pieter van der bijl, emeritus professor and former head of pharmacology, faculty of health sciences,...
TRANSCRIPT
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
Drug
AbsorptionDistributionMetabolismExcretion
Blood levels
Drug
ReceptorTranscriptionfactors
CellAdverse drugreactions
Beneficial effects
reactions
Genes
Genes
Genes
Genes
GDF: Effects of genes on drugs : 4
GDF: Variable efficacy of drugs: 5
Drug Class Insufficient response (%)
SSRIsSSRIs 10-2510-25
ACE-inhibitorsACE-inhibitors 10-3010-30
-blockers-blockers 15-2515-25
AntidepressantsAntidepressants 20-5020-50
StatinsStatins 30-7030-70
22-agonists-agonists 40-7040-70
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-fits-all’ 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 DiseaseFDA class.
EMA labels
Aim of genotyping
G6PD deficiencyG6PD deficiency PrimaquinePrimaquine MalariaMalaria ++Elimination of Elimination of
ADRsADRs
NAT variantsNAT variants INHINH TuberculosisTuberculosis ++ **Elimination of Elimination of
ADRsADRs
CCR5 expressionCCR5 expression MaravirocMaraviroc HIVHIV ++++++ **** EfficiencyEfficiency
C-KIT expressionC-KIT expression ImatinibImatinib GI stromal tumourGI stromal tumour ++ **** EfficiencyEfficiency
CYP2C9 & VKORC1 CYP2C9 & VKORC1 variantsvariants WarfarinWarfarin ThromboembolismThromboembolism ++++ Elimination of Elimination of
ADRsADRs
CYP2C19 variantsCYP2C19 variants VoriconazoleVoriconazole Fungal infectionFungal infection ++Elimination of Elimination of
ADRsADRs
EGFR expression and K-EGFR expression and K-RAS mutationRAS mutation CetucimabCetucimab Colorectal CAColorectal CA ++++++ **** EfficiencyEfficiency
HER/neu overexpressionHER/neu overexpression TraztuzumabTraztuzumab Breast CABreast CA ++++++ **** EfficiencyEfficiency
Ph1 chromosomePh1 chromosome ImatinibImatinib ALLALL ++++++ **** EfficiencyEfficiency
TPMT variantsTPMT variants MercaptopurineMercaptopurine ALLALL ++++ ** EfficiencyEfficiency
UGT1A1 variantsUGT1A1 variants IrinotecanIrinotecan Colorectal CAColorectal CA ++++ Elimination of Elimination of ADRsADRs
+++ required; ++ recommended;+ for information only
** 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-SGGSH) 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 fragilityhaemolysishaemolytic 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 areexcreted in the urine
Hepatic insufficiency may t½
N CO-NH-NH2
Acetyl CoA acts as a donor of the acetylgroup on INH
Isoniazid (INH)
N-Acetyltransferase(NAT2)
Acetyl-Isoniazid (INH)
GDF: N-acetylation: 14
CoA-COCH3+
Acetyl-Coenzyme A
N CO-NH-NH-COCH3 CoA+
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
Wide variation in other ethnic populations found (Eskimo’s, Asians, Africans,European & Egyptian)
F20%
I50%
S30%
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
Y
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
Tyrosine kinase
O
H3C
N
HN
CH3
N N N
N
HN
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: 26Conclusions 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 specificdrug development increased quality of life
GDF: Personalised prescribing- the future: 27
•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
1. mRNA extracted from sample2. 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 scanner6. Expression pattern obtained
?
большое cпасибо