Transcript Our Genes, Our Drugs and our Future

Pieter van der Bijl, Emeritus Professor and
Former Head of Pharmacology, Faculty of
Health Sciences, Stellenbosch University,
Cape Town, South Africa
GDF: Introduction: 1
 The focus of traditional medical practice is on
clinical signs and symptoms in accordance
with medical history
 Not always the most effective approach given
the different genetic profile of each individual
 Pharmacogenetic studies over many decades
have documented that genetic variability can
affect PK and PD
 Polymorphisms of drug metabolising
enzymes, transporters and receptors
contribute to variable drug responses (in
addition to environmental , physiological & compliance
factors)
GDF: Introduction: 2
 Most drugs act on:
 Enzymes
 Transporters
 Membrane ion channels
 Receptors
and
 Are biotransformed by:
 Drug metabolising enzymes
Drug
GDF: Introduction: 3
 Foregoing molecular systems are all proteins




coded for by certain genes
Not surprising that genetic factors are major
determinants of variability of drug effects and
many pts do not respond adequately to their
medication ( confusion in the‘therapeutic
jungle’)
Some blockbuster drugs have only limited
efficacy in 70% of pts
Many reasons for this, but pharmacogenetics
plays an important role
Most information hitherto from genetic diversity
obtained wrt drug metabolising enzymes
GDF: Effects of genes on drugs : 4
Genes
Drug
Absorption
Distribution
Metabolism
Excretion
Blood levels
Drug
Genes
Adverse drug
reactions
Cell
Transcription
factors
Beneficial
effects
reactions
Receptor
Genes
Genes
GDF: Variable efficacy of drugs: 5
Drug Class
Insufficient response (%)
SSRIs
10-25
ACE-inhibitors
10-30
-blockers
15-25
Antidepressants
20-50
Statins
30-70
2-agonists
40-70
GDF: Pharmacogenetics/-nomics: 6
 Recently pharmacogenetics has evolved into




