Herceptin survival rate plus chemotherapy: 79 % and the chemotherapy :68% so difference improvement is only 11% .Herceptin described only for phase 4 only.
In the context of polymorphic drug metabolizing enzymes, some limitations in applying pharmacogenetics to therapeutics are already self evident. These are:Very few drugs are metabolized by a single enzyme. Furthermore, PMs are often able to utilize alternative, but often less effective, pathways of elimination.Many drug metabolizing enzymes are subject to variant alleles which express enzymes with altered substrate specificity or altered functional activity.Not all ADRs of a drug are genetically determined even if a drug is metabolized by a single pathway. Whereas only one or two of these may have genetic basis. Small systematic studies suggest that often, not even the serious ADRs are associated with a specific genotype.In addition to drug metabolizing enzymes, P-glycoprotein(These are part of a larger family of efflux transporters.) and associated organic ion transporters also influence the disposition of many drugs. These play an important role in the absorption of drugs and their transport into the cells and elimination into the bile or urine. Not all toxic effects need have a pharmacokinetic basis.
insufficient information regarding potential variability in the target populationThe field of pharmacogenomics is fairly dynamic, and laboratory data are generated at a very high speed. What might be the ‘best’ pharmacogenomics test for a certain condition today, might not be six months later.arbitrary exclusion criteria since multiple enzymes frequently involved in drug metabolism and subjective exclusion and inclusion of the groups or persons.disregard for the presence of multiple variant alleles at a given locus, which may have different substrate specificity—which genotypes are candidates for exclusion?not possible to investigate safety and efficacy of even the lower doses in genotypes excluded so the results will be missing the exclusion part.as proposed and currently applied, this design overlooks the importance of pharmacodynamic polymorphisms and of haplotypes
Available data illustrate an important point from the regulatory perspective. Promises of potential clinical benefits from integrating pharmacogenetics in clinical medicine are often based on inappropriate presumptions on the role of polymorphic drug metabolizing enzymes or pharmacological targets. As discussed below, a number of drugs illustrate this point and often, the results from pharmacogenetic studies of specific drug-induced toxic effects are inconsistent or contradictory.Thioridazine has been shown in healthy volunteers to have a dose related effect on ventricular repolarization,primarily due to the parent drug with a possible contribution from the metabolites (Hartigan-Go et al.1996). One recent study reported that CYP2D6 status might be an important determinant of the risk for thioridazine-induced QTc interval prolongation Llerena et al. 2002) while another reported that CYP2D6 genotype does not substantially affect the risk of thioridazine-induced QTc interval prolongation(Thanaccody et al. 2003). This discrepancy is present in this research and many others. To further add, Two classes of drugs, antidepressants and neuroleptics,have narrow therapeutic index and are generally metabolized predominantly by CYP2D6. Althoughsmall retrospective studies appear to show a correlation between genotype and toxicity or failure to respond (Rau et al. 2004), overall analyses of studies correlating CYP2D6 genotype with response to these drugs(referred to as phenotype) have been cautious in their Conclusions. These disappointing findings are hardly surprising since a number of these drugs are also metabolized by pathways other than those mediated by CYP2D6 and frequently, these drugs have metabolites that are pharmacologically active in terms of efficacy and ADRs.A more recent study has also found no evidence of impaired metabolism of oral diclofenac in heterozygous and homozygous carriers of the CYP2C9 alleles *2 and *3 compared with the wild type allele and marked diclofenac-mediated inhibition of COX-1 and COX-2 activity was detected in all individuals independent of CYP2C9 genotype(Kirchheiner et al. 2003c).
pharmacogenetic approaches during drug development will have to be more ‘holistic’. These approaches will have to focus on investigating genetic influences not only at pharmacokinetic (drug metabolizing enzymes and transporters) but also at pharmacodynamic (pharmacological targets) levels to fully characterize the pharmacology of drugs. Clearly, a patient’s overall genotype that determines a drug response (phenotype) must take into account the presence of normal wild type and mutant alleles in heterozygous and homozygous states at both these key components of the dose–response relationship. The situation becomes even more complex when one also considers the presence of multiple alleles at a single locus. it may be too optimistic to believe that all relevant pharmacogenetic variations will be SNPs,especially as we already know examples of large deletions, amplifications and re-arrangements (Idle et al. 2000).An important factor that is likely to limit the potentially beneficial application of pharmacogenetics is the interaction between the genotype and extrinsic factors ( menstrual cycle, stress,... Drug–drug interactions are another major problem and have frequently resulted in withdrawal of drugs from the market, for example terfenadine, mibefradil, cerivastatin, cisapride and levacetylmethadol. The inhibition of drug metabolizing enzymes by other drugs is an important point of intersection between pharmacogenetics and drug response.In the meantime, prescribing should comply with the information provided while pharmacogenetic research is deservedly supported by all concerned but without unrealistic expectations. education of the prescribing community should also be considered.
