University Malaya Medical Centre Kuala Lumpur outline Definitions - - PowerPoint PPT Presentation

Gan GG Department of Medicine University Malaya Medical Centre Kuala Lumpur

• utline

 Definitions  Genetic polymorphisms and drugs therapy

a)Warfarin b) Mercaptopurine c) Methotrexate d) Clopidogrel e) others

Definitions

• Genetic polymorphisms-difference in DNA sequence among

individuals, groups or populations that gives rise to different forms e.g. human blood groups

• Single nucleotide polymorphisms--variation in a single base in the

genetic code between different individuals

• Haplotypes– a set of closely linked genetic markers on one

chromosome that tend to inherit together

• Pharmacogenomics-Genetic variation on drug response by correlating

gene expression or SNPs with drugs’ efficacy and toxicity

• Pharmacodynamics-study of the biochemical and physiological effects
• f drugs and the mechanisms of their actions, including the correlation
• f their actions and effects with their chemical structure
• Pharmacokinetics--The process by which a drug is absorbed,

distributed, metabolized, and eliminated by the body

Pharmacogenomics

 Rationalised the use (individualised) and optimising

the drug in relation to patients’ genotype to ensure maximum efficacy and minimised toxicity

 Genetic information has been used to identify disease

risk (e.g. BRCA1); choice of treatment and drug dose

Warfarin

 narrow therapeutic window  large interpatient variability  influenced by environmental factors, age, dietary

intake and ethnicity

 Asian patients required a lower dose compared to the

African and Caucasian patients

• Warfarin is a racemic

mixture of S-warfarin and R-warfarin

• Warfarin inhibits the

action of vit K epoxide reductase

• Reduced Vit K is a cofactor

for post-translational γ- carboxylation of glutamic acid in coagulation factors

• VKORC1 gene-vit K

epoxide reductase complex subunit1 responsible for metabolism of vit K

Gage 2006

 3 genes involved in metabolism and pharmacodynamic

response

 CYP2C9  VKORC1  CYP4F2

CYP2C9

• CYP2C9*2 and *3 associated with increased

bleeding complications and also lower dose requirement

Gage 2006

Local Malaysian data on CYP2C9

Gan 2004

Ngow 2009

VK



4 SNPs to infer haplotypes (position 861, 5808, 6853, 9041)



H1 and H2 lower dose and H7and H9 higher dose ( 2.9 vs 3 vs 6 vs 5.5mg)



Haplotype AA mean dose 3.2mg; AB dose 4.4mg and BB 6.1mg



VKORC1 haplotype predict 21-25% of dose variance in caucasian population compared to CYP2C9 (6-10%)

Reider NEJM2005

Veenstra 2005, Larramendy-gozalo 2006

Lee 2006

Local Malaysian data for VKORC1

• VKORC1 gene accounts for 30%
• CYP2C9 accounts for 12%
• CYP4F2 accounts for 1.2%

Dose variance

Takeuchi 2009

 Loading dose ? Should be individualised  Complications  Algorithm

Commonly used in ALL treatment (part of maintenance therapy) Activated to 6 thiogunaninenulceotides(TGN) by hypoxanthine guanine phosphoribosyl transferase TPMT(thiopurine methytransferase) inactivates 6MP and decreases formation of active TGN in hematopoietic tissue TPMT activity has been showned to correlate with 6MP toxicity and therapeutic efficacy Metabolism pathway

 Trimodal activity of TMPT– 90% high; 10% intermediate

and 0.3% low or undetected

 The higher activity associated with less toxicity but

increase relapse

 Heterozygote individual– intermediate activity (10-11%

white caucasians) and homozygous mutant (0.2-0.6%) causing low activity

 Identify 21 variations in TPMT but 17 showned to reduce

TPMT activity

 TPMT*2,*3A,*3C account for 90% of intermediate or low

TPMT activity

 Thereby screening these 2 polymorphisms can reduce

toxicity

Br j clin pharmacol 2004 J pediatric hematol/oncol 2002

 Led to change in 6MP labelling in 2004 with TPMT

testing and dosage recommendation for those with deficient TPMT activity

 Found to cost saving in 4 European countries

(Germany,Ireland, UK and Netherlands)

