1 / 38

Prospettive della farmacogenetica e della farmacogenomica

Prospettive della farmacogenetica e della farmacogenomica. Stefano Vella Dipartimento del Farmaco Istituto Superiore di Sanità. Pharmacogenetics & Pharmacogenomics. An opportunity to improve drug development Choice of drug targets An opportunity to improve clinical care

freya-bullock
Download Presentation

Prospettive della farmacogenetica e della farmacogenomica

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Prospettive della farmacogenetica e della farmacogenomica Stefano Vella Dipartimento del Farmaco Istituto Superiore di Sanità

  2. Pharmacogenetics & Pharmacogenomics • An opportunity to improve drug development • Choice of drug targets • An opportunity to improve clinical care • Individualized medicines through stratification • More rational decisions on therapeutic options

  3. Pharmacogenetics & Pharmacogenomics • An opportunity to improve drug development • Choice of drug targets • An opportunity to improve clinical care • Individualized medicines through stratification • More rational decisions on therapeutic options

  4. Druggable Genome Predictions GPCRs Kinases Proteases Transporters Ion Channels Gene family distributions of predicted druggable genome

  5. Future Drug Target Space Human Genome 24000 Predicted druggable genome genetic association** mouse K/O* Lead/chemical tools Drugs 6465 ~2400 ~145 160 170578 3505 ~320 1769 *Zambrowicz & Sands, Nature Drug Disc. Rev. (2003), 2,38-51C **Genetic association linkage data estimated by text-mining from entity co-occurrence within Medline abstracts. Data produced by Anna Gaulton and Andrew Hopkins, using a modified version of Lucene, by Lee Harland, to text-mine Medline,

  6. Accessible Genome: protein therapeutics 1516 genes likely to encode proteins drugable by both small molecules and protein therapeutics Total number druggable by protein therapeutics = 3258 genes Total number druggable by small molecule therapeutics = 3505 genes Human Genome 24000

  7. Stages of HIV-1 Life Cycle Targeted by Anti-HIV Drugs The International AIDS Society–USA In: Gulick RM, Topics HIV Med, 2002;10(4).

  8. Chemokine Co-receptors in HIV Entry • HIV gains entry into cells that express CD4 and 1 of 2 secondary receptors, either: • C-C chemokine receptor 5 (CCR5) • Expressed on monocytes and T cells • C-X-C chemokine receptor 4 (CXCR4) • Expressed on T cells, B cells, monocytes, and neutrophils 1Deng H, et al. Nature. 1996;381(6584):661-666. 2Feng Y, et al. Science. 1996;272:872-877.

  9. CD4 Binding Co-receptor Binding Virus-Cell Fusion Fusion inhibitors CCR5 antagonists CD4 bindinginhibitors gp41 gp120 V3 loop CD4 Cell Membrane CCR5/CXCR4 (R5/X4) HIV Attachment and Fusion Targets for Inhibition Adapted from Moore JP, et al. Proc Natl Acad Sci U S A. 2003;100:10598-10602.

  10. CCR5 D32  CCR5 32 CCR5 wild type  Normal Heterozygotes Homozygotes wt/wt 32/32 wt/32 2 normal copies 1 copy of 32 2 copies of 32 Standard disease progression Delayed disease progression “Resistant” to HIV infection

  11. CCR5-tropic HIV (R5 virus) • Nearly all new sexually transmitted HIV-1 infections are with R5 virus • Infect dendritic cells, macrophages, and T cells • Predominate throughout infection • X4 virus may appear over time, but ~50% of patients with HIV-1 subtype B who die from AIDS have only R5 virus1,3 • A tropism shift from R5 to X4 virus is associated with the presence of basic amino acids at codons 11 and/or 25 of the V3 loop of gp1204

  12. Maraviroc (UK-427,857) Activity Results:Mean Reduction in Viral Load over Time Last day of dosing 0.5 0.0 Maraviroc dose n -0.5 Placebo 015 4 Change from baseline (log10 HIV-1 copies/mL) Placebo 007 12 25 mg QD 8 -1.0 50 mg BID 8 100 mg QD 8 100 mg BID 7 150 mg BID Fast 8 -1.5 150 mg BID Fed 8 300 mg QD 8 300 mg BID 8 -2.0 Baseline 5 10 15 20 25 30 35 40 Time (day) Study 1007/1015

  13. Pharmacogenetics & Pharmacogenomics • An opportunity to improve drug development • Choice of drug targets • Optimization of clinical trials • An opportunity to improve clinical care • Individualized medicines through stratification • More rational decisions on therapeutic options

  14. Are Drugs Effective? Disease Efficacy Annual Rx Cost Alzheimer’s 30% $ 1,500 Analgesics 80% $ 1,350 Cardiac arrhythmia 60% $ 650 Depression 60% $ 700 Diabetes 55% $ 1,300 Hepatitis C 45% $ 5,000 Incontinence 40% $ 1,000 Migraine 50% $ 600 Oncology 25% $ 3,500 Prescribed drugs are generally effective in about 50% of patients.

