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Pharmacogenomics: Clinical Application and Effects on Drug Metabolism

Pharmacogenomics: Clinical Application and Effects on Drug Metabolism. Rodney J. Hunter, Pharm.D. Assistant Professor Texas Southern University College of Pharmacy and Health Sciences SNPhA Regional Conference District III, IV, & V February 19 th , 2011. Financial Disclosure.

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Pharmacogenomics: Clinical Application and Effects on Drug Metabolism

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  1. Pharmacogenomics: Clinical Application and Effects on Drug Metabolism Rodney J. Hunter, Pharm.D. Assistant Professor Texas Southern University College of Pharmacy and Health Sciences SNPhA Regional Conference District III, IV, & V February 19th, 2011

  2. Financial Disclosure I have no conflicts of interest in regards to this program

  3. “Why genetic polymorphisms? Why pharmacogenomics and oncology? Why so much excitement in this field?”

  4. Objectives • Describe pharmacogenomics and the clinical relevance of this field of study in relation to oncology • Outline the drug metabolism pathways affected by pharmacogenomic abnormalities in the oncology patient population • Identify the different drug classes and significant adverse drug effects associated with pharmacogenomic changes in the oncology patient population

  5. Human Genome Project • Begun in 1990 with an expected completion date of 2005, it was completed in 2003 due to advances in technology • Set out to map the 20,000-25,000 human genes • 3 billion DNA bases

  6. Introns and Exons http://www.emc.maricopa.edu .

  7. Genetic Polymorphisms • Single Nucleotide Polymorphism (SNPs) • 1/1000 base pairs • Types of SNPs • Insertion-Deletion • Tandem repeats • Frameshift mutation • Defective splicing • Aberrant splice site • Premature stop codon Dipiro JT, Talbert RL, et al. Pharmacotherapy 7th ed. 2008;6:31-45.

  8. Rationale for Pharmacogenomics • Meta-analysis estimated ~2 million ADR/yr in the US • ADR accounting for 100,000 deaths • Cost in 2000 ~$177.4 billion Lazarou, J et al JAMA. 1998;279:1200-05.

  9. Goals of Pharmacogenomics • Prevent and predict adverse drug reactions • Optimize drug therapy • Lead to novel approaches to drug discovery

  10. Goals of Pharmacogenomics Evans WE and Johnson JA. Annu Rev Genomics Hum Genet. 2001;2:9-39.

  11. Other Pharmacogenomic Implications Evans, WE and McLeod HL. N Engl J Med. 2003;6:538-49.

  12. Pharmacogenomics in Oncology • Drug effects • Drug metabolism • Drug Targets • Drug Transporters • Somatic mutations in malignant tissue • Narrow therapeutic index

  13. Metabolism and Genetics WT/WT = homozygous wild-type allele, Wt/V = heterozygous for one wild-type and one variant allele, V/V = homozygous for variant allele, AUC = area under the curve Evans, WE and McLeod HL. N Engl J Med. 2003;6:538-49.

  14. Efficacy and Genetics WT/WT = homozygous wild-type allele, Wt/V = heterozygous for one wild-type and one variant allele, V/V = homozygous for variant allele, AUC = area under the curve Evans, WE and McLeod HL. N Engl J Med. 2003;6:538-49.

  15. Polygenic Drug Response Evans, WE and McLeod HL. N Engl J Med. 2003;6:538-49.

  16. Thiopurine-S-methyltransferase (TPMT) • Mechanism of Action 6-methylmercaptopurine TPMT 6-thioguanine Azathiopurine 6-mercaptopurine Xanthine Oxidase Thiouric Acid

  17. Thiopurine-S-methyltransferase (TPMT) • TPMT deficiency • Autosomal codominant genetic polymorphism • High TPMT activity is most common • TMPT*3A and TMPT*3C • Heterozygous phenotype • Intermediate tolerance Evans WE, Hon YY, et al. J Clin Oncol. 2001;2293-301.