‘pharmacogenomics’
The latter involves a shift from a focus on
individual candidate genes to genome-wide
association studies
Pharmacogenomics is a precursor of
personalised medicine
This constitutes a shift from ‘one-drug-fitsall’ to ‘the right drug for the right patient at
the right dose and time’
But, each pt will not be treated differently
from every other pt (economically untenable)
GDF: Pharmacogenetics/-nomics: 7
 Rather, pts will be divided into groups by
genetic and other markers that predict disease
progression and treatment outcome
 For drug treatment one needs to avoid lack of
response or toxicity
 If ADRs can be  from 5% to 2% by excluding
10% of the targeted population, the drug gains
a better risk/benefit ratio  1st choice Rx and a
 market share
 There is a growing trend to link new drugs with
diagnostic biomarkers (often genetic) (FDA,
EMA)  improved Rx outcome (personalised
medicine!)
GDF: Benefits Pharmacogenetics/-nomics: 8
 Improvement of drug choices
 In USA 100 000 pts die annually due to ADRs and
2 000 000 are hospitalised
 Pharmacogenomics will predict who will have a + or reaction
 Safer dosing options
 Testing of genomic variation will  correct dosing
 Improved drug development
  industry to determine in which populations new drugs
will be effective
 Decreased health care costs
  deaths and hospitalisation due to ADRs
  purchase of drugs ineffective in certain pts
 Speed up clinical trials for new drugs
GDF: Benefits Pharmacogenetics/-nomics: 9
GDF: Altered drug responses: 10
P-genetic biomarker
Drug
Disease
FDA
class.
EMA
labels
Aim of
genotyping
Elimination of
ADRs
G6PD deficiency
Primaquine
Malaria
+
NAT variants
INH
Tuberculosis
+
*
Elimination of
ADRs
CCR5 expression
Maraviroc
HIV
+++
**
 Efficiency
C-KIT expression
Imatinib
GI stromal tumour
+
**
 Efficiency
CYP2C9 & VKORC1
variants
Warfarin
Thromboembolism
++
Elimination of
ADRs
CYP2C19 variants
Voriconazole
Fungal infection
+
Elimination of
ADRs
EGFR expression and KRAS mutation
Cetucimab
Colorectal CA
+++
**
 Efficiency
HER/neu overexpression
Traztuzumab
Breast CA
+++
**
 Efficiency
Ph1 chromosome
Imatinib
ALL
+++
**
 Efficiency
TPMT variants
Mercaptopurine
ALL
++
*
Efficiency
UGT1A1 variants
Irinotecan
Colorectal CA
++
+++ required; ++ recommended;
+ for information only
Elimination of
ADRs
** included into indication or contraindication label
* included in the other label information
GDF: G6PD deficiency: 11
 G6PD (glucose-6-phosphate dehydrogenase) an
enzyme in hexose monophosphate shunt (a main
source of NADPH generation)
 NADPH needed to reduce disulphide bonds of
glutathione (GS-SGGSH) and other proteins
 Many drugs and their metabolites can use up
GSH and lead to  GSH levels in G6PD deficient
pts
 GSH deficiency in RBC results in:
 Membrane fragilityhaemolysishaemolytic anaemia
GDF: G6PD deficiency: 12
GDF: N-acetylation: 13
 In late 1940’s discovered that there was a
high incidence of peripheral neuropathy in
pts Tx with isoniazid (INH) for tuberculosis
 INH is cleared from the blood after
acetylation in the liver by
N-acetyltransferase (NAT2)
 Hereafter the N-acetyl INH and
some minor metabolites are
excreted in the urine
 Hepatic insufficiency may  t½
GDF: N-acetylation: 14
Acetyl CoA acts as a donor of the acetylgroup on INH
N
CO-NH-NH2 + CoA-COCH3
Isoniazid (INH)
N
N-Acetyltransferase
(NAT2)
Acetyl-Coenzyme A
CO-NH-NH-COCH3 + CoA
Acetyl-Isoniazid (INH)
Coenzyme A
GDF: Rapid and slow acetylators: 15
 Individuals who are rapid acetylators:
 Have  failure rate with INH in Tx of TB
 Require  doses of hydralazine to control HT
 Individuals who are slow acetylators have
risk of:
 Drug-induced SLE with hydralazine
 Haematological ADRs after INH
 Idiosyncratic ADRs to sulphonamides
 Bladder CA after exposure to carcinogenic
arylamines
 Breast CA in postmenopausal females (4x)
GDF: N-acetylation: 16
 Work done in the Department of Pharmacology, SU
has shown that there exist three well-defined
groups of acetylators of INH [N-acetyltransferase
(NAT2)] in the Western Cape Coloured population
(mixed-race)
 The proportion of patients in these groups (fast,
intermediate and slow) depends on racial
characteristics
I
50%
 Wide variation in other
ethnic populations found
S
30%
(Eskimo’s, Asians, Africans,
European & Egyptian)
F
20%
GDF: Warfarin: 17
 The most commonly prescribed anticoagulant (vit
K antagonist) (role of dabigatran & rivaroxaban)
 Has a narrow therapeutic index that varies widely
between individuals (monitoring)
 Pts may be:
 Resistant and need  dose to prevent CVAs (strokes)
 Sensitive and need  dose to prevent CNS bleeding
 Metabolised by CYP450 (CYP2C9*2 and *3)
 Vit K is recycled by vit K epoxide reductase
(VKORC1)
GDF: Warfarin: 18
GDF: Genomics/Proteomics: 19
 Implications of postgenomic medicine
wrt drug development
 Apart from improved drug choices and
development, safer dosing and
decreased health costs genetically
modified organisms can be used for
drug production, eg insulin,
monoclonal antibodies etc
GDF: Genomics/Proteomics: 20
GDF: Genomics/Proteomics: 21
 First regulatory review of targeted
therapeutic agent with diagnostic test
 Approval of trastuzumab and HercepTest
for pts with HER-2/neu overexpressing in
breast CA (FDA,1999)
 Trastuzumab (Herceptin) is a humanised
IgG1 against ectodomain of the
HER-2 /neu receptor
GDF: Traztuzumab: 22
HER-2/neu
GDF: Genomics/Proteomics: 23
 Another example, diagnostic kit for
Bcr-Abl translocation in CML and
selection for Rx with small molecule
drug, imatinib (Gleevec)
 Acts by inhibiting tyrosine kinase and
activation of target proteins in cellular
proliferation
GDF: Imatinib: 24
N
H
N
N
H3C
O
H
N
CH3
N
N
N
Tyrosine kinase
GDF: Genomics/Proteomics: 25
 Also variety of diagnostic tests for
management of major nonmalignant
diseases are becoming available
 Germline-based SNP detection or biomarkers
on serum or synovial fluid for progression of
RA and selection of Rx
 Measurement of C-reactive protein markers in
novel ways for CV disease
 Also genotyping and molecular diagnostics for
diabetes mellitus
 Viral load testing and drug resistance (HIV)
measuring is becoming standard
GDF: Genomics/Proteomics: 26
Conclusions
 Trial and error medicine  to precise
biomarker-assisted diagnosis and more
effective molecularly-guided Rx
 For drug companies efficiency,
productivity and product lines
 Over next 5 years will see large impact of
targeted drug approach guided by
diagnostic tests in Rx of CA
 Exciting future wrt new specific
drug development increased
quality of life
GDF: Personalised prescribing- the future: 27 
1. mRNA extracted from sample
2. cDNA copies made and dye
(green/red)labelled (eg CA/N)
3. Microarray, 1000’s wells (many
identical copies of same gene)
4. cDNA pipetted into each well and
hybridizes with complementary
strands (wash)
5. Microarray  scanner
6. Expression pattern obtained
•A drop of blood or smear from
buccal pouch
•Microchip (gene chip) checks for
31 variations (polymorphisms)
in two genes (CYP2D6 &
CYP2C19)
•Phenotype (eg ultrarapid
metabolisers) identified
?