Gene and therapeutic response

Question 1

What are the aims of pharmacogenetic testing

Answer 1

reduce morbidity and mortality
optimise use of roven first line therapies
cost saving to NHS reducing adverse reactions+hospital admissions

Question 2

what are pharmacogenetic variations

Answer 2

normal genetic polymorphism
high frequency coding region SNPs. repeat variation in regulatory elements. Gene duplications and deletionss
Multiple rare variants within a single gene
Markers mau ne in disequilibrium with a causative variant
nomeclature of genetic variants not consistent
all genetic variants are given a unique rsnumber

Question 3

What makes a good pharmacogenetic test

Answer 3

replication
large effect/high penetrance
predictive not prognostic (alternate therapies must be available)
clear patient benefit by reducing toxicity or improving efficacy
testing should not delay therapy
testing must be cost effectiive

Question 4

Barriers to uptake of pharmacogenetic testing

Answer 4

concern that dose reduction strategy will copromise efficacy
each trust will require a buisness case for testing
testting must be perceived to be cost effectivee
requires a change in clinical practice

Question 5

how is genomics going to be used in the future

Answer 5

personalised genomic information (exomes, whole genome, chips) linked to prescription of therapy and guides dosing. As therapy changes in evolving conditions, the same genomic information is accessed to guide new therapies

Question 6

what are potential barriers for genomics in the future

Answer 6

cost, tool for accessing genomic information and poor pharmacogenetic evidence for many drugs

Question 7

What pharmacogenetic model has not entered clinical practice and why

Answer 7

CYP3A53 variant and tacrolimus used as immunosupressant in transplantation
the variant marked ethnic diversity with different frequency. The dose of tacrolimus needed differed significantly with other genotype to maintain target trough level and area under the curve
Allopurinol (gout): HLA-B5801 allele associated with toxic epidermal necrolysis though not all carriers experience symptoms. Testing proposed clinically useful+effective but febuxostat used instead of allopurinol

Question 8

Examples of pharmacogenetic use that has entered clinical use

Answer 8

warfarin (anticoagulant): pharmacogenetic-based dosing associated with higher % time in therapeutic INR range
Azathioprine-lack of TPMT prevents conversion into methyl metabolites and causes increased drug activation and overdosing. TPMT 0 use alternative therapy, carrier adjust dose.TPMT testing before therapy
Fluoropyrimidine/5-fluorouracil-DPD deficiency causes 5FU toxicity. complte 5FU fatal toxicity, herterozygous-severe toxicity. DPYD genotyping before therapy

Question 9

What are tha barriers to uptake of pharmacogenetic test for DYPD

Answer 9

concern that dose reduction strategy will compromise efficacy
each trust require business case for testing. Testing must be perceived to be cost effective
requires change in clinical practice