Drug Development: Genetics and ADME

Question 1

CYP2D6 polymorphisms

Answer 1

Located chromsome 22q13
Ultra-Rapid (UM)- gene duplication
Extensive (EM)- 2 functional alleles
Intermediate (IM)- one functional allele
Poor (PM)- lack functional alllele

Geographical variation- Middle Eastern/ North African greatest population of UMs

Question 2

Succinylcholine and BCHE response

Answer 2

Succinylcholine NM blocker- reduces respiration in GA
Metabolised by BChE
3 Novel mutations of BChE responsible for low BChE activity
Severely prolonged Succinylcholine activity- respiratory depression

Severe reactions to Donepezil

Question 3

HER-2 facts

Answer 3

Human Epidermal Growth Factor 2
Overexpressed in up to 20% breast cancer patients
Also found in gastric cancer patients

Question 4

HER-2 Breast cancer

Answer 4

HER2 O/E patients clinical trials
P2: effective monotherapy
P3: effectively enhances 1st line chemo

Question 5

HER-2 Gastric cancer

Answer 5

O/E patients identified with FISH/IHC
Increased overall and progression free survival in HER2 patients when used alongside chemo
Similar AEs vs chemo-only group
Overexpression is associated with worse prognosis

Question 6

Irinotecan

Answer 6

Irinotecan- cytotoxic drug prevents DNA transcription by inhibiting Topoisomerase I
SN38 (active metabolite) Broken down by UDP Glururonyltransferase
Gilberts Syndrome: Polymorphism of UDP Gluc. gene (UGT1A) with expansion of TATA box

Studies identified that patients with polymorphism developed more neutropenia

Question 7

Thiopurine Drugs and TPMT

Answer 7

e.g. Azathioprine- narrow TI, immunosuppression
Normally metabolised by TPMT to 6-Methyl MP

Genetic variability in TPMT activity can lead to formation of 6-Thioguanine nucleotides- cause myelosuppression
3A allele (caucasians), 3C allele (East asians)

High TPMT activity: less myelosuppression, lower AZA activity
Low TPMT activity: drug more efficacious but more 6TGNs produced