Pharmacogenetics of drug-gene interactions

Muh. Akbar Bahar

“It is more important to know what sort of person has a disease than to know what sort of disease a person has.”
-Hippocrates (460 BC – 370 BC)
 Why do we need to know about
pharmacogenetics and what is it?
 What are the criteria of ideal therapy (drug)?

Max. Min. Ideal

Affordable
Efficacy Toxicity Therapy
Drug response rate range about 25% to 80%.

80

70

60
Efficacy rate (%)

50

40

30

20

10

Spear, Brian B., Margo Heath-Chiozzi, and Jeffrey Huff. "Clinical application of pharmacogenetics." Trends in molecular medicine 7.5 (2001): 201-204.
 Buletin Berita MESO Volume 36, No 1 Edisi Juni 2018
https://e-meso.pom.go.id/
 Why?

Universitätsinstitut für Klinische Chemie (UKC)

 Physiology:
Age, gender, pregnancy, lactation, liver
Genotype and kidney function, BMI, GI function,
immune system, albumine elevel, CV
function, etc.

Drug Response

Life style: Environment:

Smoking, alcohol intake, exercise, Occupational exposure, other
suupplement and herbs, stress level, medications, comorbidities, infections,
adherence, etc circardian and seasonal variations, etc.
Definition and Goal
Personalized medicine (PM) is the tailoring of medical treatment to the individual
characteristics of each patient including age, gender, height/weight, diet,
environment, allergies, GENE, etc.

Redekop, W. Ken, and Deirdre Mladsi. "The faces of personalized medicine: a framework for understanding its meaning and scope." Value in Health 16.6 (2013): S4-S9.

PHARMACOGENETICS
The study of variability in drug response due to heredity
(Nebert DW, 1999).
Vision

New Yorker, 2000

‘The pharmacy profession as a whole,
however, has been slow to embrace
the concept of clinical
pharmacogenetics and is now facing a
critical juncture that can potentially
redefine the professional identity of
the pharmacist. Before practice
transformation can occur, however, it
is important for our profession to ask
and fully explore the following
question: Are pharmacists ready for
the challenge of personalized
medicine?’

‘ The time is right and the stage is set

for pharmacy to embark on another
transformative journey – a journey
that will redefine the role of the
pharmacist and will secure a place
for pharmacy in the era of
personalized medicine and beyond’
 Pharmacist responsibilities
‘Most of the suggested responsibilities are focused around the clinical application
of pharmacogenetics and include activities such as:
recommending pharmacogenetic testing,
 interpreting test results and, Kennedy, Mary Jayne. "Personalized medicines–are
pharmacists ready for the challenge?." Integrated
Pharmacy Research & Practice 7 (2018): 113.

 designing patient-specific drug and dosage regimens.’

http://www.thegaptest.com/pharmacogenetics/personalized-
medicine/
Basic concept

How different are we below the skin?

DNA

Each chromosome is a (very) long molecule that is a chain of subunits called bases.
 This book is belong to Prof. Stylianos E.
Chromosome 21: the Antonarakis (Professor and Chairman of Genetic
Medicine at the University of Geneva Medical
smallest human School, and director of the iGE3 institute of
chromosome (234 Genetics and Genomics of Geneva).

genes), 1470 pages,

31775 nucleotides
per page (font
number 5)
 A single-nucleotide
variant (SNV) is a
variation in a single
nucleotide at a specific
position in the genome.

If a pair of human chromosomes
are compared base by base, each
of us is heterozygous for a
nucleotide substitution roughly
every 1000 bp.
Single-nucleotide
polymorphisms (SNPs) are
individual nucleotide positions
in the genome that vary at
polymorphic levels in human
populations, and must have a
frequency of at least 1%.

An allele is an alternative form of a gene (one member of a pair) that is

located at a specific position on a specific chromosome. Ex. CYP2C19*1,
CYP2C19*2, dll. Human -> diploid -> CYP2C19*1/*2
Some basic terms

Original meaning Modern meaning

Phenotype: • Observable • Observable and
properties molecular properties

Genotype: • Inferred cause • DNA sequences of

(genes) chromosomes
Some basic terms
• CYP2C19*1 (normal metabolic function)
• CYP2C19*2, CYP2C19*3 -> allele (decreased metabolic function)
• CYP2C19*1/*2 (diplotype) -> Genotype
• Phenotype: Intermediate Metabolizers (IM)
 Gene-Drug-Interaction?
A drug–gene interaction occurs when a patient's genetic (e.g., CYP2D6 poor
metabolizer) affects the activity of a drug and/or the fate of a drug inside
the body.
Pirmohamed, M. et al. Genetic susceptibility to adverse drug reactions. Trends in
Pharmacological Sciences 22, 298-305 (2001).
PAINE, Mary F., et al. The human intestinal cytochrome P450"
pie". Drug metabolism and disposition, 2006.
 PM: No or vey
low metabolic
function.