 Limited to only few academic centres includes st judes

children hospital

Methotrexate (MTX)

• At oral dose <20mg/m2,bioavailability 50-90% & half life 4-

6 hours and excreted unchanged in urine

• High dose– some metabolised 7-hydroxy MTX by hepatic

aldehyde oxidase, small proportion metabolised to inactive metabolite (4 amino-4 deoxyN-methylpteroic acid DAMPA)

• Active compound –methotrexate polyglutamates
• Blocked DNA synthesis - mucositis, marrow

suppression, leukemic cell death, liver toxicity and neurotoxicity, renal toxicity

• Predicting MTX toxicity—dosage;renal function;hydration;

alkalinisation; use of leucovorin rescue; coadministration

• f other anticancer agents; pharmacogenetics

Genetic polymorphism has been described in all enzymes involved Important enzymes MTHFR (5,10 methylenetetrafolate dehydrogenase) and TYMS (thymidylate synthetase); and possible DHFR (dihydrofolate synthetase)

Krajinovic 2004

Genotype 520 children with ALL MTHFR has 3 functional functional polymorphism (C677T and A1298G) Frequencies varies within ethnic groups C677T variant allele present in caucasians (34%) & African American (14%) A1298G present in caucasians 27-36% and little data on African American MTHFR C677T variant allele associated with relapse risk (p=0.036)

Aplenc 2005

 Pharmacogenetic-dynamic associations with MTX can

• nly interpreted with specific protocol adjusting for

folate dietary intake

 Genetic variations in folate and antifolate

pharmacology affect not only adverse reaction but also relapse rate

 Need further studies

Plavix gets new FDA warning WASHINGTON Fri Mar 12, 2010 4:01pm EST Related News UPDATE 2-Plavix gets new U.S. FDA warning Fri, Mar 12 2010 UPDATE 1-Plavix gets new U.S. warning on poor responders Fri, Mar 12 2010 WASHINGTON (Reuters) - The blockbuster anti-clotting drug Plavix will carry a new warning about patients who have a poor response to the drug because they do not break it down well, U.S. regulators said on Friday. The Food and Drug Administration said it was adding a new boxed warning to Plavix, an $8-billion-a-year drug sold by Bristol-Myers Squibb Co and Sanofi-Aventis SA. The new language will "warn about reduced effectiveness in patients who are poor metabolizers of Plavix," the FDA said in a notice on its website. Poor metabolizers are people whose bodies do not effectively convert Plavix to its active form. "Because the patient makes less of the active form there is less anti-platelet effect in the blood and the patient may not receive the full benefit of Plavix treatment," Mary Ross Southworth of the FDA's Center for Drug Evaluation and Research told reporters in a teleconference. An estimated 2 percent to 14 percent of the population are poor metabolizers of Plavix, the FDA said.

Study population– Amish and sinai hospital of Baltimore (62% white, 37% african american)

Hematologica 2009

Others

Tamoxifen

• CYP2D6, CYP2C19– metabolises

tamoxifen (breast cancer)

• Poor metaboliser for CYP2D6

respond worse with tamoxifen (higher recurrence;less hot flushes)

• Interethnic differences– poor

metabolisers found mainly in Europe and ultrarapid metabolizers in North Africa and Oceania; intermediate in Asians

• CYP2C19*2 respond better to

tamoxifen compared to wild type Irinotecan

• used for lung and colon cancers
• 30% has unacceptable side

effects (neutropenia and diarrhoea)

• Metabolised to more active

metabolite SN-38

• UGT1A1 ( UDP-

gluconosyltransferase 1A1) conjugates SN38 to inactive compound

• UGT1A1 *28 homozygous

associated with decreased UGT1A1 expression and hence has more side effects

Aspergillus infection

• Polymorphism in gene which encodes innate

immune system which may affect host defense system against IFI

• Gene looked at – not just for recipients but also

donors

• SNPs at Toll-like receptor(TLR4 gene), CXCL-10,

TLR1,TLR6, IL1,IL10 and TNFα all been implicated

• TLR4 1063G and 1363T are virtually absent in Asian

population compared to the Caucasian and African American

Cautions

 Understand the genetic

and nongenetic factors

 Caution- self reported

ethnicity maybe imprecise

 Social implications

JCO 2006