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BMSC3149 Drug Discovery > ADME > Flashcards

ADME Flashcards

1
Q

Drug response (efficacy) and adverses lead to..

A

many drugs not completing clinical trials

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2
Q

What percent of compounds entering Phase 2 fail prior to Phase 3?

A

66%

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3
Q

Failure rate at Phase 3?

A

33%

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4
Q

DD process is very costly, why important?

A

$1.8bn per NME, no adverses cause its withdrawal from market

Importance of thorough ADME testing (Paul et al., 2008)

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5
Q

Importance of ADME

A

Need of in vitro studies to assess efficacy and safety of drugs metabolised by polymorphic enzymes and those inhibited by other drugs (D-D interactions)

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6
Q

What percent in the US of hospital patients experience SADRs? How many die from SADRs?

A

6.2-6.7% have SADRs
5% die from SADRs
(Wilkie et al., 2007 & Wester et al., 2008)

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7
Q

Contributing factors to ADME

A

Disease
Age
D-D interactions (number of patients being treated with multiple medications continues to increase) Huang et al., 2008
Environment (foodstuffs like grapefruit juice affects CYP3A4/2D6 and dietary supplements)
Compliance (~50% of schizophrenic patients fail to take drugs as perscribed)

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8
Q

Thiopurine drugs

A

6-MP
6-TG
Azothioprine

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9
Q

Thiopurine drugs are used for

A

Neoplastic disorders (acute lymphocytic leukaemia)
Autoimmune disorders
IBD
Organ transplants

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10
Q

Major toxicity of thiopurine drugs

A

Myelosuppresion

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11
Q

What is azothioprine converted to?

A

6-MP

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12
Q

TPMT enzyme is responsible in part for what?

A

Methylation of 6-MP to the inactive metabolite 6-methyl MP

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13
Q

What does methylation of 6-MP prevent?

A

Prevents 6-MP being activated to cytotoxic TGN nucleotides

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14
Q

Cytotoxic TGN nucleotides…

A

TGMP
TGDP
TGTP

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15
Q

What do cytotoxic TGN nucleotides do

A

Incorporate into DNA during S-phase

Inhibit GTP-binding protein Rac-1 - which regulates Rac/Vav pathway

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16
Q

TPMT (thiopurine methyltransferase) is

A

A genetic polymorphism

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17
Q

Prevalence of TPMT polymorphism

A

1 in 300 people are deficient for TPMT

National Centre for Biotechnology Information, 2012

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18
Q

How many polymorphisms found for TPMT, and the most common?

A

> 30 polymorphisms
More common: TPMT3A and TPMT3C
Both point mutations

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19
Q

Genetic variants mapping to TPMT region detemine what

A

Mapping at chromsome 6
Primary determinants of TPMT activity in humans
(Tamm et al., 2017)

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20
Q

Why are TPMT*3A and 3C alleles non-functional

A

Affect protein activity by post-translational modification and increase protein degradation
(Tamm et al., 2017)

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21
Q

TPMT degradation by ATP-dependent proteasome mediated pathway results in..

A

Loss of catalytic activity of the enzyme

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22
Q

Patients treated with thiopurine drugs require what

A

Genotyped before being prescribed

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23
Q

Irinotecan (Innocenti et al., 2004)

A

Used for metastatic colorectal cancer

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24
Q

Side effects of irinotecan

A

Severe diarrhoea and neutropenia (abnormally low neutrophils)

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25
Q

Percentage of patients with SADRs using irinotecan

A

20-35%

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26
Q

Prevalence of fatal events during single-agent irinotecan treatment

A

5.3%

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27
Q

Irinotecan activated by hydrolysis to..

A

SN-38

28
Q

What is SN-38?

A

A potent topoisomerase 1 inhibitor

29
Q

What inactivates SN-38?

A

UGT1A1

Inactivated by biotransformation into SN-38 glucuronide

30
Q

UGT1A1 catalyses what?

A

Bilirubin glucuronidation

5-8 repeats in the TATA box

31
Q

TA6 genotype prevalence

A

50% of population

Normal expression

32
Q

TA7 genotype associated with..

A

Classical Gilbert’s syndrome

Common milk hyperbilirubinemia and decrease activity of the bilirubin uridine di-p glucuronosyltransferase

33
Q

TA7 geneotype prevalence

A

Up to 40% of population
Results in decreased UGT1A1 expression
Increase risk to toxicity

34
Q

Results of Innocenti et al 2004 show what percent of 7/7 homozygous patients develop grade 4 neutropenia

A

50% of 7/7 homozygous patients develop Grade 4 neutropenia

35
Q

What percent of 6/7 patients develop Grade 4 neutropenia?