  15. Are Drugs Safe? Adverse drug reactions (ADRs) represent the 4th leading cause of hospitalization (2 million/yr) and are responsible for 100,000 deaths/yr in the U.S.

  16. Pharmacogenetics of Phase I Drug Metabolism Weinshilboum R. N Engl J Med 2003;348:529-537

  17. Pharmacogenetics of Nortriptyline Weinshilboum R. N Engl J Med 2003;348:529-537

  18. Pharmacogenetics of Acetylation Weinshilboum R. N Engl J Med 2003;348:529-537

  19. Genetic Polymorphisms in Drug Target Genes That Can Influence Drug Response Evans W and McLeod H. N Engl J Med 2003;348:538-549

  20. Tamoxifen and Breast Cancer • 1971: some breast tumors express the estrogen receptor (ER), which drives tumor growth • Tamoxifen (ER receptor antagonist) was first administered regardless of tumor ER status • Ligand binding assay for ER status introduced – complex assay requiring fresh tissue • Immunohistochemical assays – variable results

  21. ErbB2 expression is associated with metastatic breast cancer! 1995 Reactivity on tumour samples About 25-30% of women who have metastatic breast cancer overexpress HerB2(EGF) receptor

  22. Relapse-free Survival (Panel A) and Overall Survival (Panel B) among Women with Breast Cancer, According to HER2 Amplification Status on FISH Pritchard K et al. N Engl J Med 2006;354:2103-2111

  23. Herceptin (TrastuzuMAb) (anti-HER MAbs) 1999:Approved

  24. HER-2/neu Genetic Test Current genetic testing uses fluorescence markers (FISH technology) – look for increased copies of HER-2/neu gene with fluorescent DNA probes – labor-intensive and expensive Gene amplified Normal HER-2/neu positive patients Most responsive to therapy HER2 testing is covered by and required for most drug benefit plans

  25. Real-time quantitative PCR for detection of HER-2/neu gene amplification 10-fold amplified Her-2/neu non-amplified Her-2/neu

  26. Polygenic Determinants of Drug Response Evans W and McLeod H. N Engl J Med 2003;348:538-549

  27. All patients with same diagnosis Non-responders and toxic responders Treat with alternative drug or dose Responders and patients not predisposed to toxicity Treat with conventional drug or dose Potential of pharmacogenetics: the right dose of the right drug, the first time

  28. Possible Designs for Pharmacogenomic Clinical Trials

  29. (+) Genetic analysis (-) (+) (-) sampling Retrospective Design Randomized, Double Blind, Placebo-controlled Trial Treatment period Placebo Drug A entry • Patient numbers in a arm maybe unbalanced? • Sampling maybe limited in some patients? • Results are not confirmative? → Confirmative trial would be necessary

  30. Therapy as usual Genetic analysis Treatment period (+) (-) sampling Prospective Design 1 Drug A randomized • To test clinical utility • PGx test is really necessary? • Cost-benefit relationship • Results are confirmative

  31. Prospective Design 2 Treatment period Placebo Genetic analysis (+) randomized Drug A (-) sampling Randomized, Double Blind, Placebo-control Trial Enrichment approach No entry • Increase analytical power of trial • Results are confirmative • But, data in gene(-) patients can not be obtained • May lose a chance of treatment for (-) patients

  32. Treatment period Genetic analysis Placebo (+) Drug A randomized Placebo (-) Drug A sampling Prospective Design 3 Randomized, Double Blind, Placebo-control Trial

  33. More drugs, more appropriate Benefit of Pharmacogenomics • Improving benefit/risk ratio • More safe, more effective drugs • Adjusting Dose • Determine the best dose • Increasing successful rate of clinical trials • Focusing on data in responder

  34. Except for monozygotic twins, each person's genome is unique. • All physicians will soon need to understand the concept of genetic variability, its interactions with the environment, and its implications for patient care. • With the sequencing of the human genome, the practice of medicine has now entered an era in which the individual patient's genome will help determine the optimal approach to care, whether it is preventive, diagnostic, or therapeutic.

  35. A possible future…. • Doctor Examines Patient and Makes Initial Diagnosis • Laboratory Buccal Swab or Blood Sample • Genetic Analysis

  36. Drug Prescribing Based on the Patient’s Genetic Markers 20 18 16 14 12 10 8 6 4 2 0 -5.0 10.0 25.0 40.0 55.0 Non-Responders Responders

More Related