likely to have treatment failure and decreased
quality of life
Drug Targeted Therapies
 Breast Cancer



Herceptin (Trastuzumab)
Human Epidermal Growth Factor Receptor 2 (HER-2) is
over expressed in about 25-30% of breast cancers
Helps clinicians predict the performance of therapy early
and with a high degree of certainty
 Colorectal Cancer




Vectibix (Panitumumab) and Erbitux (Cetuximab)
KRAS mutation is predictive of a very poor response to the
following targeted therapies
Patients with wild-type KRAS will typically respond to
Vectibix but is not a guarantee
Patients in the Phase III CRYSTAL study with wild-type
KRAS gene treated with Erbitux showed a response rate of
59% and a 32% decrease in risk of disease progression
Drug Targeted Therapies
 Gastrointestinal Stromal Tumors (GIST)
 CD117 is a proto-oncogene and overexpression can
lead to cancer
 Mutation of CD117 have also been implicated in
leukemias, melanomas, and mast cell disease
 Efficacy of Gleevec (Imatanib) is determined by the
mutation status of CD117
 Mutation is exon 11 is more responsive to Gleevec,
however if the mutation is on exon 17 the receptor is
not inhibited by Gleevec
Drug Targeted Therapies
 APOE (apolipoprotein E) gene is associated with
increased risk for Alzheimer’s disease
 APOE-4 allele correlates with a poorer prognosis and
therapeutic response
 60% of APOE-4 carriers demonstrated a lower response
to Tacrine than 80% of APOE-4 non-carriers
 APOE-4 non-carriers have been shown to exhibit
cognitive and functional improvement with rosiglitazone,
whereas APOE-4 carriers showed no improvement or
some decline
 Better response to donepezil has been observed in
APOE-4 carriers
Case Study
 65 year old female with refractory hip
pain with morphine and elevated INR
with coumadin
 What polymorphisms does this
patient most likely have?
 What changes in her therapy should
be made?
Answers
 This patient most likely has a CYP2D6 and CYP2C9
polymorphism
 The CYP2C9 polymorphism decreases her metabolic rate
of coumadin, leading to a lower dose requirement for her
goal INR of 2-3
 The analgesic effect of morphine is decreased in CYP2D6
polymorphisms so she will require an analgesic that is
metabolized by a different enzyme, such as
hydromorphone (glucuronidation)
Bonus Questions
 If this patient was a poor metabolizer
of CYP2D6 and were to develop
Alzheimer’s disease, what
medications would render the best
response?
 What medications would result in a
poor response?
Bonus Answers
 Namenda, exelon, and tacrine are
metabolized by other mechanisms that
are unaffected by liver insufficiency.
These would result in a better
therapeutic response in this patient.
 Galantamine, razadyne and donepezil
are metabolized in the liver by CYP2D6
and would be associated with a poor
response
Conclusions
 Therapeutic response in many disease
processes is genotype-specific and
multifactorial
 Tailoring medication regimens based on
patient genomes maximizes efficacy and
compliance while avoiding adverse
effects and drug-drug interactions
 Personalized therapeutics is the
future of medicine!
References
1.
2.
3.
4.
5.
6.
7.
Cacabelos, Ramon. "Pharmacogenomics and Therapeutic Prospects in
Dementia." Eur Arch Psychiatry Clin Neurosci 258 (2008): 28-47. PubMed.
EuroEspes Biomedical Research Center. Web. 29 Jan. 2012.
Takeda, Masatoshi et al. "Pharmacogenomics of Alzheimer's Disease." AsiaPacific Psychiatry 3 (2011): 10-16. PubMed. Osaka University Graduate School
of Medicine, 7 Dec. 2010. Web. 29 Jan. 2012.
Shenfield, Gilliam M. "Genetic Polymorphisms, Drug Metabolism and Drug
Concentrations."Clinical Biochem Review 25.4 (2004): 203-06. Genetic
Polymorphisms, Drug Metabolism and Drug Concentrations. NCBI. Web. 25 Jan.
2012.
"Pharmacogenomics." Wikipedia, the Free Encyclopedia. 12 Dec. 2011. Web. 28
Jan. 2012. <http://en.wikipedia.org/wiki/Pharmacogenomics>.
Hajjar, Ihab, Stephen Kritchevsky, Anne B. Newman, Rongling Li, Kristine Yaffe,
Eleanor M. Simonsick, and Lewis A. Lipsitz. "Renin Angiotensin System Gene
Polymorphisms Modify Angiotensin-Converting Enzyme Inhibitors' Effect on
Cognitive Function: The Health, Aging and Body Composition Study." Journal of
the American Geriatrics Society 58.6 (2010): 1035-042. Print.
Furuta,T.et.al. Ann Intern Med 1998;129:1027-1030
Higashi et al. “Association Between CYP2C9 Genetic Variants and
Anticoagulation-Related Oucomes During Warfarin Therapy” JAMA 2002;28