Expression analysis of the XPRSS-Int data set in breast tumors. Top right, comparison of gene expression in BRCA1mut breast tumors relative to sporadic breast tumors both for genes in the XPRSS-Int set (vertical lines) and for 100 randomly generated equivalent sets of genes (curves; see Methods).Left, network representation of genes in the XPRSS-Int set that show expression changes in BRCA1mut breast tumors relative to sporadic breast tumors. Edge distances to the four reference genes are optimized to be inversely proportional to their average PCCs across normal tissues (in other words, shorter edges indicate higher coexpression values).To identify potential functional associations involving all four reference genes, we focused on those transcripts found in the ‘expressionintersection’ (XPRSS-Int) of the four coexpression sets.
It is known that for several types of cancers, an effective therapy requires the simultaneous inhibition of multiple oncogenic kinases  or the targeting of many different pathways .The Map of total modules of liver cancer. The interaction network of modules extracted from the global network containing 234 liver cancer-associated genes, 1056 nodes and 3425 edges [downloaded from the OMIM database on July 6, 2012 and analyzed by the Agilent Literature Search plugin (version 2.77) in Cytoscape (version 2.8.2)]. The module interaction network is constructed using 166 modules identified by Markov clustering (MCL, Inflation = 2) (average size: 6.331, maximum size: 59, minimum size: 2, modularity: 0.534). The green nodes, blue square and gray edges denote the liver cancer-associated genes we entered, a module and the inter-module connections, respectively.
1.Major limitation is the lack of genotyping data. There is limited evidence to justify prospective pharmacogenomic testing. Furthermore, the infrastructure for genotyping is only available in a subset of centres.3.To determine whether or how to use pharmacogenetic test to predict ability of an individual patient to metabolize,transport,and respond to a given drug will require reliable prospective genotype to phenotype evaluation.4.Bcoz conventianol trial-and-error and one size-fits-all approaches to prescribe medicines hv long been widely accepted by most practising physicians who graduated b4 the era of human genome.
Practically, due to complexity & polymorphism of genome, it is impossible to achieving distinct genotype in phenotype-genotype association studies of human populations. Examples:CYP genes encodes enzymes responsible for metabolism of almost all drugs. CYP2D6 monooxygenase, metabolises 25-33% of drugs. It is difficult to know how the patient would react to a drug knowing that there are 75 variant alleles of CYP2D6 gene, and all should be tested before speculate drug metabolism pattern of patientThe human genome contains 57, putatively functional, CYP genes that encode phase I enzymes involved in oxidative and reductive reactions……..Therefore, unless every variant site in the genome that affects CYP2D6 expression is tested, it is difficult to conclude that a patient is a poor, intermediate, efficient, or ultra-rapid metabolizer
There are some issues regarding patient’s informed consent needed to be considered.
In year 2000, researchers in Canavan’sgene were taken to court by 3 families and 2 Canavandisease associations, who provided participants to the research to block gene patent which used in commercial test.
The extensiveacquisition of genetic information that a wide-ranging programme of pharmacogeneticswould involve might also lead to violations of legitimate expectations of confidentiality andprivacy, and unfair discrimination.
There has been a lot of concern about whether the approval of ethnic drugs would promote the re-biologisation of race within medical research and practice. However, BiDil® does show that subgroup-directed treatment of ethnic minority groups can also have a positive discriminative effect.Race and ethnicity are not the key to unlocking the secrets of the causes of disease, but are constantly evolving conceptual tools for assessing needs and inequality and for guiding health policy and practical actions. As such, racial and ethnic differences and similarities in the susceptibility of specific diseases might even provide the basis for reinventing community-based public health.Nevertheless, a clinical study designed to investigate the efficacy of BiDil® in people of different races never took place. There is still a debate going on about whether genetic variance may explain the drug efficacy in African Americans, and whether BiDil® can be considered a pharmacogenomics application.The working mechanism of the drug remains to be clarified.