A

12.5%

36
Q

What percent of 6/6 patients develop Grade 4 neutropenia?

A

0%

37
Q

Dosage and duration of patient treatment by Innocenti et al 2004

A

350mg/m^2 every 3 weeks

38
Q

Overall percentage of grade 4 neutropenia?

A

9.5%

39
Q

Grade 4 neutropenia highly correlated with..

A

TA indel genotype (promoter variant)

40
Q

What was TA7 allele a significant predictor of?

A

Severe toxicity

41
Q

-3156G>A promoter variant may be a better predictor of what?

A

UGT1A1 status than TA indel

Increase in SN-38 levels are systemically available when UGT1A1 is deficient

42
Q

Overall conclusion by Innocenti et al 2004

A

Irinotecan 350mg/m^2 is relatively safe in cancer patients with -3156GG genotype
Should get a lower dose or an oxaliplatin-fluoropyrimidine regime

43
Q

Enzymes in CYP1-3 families show polymorphism, including

A

CYP2D6, 2C19

44
Q

2D6 shows highest polymorphic profile, why is that important?

A

Involved in metabolism of 25% of all clinical drugs

Oxidation reactions

45
Q

What is CYP2D6 required for?

A

Conversion of codeine into morphine in pain relief

Poor metabolisers will not get pain relief but ultrarapid metabolisers may receive significant toxicicty

46
Q

CYP2D6 required in treatment of breast cancer for..

A

Conversion of tamoxifen to endoxifen
100X greater affinity for ER
Prevent/ treat breast cancer

47
Q

Role of pharmacogenomics in atypical medication for schizophrenic patients

A

Foster et al, 2007

48
Q

Problem with atypical medication for schizophrenic patients

A 
Weight gain
Diabetes 
Hyperlipidemia 
Movement disorders 
CV effects
49
Q

What percentage of drugs responsible for adverses are metabolised by polymorphic phase 1 metabolism enzymes

A

50%, of these 86% are metabolised by CYP450

50
Q

CYP450 1A2/3A4 are important in..

A

Metabolism of atypicals

51
Q

CYP2D6 metabolises many psychotropic drugs including

A

Haloperidol and risperidone

52
Q

How many variants of CYP2D6?

A

> 70 variants

Classified into 4 phenotypes

53
Q

Poor metabolisers phenotype of CYP2D6

A

Lack functional enzyme
Have 2 non-functioning copies
No 2D6
Increase risk of adverses

54
Q

Intermediate metabolisers phenotype of CYP2D6

A

1 functional allele and 1 lower activity level allele
= lower than normal metabolic rate of substrates
Heterozygous

55
Q

Extensive metabolisers phenotype of CYP2D6

A

2 functional alleles

= normal metabolic rate

56
Q

Ultra metabolisers phenotype of CYP2D6

A

Gene duplication
3 or more copies of functional 2D6 activity
Rapid metabolic rate
Limited clinical response

57
Q

Phenotypes in ethnicities vary in CYP2D6..

A

5-10% Caucasians are PMs

29% of North Eastern Africans and Middle Easteners are UMs

58
Q

CYP2D6 genotype 3/5 has predicted phenotype..

A

PM

59
Q

CYP2C19 genotype 1/1 has predicted phenotype..

A

EM/ normal

60
Q

Phenotype of CYPs may inform..

A

Prescription of someone with type 1 bipolar disorder

61
Q

FDA-approved what pharmacogenetic test for detecting CYP450s

A

AmpliChip

62
Q

AmpliChip can detect..

A

20 alleles for 2D6
3 alleles for 2C19
Identifies true UMs

63
Q

AmpliChip is useful when

A

In cases of atypicals where adverses (weight gain, sedation, motor problems and response are issues)
e.g. risk of EPS from haloperidol is significantly increased in PMs for 2D6

64
Q

Problem with AmpliChip

A

Process needs development

Genotyping found to only prevent side effects in 5% of those given haloperidol

65
Q

Other factors contributing to response and tolerability ADME

A 
Age
Sex
Ethnicicty 
Concomitant disease 
Liver/ kidney function 
Diet 
Smoking 
D-D interactons
66
Q

Consequences for drug development process

A

Less propensity for metabolism by polymorphic CYPs can be developed
Target medication to patients most likely to receive a response and less likely to receive a SADR
More effective and safer clinical trials
Better post-marketing surveillance - prevent SADR in general population and sub-population that weren’t picked up in clinical trial
Loss of blockbuster drug, no one size fits all..

BMSC3149 Drug Discovery (2 decks)

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