  18. Thiopurine-S-methyltransferase (TPMT) • Patient population • Patient referred due to excessive toxicity secondary to 6-MP or AZA • Twenty-three patients evaluated • Hospitalizations, platelet transfusions, and missed chemotherapy doses • Genetic Testing • TMPT genotype determined by PCR Evans WE, Hon YY, et al. J Clin Oncol. 2001;2293-301.

  19. 90% Thiopurine-S-methyltransferase (TPMT) Evans WE, Hon YY, et al. J Clin Oncol. 2001;2293-301.

  20. Thiopurine-S-methyltransferase (TPMT) • Summary • A dosage reduction of 90% has benefited patients with homozygous TPMT deficiency • Homozygous TPMT deficient patients have a high incidence of hematopoetic toxicity induced by thiopurines • Heterozygous patients can tolerate full doses in most cases

  21. “JP has a homozygous TPMT deficiency, JP’s full dose of 6-MP is 500 mg/m2/week. What dose should JP receive?”

  22. UGT1A1 • Mechanism of Action

  23. UGT1A1 • UGT1A1 • UGT1A1*28 • Extra TA dinucleotide promotor region • Decreased expression of UGT1A1 protein • Increased risk of irinotecan toxicity • Mainly in homozygous patients Cote JH, Kirzin S, et al. Clin Cancer Res. 2007;3269-75.

  24. UGT1A1 • Patient population • 400 patients with high-risk stage III colon cancer • Patients randomized • 5-fluorouracil/Leucovorin (Arm A) or FOLFIRI (Arm B) • Genetic Testing • DNA from 184 patients was evaluated • UGT1A1, ABCB1, and CYP3A5 Cote JH, Kirzin S, et al. Clin Cancer Res. 2007;3269-75.

  25. UGT1A1 • Results Cote JH, Kirzin S, et al. Clin Cancer Res. 2007;3269-75.

  26. UGT1A1 • Summary • Homozygous patients usually require at least one level dosing reduction • Heterozygous patients can tolerate normal doses • Irinotecan screening • FDA-approved genotype test (Invader® Molecular Assay) Cote JH, Kirzin S, et al. Clin Cancer Res. 2007;3269-75.

  27. Dihydropyrimidine dehydrogenase (DPD) Watters JW, McLeod HL. Biochimica et Biophysica Acta 2003 1603; 99–111

  28. Dihydropyrimidine dehydrogenase (DPD) • DPD deficiency • AG to C single nucleotide change on exon 14 • Decreased activity of DPD responsible for 5-FU breakdown • Major Symptoms • Diarrhea, neutropenia, and neurotoxicity

  29. Thymidylate synthase (TS) Watters JW, McLeod HL. Biochimica et Biophysica Acta 2003 1603; 99–111

  30. Thymidylate synthase (TS) • 5’-promotor enhancer region (TSER) gene

  31. Methylenetetrahydrofolate Reductase (MTHFR) • Mechanism of action in relation to fluoropyrimidines and antifolates • Antifolates • Methotrexate and pemetrexed • Fluoropyrimidines • 5-fluorouracil

  32. Methylenetetrahydrofolate Reductase (MTHFR) • C677T and A1298C • Caucasian and Asian Population • Possible increase susceptibility • 5-FU increased activity • Other implications • Further study mandated • Folate status and geographic origin Dezemtje VO, Guchelaar HJ, et al. Annu Rev Clin Cancer Res 2009;15:15-21.

  33. Thymidylate synthase (TS) • Patient population • 76 patients initiated on 5-FU therapy • TS, DPD, and MTHFR analyzed • Patient Genetic Characteristics • TS 2R/2R – 18%; 2R/3R – 50%; 3R/3R - 30% • MTHFR polymorphisms evenly spread • DPD deficiency in 1.6% Capitain O et al. Pharmacogenomics J 2008;6:256-67.

  34. 5-FU, Genetics, and Outcome • Advanced colorectal cancer patients • Receiving 5-FU (n = 76) • Efficacy • TS 3R/3R genotype (log-rank test p = 0.0065) • Toxicity • DPD (p = 0.031) • MTHFR 1298 A > T (p = 0.0018) Capitain O et al. Pharmacogenomics J 2008;6:256-67.