Unlike medical history, pharmacogenomic information is very easy to obtain.In research, ethical thinking evolves due to the fast pace of research. Genome-wide association studies trying to identify genes thatcontribute a small risk to common diseases can only be performed on an international scale. Meanwhile, it is becoming more and moreclear that genomic information is hard to hide. Thus the traditional promise in research that privacy will be protected appears to be lessrealistic. Nowadays, adequate information (veracity) and protection against potential risks of discrimination based on predictive medicalinformation is required. A new balance needs to be found.The person who is going through genetic testing may learn info about themselves and family members.(Nash)They may also know about adoption.(Nash)And this causes strained relationships among relatives
Total doctors registered on LRMP 252,469 63.2% from the UK (GMC, 2012)More than 50,000 registered pharmacists (GPhC, 2010)LRMP : list of registered medical practitioners.Not only british also international doctors who need to be educated too .GMC : general medical councilGPhC: general pharmaceutical councilEvery year should the pharmacists be registred.
FDA approval, BiDil’s projected market opportunity nearly tripled to $3 billion as NitroMed announced BiDil pricing at $1.80 per pill, or $10.80 per day, based on the target dose of six pills per day.
In recent debates,Chadwick and Knoppers have proposed a new framework of ethicalprinciples to address research in human genetics and genomics :Reciprocity (exchange information between researchers and participants; transparency, also concerning possible commercialisation)• Mutuality (genetic information and DNA as family property –risk-sharing within families)• Solidarity (a willingness to share information for the benefit of others; common interests or interest in common)• Citizenry (public involvement with science [policy]; genetic heritage and collective identity)• Universality. (the human genome as a shared resource; common heritage of humanity; obligations to future generationsand benefit sharing)
BiDil : Charmaine Royal, Ph. D., director of the GenEthics Unit at the National Human Genome Center, says African Americans should not be treated as a monolith when it comes to drug therapy.
Are there other Non-Genetic factors involved?What about Children?
Genetic Profiling Debate
Geneting Profiling Shaza El Nemr Nashwa Albaaini Khaled Ibrahem
Preface• Definitions• Factors Affecting Genomic Analysis• ‘Pharmacogenetics in clinical medicine’• The Complexities• “Credibility” of pharmacogenetics!• Disadvantages• Pharmacogenomics Testing!• Issues
Definitions• Pharmacogenetics is the study of genetic variation that affects response to medicines.• Pharmacogenomics use of genome based techniques in drug development• Personalized Medicines treatment, based upon the individual-specific factors underlying disease and drug response (Vijverberg et al., 2010)
Factors of Pharmacogenesis• Pharmacogenetic factors operate at pharmacokinetic (PK) levels pharmacodynamic(PD) levels (Shah RR., 2005)• The role of genetic factors when investigating a drug for its pharmacokinetics, pharmacodynamics, dose– response relationship and drug interaction potential. (Vijverberg et al., 2010)
Clinical significance of pharmacogenetic variability in pharmacokinetics• Metabolizing drugs needs more than a single enzyme.• Expression of drug metabolizing enzymes with altered specificity/functional activity.• Even the serious ADRs are not related to a specific genotype (Clark et al., 2004).• P-glycoprotein and associated organic ion transporters also affect the disposition of many drugs.• PK is not an essential basis of all toxic effects. (Shah RR., 2005)
Factors Affecting Genomic Analysis (Ding et al., 2010) Copy Number variationPathway MutationAnalysis Spectrum Methylation
Disadvantages of Pharmacogenetic Studies Design• Insufficient knowledge about potential variability• Overestimation of the results and efficacy of drug• More erosion of short-term and long-term safety data• Distorted comparisons in active controlled trials• Arbitrary exclusion conditions• Neglect of the presence of multiple variant alleles at a given locus• No investigation of safety and efficacy in the genotypes excluded• Design overlooks the importance of PD polymorphisms (Shah RR., 2005)
Pharmacogenetics in clinical medicine• Inconsistence and contradiction of pharmacogenetic studies of specific drug- induced toxic effects. – Discrepancy in Thiorizadine and CYP2D6 status. – Contradiction in the studies of neuroleptics and antidepressants with CYP2D6. – No evidence of impaired metabolism of oral diclofenac in heterozygous and homozygous carriers of the CYP2C9 alleles (Kirchheiner et al. 2003c).
