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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.

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Opioid Pharmacogenomics: The Path to Personalized Medicine

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  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

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