  35. 5-Fluorouracil (5FU) • Summary • Patients with verified homozygous DPD deficiency should be changed to another treatment regimen • Patients with DPD deficiency develop significantly earlier than patients with normal DPD activity • Increased TS activity linked to poor outcomes in patients treated with 5-FU and its derivatives

  36. “Should RS, a patient with homozygous DPD deficiency be treated with 5-fluorouracil?

  37. Tamoxifen Pharmacogenetics Marsh S and McLeod HL. Expert Opin. Pharmacother. 2007;8:119-27.

  38. CYP 2D6 polymorphism • Mechanism of Action Dezemtje VO, Guchelaar HJ, et al. Annu Rev Clin Cancer Res. 2009;15:15-21.

  39. CYP 2D6 polymorphism • Patient enzyme activity identified by probe • Patients separated in to four groups • Poor, intermediate, extensive, or ultra-rapid metabolizers • Higher rates of recurrence in poor metabolizers Dezemtje VO, Guchelaar HJ, et al. Annu Rev Clin Cancer Res. 2009;15:15-21.

  40. CYP 2D6 polymorphism • Summary • Majority of studies conducted failed to account for tumor grade and prognostic factors • Only one of the major studies accounts for the use of other CYP2D6 inhibitors • Recent studies showing some “negative data” published • AmpliChip CYP450 test is an FDA approved test

  41. Food and Drug Administration • Endocrinology and Metabolic Drugs FDA Advisory Committee • October 16th, 2006 • Package insert updated for tamoxifen “Increased risk of breast cancer recurrence in postmenopausal estrogen receptor positive patients who are CYP2D6 poor metabolizers”

  42. Epidermal Growth Factor Receptor (EGFR) • Small Molecule Inhibitors • Gefitinib and Erlotinib • Monoclonal Antibodies • Cetuximab and Panitumumab • EGFR prognostic or predictive

  43. Epidermal Growth Factor Receptor (EGFR) • Tyrosine Kinase Domain Mutations • Cluster around the ATP-binding sites • Exons 18, 19, and 21 • Most common mutations • L858RA (exon 21) • E19del Yong WO et al. Br J Pharmacol. 2006;62:35-46.

  44. Epidermal Growth Factor Receptor (EGFR) • Major focuses of new research • Somatic mutations tyrosine kinase domain • Erlotinib and Gefitinib • Development of skin rash • Transcriptional activity and expression of EGFR Yong WO et al. Br J Pharmacol. 2006;62:35-46.

  45. Epidermal Growth Factor Receptor (EGFR) • Gefitinib • ISEL • Efficacy associated with nationality • Japanese vs. Caucasian • High gene copy number • Erlotinib • BR.21 • Gene status had no significant contributions to activity

  46. Epidermal Growth Factor Receptor (EGFR) • Patient population • Prospective clinical study • NSCLC, Head and neck CA, and Ovarian CA • Erlotinib • Pharmacokinetics, toxicity, and polymorphic changes • ABCG2 levels Rudin CM et al. J Clin Oncol 2008;26:1119-27.

  47. Phase II studies using EGFR TKIs in EGFR mutation (+) patients Heist RS et al. Pharmacogenomics. 2009;10:59-68.

  48. Kristen-rat Sarcoma (K-Ras) Gene • Mechanism of Action Khambata-Ford S et al. J Clin Oncol. 2007;25:3230-7.

  49. K-Ras • K-Ras mutation • Codon 12 or 13 mutations • G-protein coupled receptor signaling • Cell proliferation and survival • Adenocarcinomas in North America • Progression free survival and overall survival implications?

  50. K-Ras Testing and Economic Implications • Annual incidence of 29,762 mCRC cases • Cetuximab Cost $4,032 loading dose, $2,880/weekly • $753 million annually • K-Ras testing • PCR-based = $452/patient • $13 million annually • Theoretical cost savings of $740 million Shankaran V et al. ASCO GI Cancer Symposium. 2009; abstract 298.

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