1 / 50

Opioid Pharmacogenomics: The Path to Personalized Medicine

Opioid Pharmacogenomics: The Path to Personalized Medicine. Leigh M. Boehmer , Pharm.D ., BCOP Clinical Pharmacist, Medical Oncology Barnes Jewish Hospital March 8, 2014. Disclosure. Leigh M. Boehmer, Pharm.D., has no real or apparent conflicts of interest to report. Objectives.

cutter
Télécharger la présentation

Opioid Pharmacogenomics: The Path to Personalized Medicine

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. Opioid Pharmacogenomics: The Path to Personalized Medicine Leigh M. Boehmer, Pharm.D., BCOP Clinical Pharmacist, Medical Oncology Barnes Jewish Hospital March 8, 2014

  2. Disclosure • Leigh M. Boehmer, Pharm.D., has no real or apparent conflicts of interest to report

  3. Objectives • Describe the principles and therapeutic implications of pharmacogenomics related to pain management • Review several novel analgesic drug targets identified from pharmacogenomic studies • Evaluate limitations and practical challenges of pharmacogenomic testing and adoption of results

  4. Objectives • Describe the principles and therapeutic implications of pharmacogenomics related to pain management • Review several novel analgesic drug targets identified from pharmacogenomic studies • Evaluate limitations and practical challenges of pharmacogenomic testing and adoption of results

  5. Clinical Genetics Defined • Pharmacodynamics: drug activity at the target site/receptor • Pharmacokinetics: drug absorption, distribution, metabolism, elimination (ADME) • Pharmacogenomics (PGx): how variations in human genome affect drug response Jannetto P and Bratanow N. Expert Opin Drug MetabToxicol. 2011; 7(6): 745-52.

  6. Anticipated Benefits of Genomics • Earlier detection of genetic predispositions • Improved diagnostic accuracy and speed • Gene therapies • Decrease in healthcare costs • Personalized treatment plans • Rational drug design Available at ornl.gov/hgmis. Accessed on 12.28.13.

  7. Clinical Genetics Defined • Genotype: genetic makeup of an organism • Phenotype: physical characteristics of an organism • Epigenetics: phenotypes resulting from environment-caused chromosomal changes • Allele: one of two copies of a gene inherited from each parent • Mutation: any heritable change in a DNA sequence • Polymorphism: DNA sequence differences present in >1% of the population Available at ornl.gov/hgmis. Accessed on 12.28.13.

  8. Heritability Analysis Angst M, et al. Pain. 2012. 153(7):1397-1409.

  9. Pain Management Genetic Analysis ABCB1=ATP-binding cassette, subfamily B, member 1 OPRM1=mu-opioid receptor gene COMT=catechol-O-methyltransferase UGT=uridine 5’-diphosphate-glucuronosyltransferase Jannetto P and Bratanow N. Expert Opin Drug MetabToxicol. 2011; 7(6): 745-52.

  10. Opioid Metabolism: CYP450 variations • Phase I metabolism in liver • CYP2D6, CYP3A4, CYP2C19, and others • Spectrum of enzymatic activity • Poor, intermediate, extensive, ultra rapid • Tramadol to active metabolite via -2D6 • Codeine conversion to morphine via -2D6 • Oxycodone to active metabolite via -2D6 Jannetto P and Bratanow N. Expert Opin Drug MetabToxicol. 2011; 7(6): 745-52. Ma J, et al. Journal of Pharmacy Practice. 2012; 25(4): 417-27.

  11. CYP2D6 Phenotype Correlation Gaston C and Kolesar J. Clin Adv Hematol Oncol. 2008;6:825-33.

  12. CYP2D6: Tramadol Experience PM=Poor metabolizer EM=Extensive metabolizer Stamer UM, et al. Pain. 2003; 105: 231-8.

  13. PGx and Toxicity: Paclitaxel-Induced Peripheral Neuropathy (PIPN) • Expression of drug target • β-tubulin promoter gene, TUBB2A • SNP 112A > G, rs909965: ↑ gene transcription and protection from PIPN • Inadequate stimulus response • DNA repair gene, FANCD2 • ↑ expression led to ~80% ↑ in risk of Grade 3/4 neurological toxicities SNP=single nucleotide polymorphism Hertz D and McLeod H. J Hum Genet. 2013. 58(6): 346-52.

  14. CYP2C8*3 Genotype and PIPN Hertz D, et al. Annals of Oncology. 2013. 24:1472-8.

  15. Grade 2+ Neuropathy in Mixed-Race Cohort (N=411) Hertz D, et al. Annals of Oncology. 2013. 24:1472-8.

  16. Opioid Absorption/Elimination: ABCB1 variations • Encodes P-glycoprotein (P-gp) 170 • Pumps drugs out of intracellular domain • Regulates CNS drug exposure • Fentanyl, methadone, and morphine are all P-gp substrates • Homozygous (TT) carriers of 3435C > T variant experience greater pain relief • 50-60% Caucasian population prevalence Jannetto P and Bratanow N. Expert Opin Drug MetabToxicol. 2011; 7(6): 745-52.

