Pharmacogenomics of Medications for Pain and Major Depression: Promise and Peril Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP Professor of Clinical Sciences Drake University College of Pharmacy and Health Sciences Internal Medicine Clinical Pharmacist Iowa Methodist Medical Center, Des Moines, IA Disclosure Geoffrey Wall reports no actual or potential conflicts of interest associated with this presentation 1
Learning Objective Upon successful completion of this activity, pharmacists should be able to: Review the literature for evidence for or against pharmacogenomic testing for pain and psychiatric medications. Identify the specific tests that may guide medication selection and dose adjustment for pain and psychiatric medication. Apply the findings of pharmacogenomic testing to a patient case involving pain and psychiatric medications. Summing up the Potential of Pharmacogenomics 2
Pharmacogenomics Information in the Published Literature Zineh I et al. Ann Pharmacother. 2006; 40: 639-44 Pharmacogenomics in Pain/Mental Health: Where are we? The Promise The testing is designed to improve the effectiveness of prescribing. These tests also will allow us to identify patients who might experience adverse effects from antidepressant or antipsychotic medications and may help to improve adherence Julia Bartlow, RPh. Genoa Health Cost per sample $250-500 The Peril We don t really yet know how to use pharmacogenomic data to improve medication options for people with psychiatric illness. Right now we have identified a lot of biomarkers, which means that one day we should be able to improve medication options with these tests. But little of what we have so far is definitive Shaili Jain, MD, psychiatrist at VA Palo Alto Accessed 7/29/15http://www.managedcaremag.com/archives/2014/7/should-mental-health-patients-getpharmacogenomic-testing. 3
Clinical Relevance Can we predict who will derive an optimal response? Can we predict who will have a toxicity? Host (patient) genotype determines optimal drug therapy approach Disease (pathogen) genotype determines optimal drug therapy approach State of the Evidence What we have PK/PD studies in small numbers of patients Retrospective studies looking at genomic characteristics of patients AFTER a study has been done Prospective studies with adjunctive genomic testing What we need RCTs that compare PGx guided dosing with usual care 4
PGX AND PAIN 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, et al. Expert Opin Drug Metab Toxicol. 2011; 7: 745-52. 5
CYP2D6 Polymorphisms CYP2D6 is responsible for the metabolism of a number of different drugs Antidepressants, antipsychotics, analgesics, cardiovascular drugs Over 100 polymorphisms in CYP2D6 have been identified Based on these polymorphisms, patients are phenotypically classified as: Ultrarapid metabolizers (UMs) Extensive metabolizers (EMs) Intermediate metabolizers (IMs) Poor metabolizers (PMs) 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, et al. Expert Opin Drug Metab Toxicol. 2011; 7: 745-52. Ma J, et al. Journal of Pharmacy Practice. 2012; 25: 417-27. 6
Clinical Example: CYP2D6 and Codeine Codeine requires activation by CYP2D6 in order to exert its analgesic effect Due to genetic polymorphisms, 2-10% of the population cannot metabolize codeine and are resistant to the analgesic effects Individual variability exists in the adequacy of pain relief when uniform doses of codeine are given CPIC 2014 Guidelines on PGx Dosing and Codeine Crews KR, et al Clin Pharm and Therapeutics 2014;95:376-82 7
CYP2D6 Phenotypes Roden DM et al. Ann Intern Med 2006; 145:749-57 Ethnic Variation in 2D6 Metabolism 8
CYP2D6 Phenotype Correlation Gaston C and Kolesar J. Clin Adv Hematol Oncol. 2008;6:825-33. Study: Tramadol and PGx Prospective OL trial in postoperative pain in adults n = 271 2D6 profiles in all patients then given PCA with tramadol (IV where study was conducted) Outcome: 24 pain usage/scores and rescue medication Results: PM vs EM Non-responders: 47% vs. 22% (p = 0.005) Needing rescue meds: 43% vs. 22% (p < 0.001) Stamer UM, et al. Pain. 2003; 105: 231-8 9