IM: Less than

normal metabolic
function.

EM: Normal
metabolic
function.

UM: Very fast

metabolic
function.

Meyer, Urs A. "Pharmacogenetics–five decades of

therapeutic lessons from genetic diversity." Nature
Reviews Genetics 5.9 (2004): 669.
 CYP2D6 allele frequencies across world populations

Gaedigk, Andrea, et al. "Prediction of CYP2D6 phenotype from genotype across world populations." Genetics in Medicine 19.1 (2017): 69.
Pharmacokinetic drug-gene interaction
 PM

UM

CPIC guideline

Gasche, Yvan, et al. "Codeine intoxication associated with ultrarapid CYP2D6 metabolism." New England Journal of Medicine 351.27 (2004): 2827-2831.
Kirchheiner, J., et al. "Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication." The pharmacogenomics journal 7.4 (2007): 257.
The Pharmacogenomics Knowledgebase
(PharmGKB) is a publicly available, online
knowledgebase responsible for the
aggregation, curation, integration and
dissemination of knowledge regarding
the impact of human genetic variation
on drug response.[1] It is funded by the
National Institutes of Health (NIH)
National Institute of General Medical
,Sciences (NIGMS), and is a partner of
the NIH Pharmacogenomics Research
Network (PGRN). It has been managed at
Stanford University since its inception in
2000.[2]

https://en.wikipedia.org/wiki/PharmGKB

https://www.pharmgkb.org/chemical/PA449088/guideline
https://cpicpgx.org/guidelines/guideline-for-codeine-and-cyp2d6/
Pharmacodynamic drug-gene interaction
Inter-individual variability of warfarin: one dose fits all?

Pharmacogenomics. 2009, 10 (12) :1955-1965

 vitamin K epoxide reductase complex

Jonas, D. E., & McLeod, H. L. (2009). Genetic and clinical factors relating to warfarin dosing. Trends in pharmacological sciences, 30(7), 375-386.
a cofactor of active
factor VII,
factor IX, and
factor X

inactive
 A common non-coding variant, VKORC1, c.-1639G>A (rs9923231), is
associated with an increased sensitivity to warfarin and lower dose
requirements. The polymorphism occurs in the promoter region of
VKORC1 and is thought to alter a transcription factor binding
site, leading to lower protein expression. As a result,
patients starting warfarin therapy who are carrying at least one “A“ allele
at -1639 locus require lower initial and maintenance doses compared
with patients carrying a G/G genotype at this locus.
 Curent state of PGx
6000

5000

4000

3000

2000

1000

pubmed - pharmacogenetic*[TIAB] OR pharmacogenomic*[TIAB] OR "personalized medicine*"[TIAB] OR "precision medicine"[TIAB]

FDA

2006-PGx in drug label ;

158 drug-biomarker pair;
12% of 385 drugs
approved.

https://www.fda.gov/Drugs/ScienceResearch/ucm572698.htm
 Guidelines

Bank, P. C. D., et al. "Comparison of the guidelines of the clinical pharmacogenetics implementation consortium and the Dutch pharmacogenetics working group." Clinical Pharmacology & Therapeutics 103.4 (2018): 599-618.
https://he.wikipedia.org/wiki/:‫קובץ‬Historic_cost_of_sequencing_a_human_genome.svg
Implementation Strategy
• Reactive genotyping -> genotyping for drug-specific variants when a
PG drug is prescribed -> time-related problem?, directly applicable to
specific patient situations and more likely to be reimbursed by
insurance companies.
• Preemptive multiplexed genetic testing -> genotyping in advance,
the genetic data can be available at the time of prescribing which
eliminates impediments to optimal patient treatment. -> Electronic
health record, DNA passport.
Van Der Wouden, C. H., et al. "Implementing pharmacogenomics in Europe: design and implementation strategy of the Ubiquitous Pharmacogenomics Consortium." Clinical Pharmacology
& Therapeutics 101.3 (2017): 341-358.
Sukasem, Chonlaphat, and Wasun Chantratita. "A success story in pharmacogenomics: genetic ID card for SJS/TEN." (2016): 455-458.
 “add genetics information q.s. (quantum satis)”
Twitter: @kbarbahar
Instagram: @akbarbahar
http://rxpgx.com/2018/05/personalized-psychiatric-treatment.html Email: akbarbahar@unhas.ac.id