Complexity in Pharmacogenetics– Pharmacokinetic levels– pharmacodynamic levels– Phenotype– Heterozygous & Homozygous States– Multiple alleles at a single locus– nucleotide polymorphism(s)– Not all relevant pharmacogenetic variations will be SNPs (Idle et al. 2000).– Interaction between Genotype and Extrinsic factors.– Drug-Drug Interaction for example terfenadine, mibefradil, cerivastatin, cisapride and levacetylmethadol. (Shah RR., 2005)
Figure1: Analysis of 164 “Expression Intersection”genes/proteins in breast tumors (Pujana et al., 2007).
Figure2: The Map of global network containing 234 liver cancer-associated genes, 1056 nodes and 3425 edges of liver cancer (Wang Z. & Wang YY., 2013).
Pharmacogenomics Testing• Lack of genotypic data.• Additional costs for genetic testing• Lack of large-scale prospective clinical evaluations for impact of genetic variability in drug disposition and response.• Relative Resistance to use genetic testing to individualize drug therapies. (Xie & Frueh, 2005)
Credibility of pharmacogenetics! Impossibility to achieve distinct genotype in phenotype-genotype associationstudies of human populations.Examples:• Reviewing 12 hospital that linked thiopurine-related drug toxicity to thiopurine methyltransferase TPMT genotype, found more than 78% of adverse drug reactions were associated with different factors other than TPMT-gene polymorphism.• CYP2D6 monooxygenase metabolises 25-30% of drugs. CYP2D6 gene 75 variant alleles detected. All to be tested before speculation.• Genetic and epigenetic background of a patient is changing via environmental changes in a decade. Patient’s genome, diet, intestinal flora, changes in lifestyle and exposure to drug and chemicals should be analysed simultaneously. (Nebert and Vesell, 2006)
Consent• Clear description of the participant’s role.• Description of all members and firms involved in the research.• Protection of confidentiality.• How the participant’s DNA will be defined and shared with other investigators.• Will the participant share benefits if the research contributed to development of a product?• What if the participant’s DNA study revealed sensitive information which might have unpleasant consequences. (Nebert & Bingham, 2001)
Consent The following is a section from consent form in genetic research:“Discoveries made with your DNA samples may be patented by us and theUniversity. These patents may be sold or licensed, which could give a companythe sole right to make and sell products or offer testing based on the discovery.Royalties may be paid to us, the University, and the Sponsor. It is not our intent toshare any of these possible royalties with you.” Commercialization of patient gene. • Example on Canavan’s gene dispute. (Marshall, 2000)
Health Insurance• Insurers might classify clients according to their genotypes.• If genotype indicates poor response to a drug (or group of drugs), the client might be denied the cover, even if he/she is completely healthy.• Health insurers could set high premium relying on only drug history of clients, as that might indicate their genotype
Social Issues• Pharmacogenomics may be used to promote ethnic/racial stereotypes.• Pharmacogenomics may broaden the healthcare gap between the rich and poor• Insurance discrimination• Employment discrimination
Privacy Issues Confidentiality and Privacy Use of pharmacogenomic information Pharmacogenomic information can be inferred from relatives. • A case when a father blocked his son from participating in a genetic research via OHRP after learning that, family history was invaded without consent. Authority abuse
Religious IssuesGenetic screening will change the way humans reproduce.1. People will use it to select for a “Better child”. Messing with god’s creation and nature.2. Abortion becomes an issue. – some religions consider any interference with the natural act of reproduction to be immoral. Like: In the Roman Catholic view, any act of reproduction that is not performed by the natural way is immoral (Smith, 1989).3. Individuals who were carriers for genetic abnormalities.. Would they be encouraged not to reproduce?
Educational Issues “Pharmacists”• Pharmacists are responsible to provide medication counseling and drug information to patients.• Assessment of the knowledge, attitudes and education of over 700 pharmacists. Total doctors registered on LRMP 252,469 63.2% from the UK (GMC, 2012) More than 50,000 registered pharmacists (GPhC, 2010) (Roederer et al., 2012)
Psychological Problems• In case of depression pharmacogenomic info can be damaging.• May lead to feeling of helplessness.• Some patients may become sad, angry or anxious if they learn that they have a mutation in a cancer susceptibility gene.• If these feelings are very intense, psychological counseling will be a necessity.