PGx Targets Summary Jannetto P et al. Expert Opin Drug Metab Toxicol. 2011; 7: 745-52. CYP2D6: Amitriptyline and Nortriptyline Amitriptyline is metabolized by both CYP2D6 and CYP2C19. Nortriptyline is metabolized by CYP2D6. Altered metabolism for CYP2D6 and CYP2C19 may warrant a change in dose or use of an alternate agent. CYP2D6 ultra-rapid metabolizers have a higher probability of failing amitriptyline or nortriptyline therapy due to subtherapeutic plasma concentrations. CYP2D6 poor metabolizers may have a higher risk of adverse events due to elevated plasma concentrations Kapur BM, et al. Clin Biochem. 2014;47:1169-87 10
PGx and Other Pain Medications NSAIDs Many metabolized by 2D6 Polymorphisms may lead in increased ADRs COX-1 and COX-2 encoded by different genes different genotypes may lead to better response to NSAIDs Kapur BM, et al. Clin Biochem. 2014;47:1169-87 PGX AND MAJOR DEPRESSION 11
CYP2D6 Polymorphisms and Psychiatric Drug Response Increased rate of adverse effects in poor metabolizers due to increased plasma concentrations of drug: Fluoxetine death in child attributed to CYP2D6 poor metabolizer genotype Side effects of antipsychotic drugs occur more frequently in CYP2D6 poor metabolizers CYP2D6 poor metabolizers with severe mental illness had more adverse drug reactions, increased cost of care, and longer hospital stays JC Stingl et al, Mol Psych 2012, 1-15 12
Systematic Review of CYP/PGx and Antidepressants Porcelli S, et al. J Psychiatry Neurosci. 2011;36:87-113 P-gp polymorphisms and response to antidepressants Antidepressants need to pass the BBB to get to the brain They do so via carrier molecules like P-gp Study: 362 patients treated with P-gp substrates (amitriptyline, citalopram, paroxetine, venlafaxine) or nonsubstrate (mirtazapine) 9.5% non-remitters carried C allele vs 45% of remitters C-carriers treated with P-gp substrate significant increased risk of remission Uhr, M. et al. Neuron 2008; 57: 203-209 13
Pharmacodynamics and PGx Tryptophan hydroxylase (TPH) Catalyzes 5-HT Biosynthesis TPH1*a allele associated with decreased 5-HT Catechol-O-methyl transferase (COMT) rs4680 polymorphism associated with worse outcomes and increased suicidality 5-HTT Serotonin Transporter 5-HTTLPR polymorphism associated with a wide variety of psychiatric disorders The most studied PD variable in PGx studies Porcelli S, et al. J Psychiatry Neurosci. 2011;36:87-113 SSRIs and 5-HTTLPR Schosser A, et al.int Clin Psychopharmacol. 2009 ;24:277-88 14
The Evidence for PGx in MDD 233 adult patients with MDD via DSM-IV OL design Patients consecutively assigned to usual care or PGx guided therapy Testing done on both cohorts but prescribers only received the results in one cohort Multiple instruments to detect response (e.g HAM-D) Standard if complex statistics Hall-Flavin DK, et al. Pharmacogenet Genomics. 2013;23:535-48 Example of PGx Report 15
Aetna considers genotyping for other cytochrome P450 polymorphisms including antipsychotic medications, and selective serotonin reuptake inhibitors experimental and investigational because the clinical value of this type of genetic testing has not been established. Aetna considers genotyping for HLA-B* 1502 medically necessary for persons of Asian ancestry before commencing treatment with carbamazepine (Tegretol). http://www.aetna.com/cpb/medical/data/700_799/0715.html - Last update 8/2013 16
Conclusions Many studies showing association of PGx with pain/depression and treatments Virtually no data showing pharmacotherapy via this method is superior to standard dosing PGx is just one factor Not yet ready for prime time Medicare B will cover Pgx testing in some select cases Kapur BM, et al. Clin Biochem. 2014;47:1169-87 Here s my sequence Maybe one day soon 17
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