  17. ABCB1: Methadone Experience . Coller JK, et al. ClinPharmacolTher. 2006; 80(6): 682-92.

  18. Opioid Receptor: OPRM1 variations • Encodes μ-opioid receptor • 118A > G variation = substitution of asparagine for aspartate • ↓ morphine, alfentanil, fentanyl, and methadone response • 20-30% population prevalence • 1-2% African Americans • 50% Japanese Argoff C. Clin J Pain. 2010;26(1):S16-20. Jannetto P and Bratanow N. Expert Opin Drug MetabToxicol. 2011; 7(6): 745-52.

  19. ABCB1/OPRM1: Morphine Pain Relief Campa D, et al. Clin Pharm Ther. 2007; 83(4): 559-66.

  20. Catechol-O-methyltransferase(COMT) • Catecholamines are metabolized by COMT and involved in pain modulation • COMT activity may contribute to variable analgesic response • 1947G > A = 3-4 fold ↓ in COMT activity • Homozygous GG patients require higher morphine doses to achieve pain control Jannetto P and Bratanow N. Expert Opin Drug MetabToxicol. 2011; 7(6): 745-52.

  21. Morphine Dose Adjustments:Non-FDA Approved Lotsch J, et al. Pain. 2006; 121: 1-5.

  22. PGx Targets Summary Jannetto P and Bratanow N. Expert Opin Drug MetabToxicol. 2011; 7(6): 745-52.

  23. Select Variables Influencing Analgesic Response • Pain related: • Kind of pain • Origin of pain • History of pain control • Severity of: • Trauma • Surgery • Tissue damage Pharmacokinetics/ Pharmacodynamics Pharmacogenomics Analgesic response • Psychological factors: • Depression • Anxiety • Coping strategies • Diagnosis • Environmental factors: • Culture • Education • Family • Occupation Adapted from Stamer U, et al. Pharmacogenomics. 2010;11(6):843-64.

  24. Objectives • Describe the principles and therapeutic implications of pharmacogenomics related to pain management • Review several novel analgesic drug targets identified from pharmacogenomic studies • Evaluate limitations and practical challenges of pharmacogenomic testing and adoption of results

  25. Objectives • Describe the principles and therapeutic implications of pharmacogenomics related to pain management • Review several novel analgesic drug targets identified from pharmacogenomic studies • Evaluate limitations and practical challenges of pharmacogenomic testing and adoption of results

  26. 2013 Pain Management Approvals • Zohydro® (ER hydrocodone) • Zubsolv® (buprenorphine and naloxone) ER=extended release

  27. Available at http://rogermontgomery.com/wp-content/uploads/2012/05/biotech-Fig-5.png. Accessed on 12.28.13.

  28. Biomarkers in Drug Discovery and Development $1.3 billion Discovery $ Development $$ Clinical $$$ 10,000 targets Lead identification Target validation Preclinical safety Animal models Proof of target Proof of mechanism Biomarkers Clinical Samples: Tissue, blood, urine Human tissue bank Proteomics Pathonomics Proteonics 250 in preclinical 5 in clinical 1 approved From The Role of Biomarkers in Drug Discovery and Development. Available at www.criver.com.

  29. Select Potential Future Targets Modulation ATP; BNF; GABA; P2X4; P2X7; CCL2; fractalkine Transduction TRPV1,2,3,4; P2X3; P2Y; Bradykinin B1/2; PGE2; NGF Transmission Nav1.7, -1.8, -1.9, -1.3; Kv9.1 Adapted from Heinzmann S and McMahon S. Current Opinion in Supportive and Palliative Care. 2011;5:111-5.

  30. Protein Kinase (PK) Inhibitors • PK are enzymes that enable/inhibit protein function and interactions • Profound upregulation of PK activity in models of neuropathic & inflammatory pain • p38 activation – allodynia/hyperalgesia; ↑ spontaneous pain perception • JNK expression – release of pro-inflammatory cytokines JNK=c-Jun n-terminal kinase Heinzmann S and McMahon S. Current Opinion in Supportive and Palliative Care. 2011; 5:111-5.

  31. Cytokine Antagonists • Cytokines induce chronic pain seen in inflammatory conditions • Cause swelling, tissue damage, and neuronal hypersensitivity • Known cytokines which enhance pain: • MCP-1 (and its receptor CCR2) • Fractalkine (and its receptor CX3CR1) • Tumor necrosis factor-α Heinzmann S and McMahon S. Current Opinion in Supportive and Palliative Care. 2011; 5:111-5.

  32. Nerve Growth Factor (NGF) Inhibitors • NGF mediates peripheral pain stimuli via small diameter sensory neurons • Upregulated in inflamed tissues resulting in hyperalgesia • Current trials exploring: • Neutralizing antibodies against NGF • NGF receptor (TrkA) antagonists Heinzmann S and McMahon S. Current Opinion in Supportive and Palliative Care. 2011; 5:111-5.