Financial/Economic Issues Commercial Goal Dominates the Scientific Goal.• OpGen Closes $17M to Market Microbial Whole-Genome Analysis Platform ( Gene Engineering and Biotechnology News, 2010)• Economic :Royal claimed, which are not being widely discussed, namely that NitroMed Inc., BiDil’s manufacturer, has a monopoly on this patent, which was due to expire in 2007 but has now been extended to 2020 as a result of the drugmaker re-marketing BiDil for use among African Americans.• Cost: BiDil sells for $1.80 per pill, far more than generic drugs at 30 cents a pill So or $10.80 per day, based on the target dose of six pills per day.• Very expensive . What about Failures Cost?
Ethical IssuesEthical Principles in Human Genetics andGenomics according to Chadwick and Knoppers :• Reciprocity• Mutuality (Family)• Solidarity• Citizenry• Universality (Vijverberg et al., 2010)
Bonnie Green (PhD Sociology/Genomics)ESRC Centre for Genomics in Society/University of Exeter(Posted 2 years ago).
Rising Questions• Would you undergo the ‘Genetic Test’? Why?• Are statistics of genetic studies sufficiently credible?• Does gene analysis stand solely in treatment sector?• Is it ethical to discriminate people in Insurance and work companies relying on their Genetic Profiling?• Do you Accept promotion of “Race Marketing”?• Would you like to hear ‘Future Bizzard’ about you which may never happen?
References• Clark, D. W., Donnelly, E., Coulter, D. M., Roberts, R. L. & Kennedy, M. A. (2004). Linking pharmacovigilance with pharmacogenetics. Drug Safety; 27: 1171–1184.• CLeod H. (2012). DisclosuresPersonalized Medicine; 9(1):19-27.• Ding L., Wendl C.M., Koboldt C.D., Mardis R.E. . (2010). Analysis of next- generation genomic data in cancer: accomplishments and challenges. Human Molecular Genetics . 19 (R2)• Huang M-S., Temple R.. (2008). Is This the Drug or Dose for You?: Impact and Consideration of Ethnic Factors in Global Drug Development, Regulatory Review, and Clinical Practice. CliniCal pharmaCology & TherapeuTiCs, nature publishing group; 84 (3):287-294.• Idle, J. R., Corchero, J. & Gonzalez, F. J. (2000). Medical implications of HGP’s sequence of chromosome 22.Lancet ; 355, 319.• Kirchheiner, J., Meineke, I., Steinbach, N., Meisel, C., Roots, I. & Brockmoller, J. (2003c). Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2. No relationship to the CYP2C9 genetic polymorphism in humans. Br. J. Clin. Pharmacol. 55:51–61.• Littlejohns P. (2006). Trastuzumab for early breast cancer: evolution or revolution? The lancet; 7:22-23.
References• Meissner D. (2007). Report of an International Group of Experts. Ethical, Legal and Social Implications of Pharmacogenomics in Developing Countries. Switzerland: World Health Organization. p2-67.• Merz JF., Magnus D., Cho MK. and Caplan AL. (2002). Protecting Subjects’ Interests in Genetics Research. Am. J. Hum. Genet. 70:965–97.• Mordini E. (2004). Ethical considerations on pharmacogenomics. Pharmacological Research; 49:375-379.• Nebert D. W. and Bingham E. (2001). Pharmacogenomics: out of the lab and into the Community. TRENDS in Biotechnology; 19:519-523.• Nebert D. W. and Vesell E. S. (2006). Can personalized drug therapy be achieved? A closer look at pharmaco-metabonomics. TRENDS in Biotechnology; 27:580-586.• Nebert DW., Jorge-Nebert L., Vesell ES. (2003). Pharmacogenomics and "individualized drug therapy": high expectations and disappointing achievements, J. Pharmacogenomics; 3(6):361-70.• Özdemir V.,Fisher E., Dove E. S., Burton H., Wright G. E. B., Masellis M., and Warnich L. (2012). End of the Beginning and Public Health Pharmacogenomics: Knowledge in ‘Mode 2’ and P5 Medicine, Current Pharmacogenomics Person Medicine; 10:1-6.
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