Gan GG Department of Medicine University Malaya Medical Centre Kuala Lumpur
outline 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 of drugs and the mechanisms of their actions, including the correlation of 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% Dose variance • CYP2C9 accounts for 12% • CYP4F2 accounts for 1.2% Takeuchi 2009
Loading dose ? Should be individualised Complications Algorithm
Metabolism pathway 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
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 of 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 only 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 I rinotecan • CYP2D6, CYP2C19 – metabolises • used for lung and colon cancers tamoxifen (breast cancer) • 30% has unacceptable side • Poor metaboliser for CYP2D6 effects (neutropenia and respond worse with tamoxifen diarrhoea) (higher recurrence;less hot • Metabolised to more active flushes) metabolite SN-38 • Interethnic differences – poor • UGT1A1 ( UDP- metabolisers found mainly in gluconosyltransferase 1A1) Europe and ultrarapid conjugates SN38 to inactive metabolizers in North Africa compound and Oceania; intermediate in • UGT1A1 *28 homozygous Asians associated with decreased • CYP2C19*2 respond better to UGT1A1 expression and hence tamoxifen compared to wild has more side effects type
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 TNF α 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
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