  33. Selective Sodium (Na) Channel Blockers • Nav1.7 mutation results in congenital insensitivity to pain • Nav1.7 plays large role in transduction of painful stimuli into action potentials • Many Na channel blockers available, but only few selective for 1.7 channel Heinzmann S and McMahon S. Current Opinion in Supportive and Palliative Care. 2011; 5:111-5.

  34. Tetrodotoxin (TTX) Derivatives • TTX-CINP-201 • Non-peptide, non-opioid neurotoxin • Derived from the puffer fish • Selectively blocks voltage-gated Na channels (Nav1.3?) • Phase II trial; recruiting participants • Safety and efficacy in chemotherapy-induced peripheral neuropathy (CIPN) Available at www.clinicaltrials.gov. Accessed on 12.29.13.

  35. TTX Mechanism of Action Available at www.mdpi.com. Accessed on 12.29.13.

  36. SpicamycinDerivatives • KRN-5500 • Non-opioid inhibitor of acetylcholinesterase and fatty acid amide hydrolase • Phase IIa, double-blind, placebo controlled • Refractory neuropathic pain & cancer (N=19) • 0.6-2.2 mg/m2; single, escalating doses • 24% ↓ pain intensity vs. 0% (P=0.03) • Most common AE: GI symptoms (92%) Weinstein S, et al. Journal of Pain and Symptom Management. 2012; 43(4): 679-93.

  37. Targeted Gene Therapy – NP2 • HSV vector delivers enkephalin to sensory nerves to block pain signals • Bypasses central nervous system • Avoids “typical” opioid adverse events • US Phase I study completed • No treatment-related AEs; no seroconversion • US Phase II study ongoing (N=32) • Randomized, double-blind, placebo controlled Available at www.clinicaltrials.gov. Accessed on 12.29.13.

  38. NP2 Mechanism of Action Available at www.paineurope.com. Accessed on 12.29.13.

  39. Investigational Analgesic Products Lotsch J and Geisslinger G. British Journal of Pharmacology. 2011: 163: 447-60. Available at www.clinicltrials.gov. Accessed on 12.29.13.

  40. Objectives • Describe the principles and therapeutic implications of pharmacogenomics related to pain management • Review several novel analgesic drug targets identified from pharmacogenomic studies • Evaluate limitations and practical challenges of pharmacogenomic testing and adoption of results

  41. Objectives • Describe the principles and therapeutic implications of pharmacogenomics related to pain management • Review several novel analgesic drug targets identified from pharmacogenomic studies • Evaluate limitations and practical challenges of pharmacogenomic testing and adoption of results

  42. PGx – Healthcare Implications • Pain management treatment strategies • Payer cost management strategies • Medical informatics • Patient prognostic expectations • Drug research and development • Accelerated drug approval • Public health policy Benson A. Personalized Medicine in Oncology. 2012; 1(4): 1-5. Sadhasivam S and Chidambaran V. Pharmacogenomcis. 2012; 13(15): 1719-40.

  43. PGx Study Limitations • Small sample sizes due to low prevalence • Variability in polymorphisms assessed • Multigenic factors altering drug responses • Limited documentation of concurrent meds • Different end points evaluated • Population characteristics may affect study outcomes Walko C, et al. Journal of Pharmacy Practice. 2012; 25(4): 439-46.

  44. Practice-Based Evidence (PBE) • Prospective, observational cohort study • Data captured as part of routine clinical pain management • Complement randomized controlled trials • Help identify phenotypic and genotypic variables associated with favorable outcomes • Limited ability to infer causality • Hypothesis generation for subsequent validation via “traditional” methodology Bruehl S, et al. The Journal of Pain. 2013; 14(2): 103-13.

  45. PGx – Limitations to Implementation • Variable treatment response • Effects of pain heterogeneity • Limited ability to interpret test results • ↑ costs/time associated with testing • Healthcare providers’ knowledge limited • Unknown drug resistance mechanisms • New alleles of interest discovered daily Ma J, et al. Journal of Pharmacy Practice. 2012. 25(4):417-27.

  46. Personalized Analgesia - Algorithm Considerations • Mandatory brain imaging • Dopaminergic modulation of opioid response • Endogenous opioid quantification • Reduced responsiveness to opioid analgesics • Effects of concurrent non-drug treatments • Acupuncture, relaxation training, exercise • Outcomes measurement • Functional magnetic resonance imaging (fMRI) Bruehl S, et al. The Journal of Pain. 2013; 14(2): 103-13.

  47. PGx Testing – Ethical Considerations Haga S and Burke W. Genet Med. 2008. 10(6): 391-5.

  48. Genomics Online Resources • www.cdc.gov/genomics/ • www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/default.htm • ghr.nlm.nih.gov/glossary • www.genome.gov

  49. “If it were not for the great variability among individuals, medicine might as well be a science and not an art.” (Sir William Osler) 1892

  50. Opioid Pharmacogenomics: The Path to Personalized Medicine Leigh M. Boehmer, Pharm.D., BCOP Clinical Pharmacist, Medical Oncology Barnes Jewish Hospital March 8, 2014

More Related