Pharmacogenomics: Pharmacogenomics: Clinical Application Clinical Application and Effects on Drug and Effects on Drug Metabolism Metabolism Rodney J. Hunter, Pharm.D. Rodney J. Hunter, Pharm.D. Assistant Professor Assistant Professor Texas Southern University College of Pharmacy and Texas Southern University College of Pharmacy and Health Sciences Health Sciences SNPhA Regional Conference District III, IV, & V SNPhA Regional Conference District III, IV, & V February 19 February 19 th th , 2011 , 2011
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Pharmacogenomics: Clinical Application and Effects on Drug Metabolism Rodney J. Hunter, Pharm.D. Assistant Professor Texas Southern University College.
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Pharmacogenomics: Pharmacogenomics: Clinical Application and Clinical Application and
Effects on Drug Effects on Drug
MetabolismMetabolism Rodney J. Hunter, Pharm.D.Rodney J. Hunter, Pharm.D.
Assistant ProfessorAssistant ProfessorTexas Southern University College of Pharmacy and Texas Southern University College of Pharmacy and
Health SciencesHealth SciencesSNPhA Regional Conference District III, IV, & VSNPhA Regional Conference District III, IV, & V
February 19February 19thth, 2011, 2011
Financial DisclosureFinancial Disclosure
I have no conflicts of interest in I have no conflicts of interest in regards to this program regards to this program
“Why genetic polymorphisms? Why pharmacogenomics and oncology? Why so much excitement in this field?”
ObjectivesObjectives
Describe pharmacogenomics and the clinical Describe pharmacogenomics and the clinical relevance of this field of study in relation to relevance of this field of study in relation to oncologyoncology
Outline the drug metabolism pathways Outline the drug metabolism pathways affected by pharmacogenomic abnormalities affected by pharmacogenomic abnormalities in the oncology patient populationin the oncology patient population
Identify the different drug classes and Identify the different drug classes and significant adverse drug effects associated significant adverse drug effects associated with pharmacogenomic changes in the with pharmacogenomic changes in the oncology patient populationoncology patient population
Human Genome ProjectHuman Genome Project
Begun in 1990 with an expected Begun in 1990 with an expected completion date of 2005, it was completion date of 2005, it was completed in 2003 due to advances in completed in 2003 due to advances in technologytechnology
Set out to map the 20,000-25,000 Set out to map the 20,000-25,000 human geneshuman genes
3 billion DNA bases3 billion DNA bases
Introns and Exons
http://www.emc.maricopa.edu
.
Genetic PolymorphismsGenetic Polymorphisms
Single Nucleotide Polymorphism Single Nucleotide Polymorphism (SNPs)(SNPs) 1/1000 base pairs 1/1000 base pairs
Types of SNPsTypes of SNPs Insertion-DeletionInsertion-Deletion Tandem repeatsTandem repeats Frameshift mutationFrameshift mutation Defective splicingDefective splicing Aberrant splice siteAberrant splice site Premature stop codonPremature stop codon
Dipiro JT, Talbert RL, et al. Pharmacotherapy 7th ed. 2008;6:31-45.
Rationale for Rationale for PharmacogenomicsPharmacogenomics
Meta-analysis estimated ~2 Meta-analysis estimated ~2 million ADR/yr in the USmillion ADR/yr in the US
ADR accounting for 100,000 ADR accounting for 100,000 deathsdeaths
Cost in 2000 ~$177.4 billionCost in 2000 ~$177.4 billion
Lazarou, J et al JAMA. 1998;279:1200-05.
Goals of Goals of PharmacogenomicsPharmacogenomics
Prevent and predict adverse drug Prevent and predict adverse drug reactionsreactions
Optimize drug therapyOptimize drug therapy
Lead to novel approaches to drug Lead to novel approaches to drug discoverydiscovery
Goals of Goals of PharmacogenomicsPharmacogenomics
Evans WE and Johnson JA. Annu Rev Genomics Hum Genet. 2001;2:9-39.
Other Pharmacogenomic Other Pharmacogenomic ImplicationsImplications
Evans, WE and McLeod HL. N Engl J Med. 2003;6:538-49.
Pharmacogenomics in Pharmacogenomics in OncologyOncology
Drug effectsDrug effects Drug metabolismDrug metabolism Drug TargetsDrug Targets Drug Transporters Drug Transporters
Somatic mutations in malignant tissueSomatic mutations in malignant tissue
Narrow therapeutic indexNarrow therapeutic index
Metabolism and GeneticsMetabolism and Genetics
Evans, WE and McLeod HL. N Engl J Med. 2003;6:538-49.
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
Efficacy and GeneticsEfficacy and Genetics
Evans, WE and McLeod HL. N Engl J Med. 2003;6:538-49.
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
Polygenic Drug ResponsePolygenic Drug Response
Evans, WE and McLeod HL. N Engl J Med. 2003;6:538-49.
Evans WE, Hon YY, et al. J Clin Oncol. 2001;2293-301.
90%
SummarySummary A dosage reduction of A dosage reduction of 90%90% has benefited has benefited
patients with homozygous TPMT patients with homozygous TPMT deficiencydeficiency
Homozygous TPMT deficient patients Homozygous TPMT deficient patients have a high incidence of hematopoetic have a high incidence of hematopoetic toxicity induced by thiopurinestoxicity induced by thiopurines
Heterozygous patients can tolerate full Heterozygous patients can tolerate full doses in most casesdoses in most cases
C677T and A1298CC677T and A1298C Caucasian and Asian PopulationCaucasian and Asian Population Possible increase susceptibilityPossible increase susceptibility 5-FU increased activity5-FU increased activity Other implicationsOther implications
Further study mandatedFurther study mandated Folate status and geographic originFolate status and geographic origin
Dezemtje VO, Guchelaar HJ, et al. Annu Rev Clin Cancer Res 2009;15:15-21.
Patient populationPatient population 76 patients initiated on 5-FU therapy76 patients initiated on 5-FU therapy TS, DPD, and MTHFR analyzedTS, DPD, and MTHFR analyzed
30%30% MTHFR polymorphisms evenly spreadMTHFR polymorphisms evenly spread DPD deficiency in DPD deficiency in 1.6%1.6%
Capitain O et al. Pharmacogenomics J 2008;6:256-67.
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.
SummarySummary Patients with verified homozygous Patients with verified homozygous DPD DPD
deficiencydeficiency should be changed to another should be changed to another treatment regimentreatment regimen
Patients with DPD deficiency develop Patients with DPD deficiency develop significantly earlier than patients with normal significantly earlier than patients with normal DPD activityDPD activity
Increased TS activity linked to poor outcomes Increased TS activity linked to poor outcomes in patients treated with 5-FU and its derivativesin patients treated with 5-FU and its derivatives
5-Fluorouracil (5FU)5-Fluorouracil (5FU)
“Should RS, a patient with homozygous DPD deficiency be treated with 5-fluorouracil?
Marsh S and McLeod HL. Expert Opin. Pharmacother. 2007;8:119-27.
CYP 2D6 polymorphismCYP 2D6 polymorphism
Mechanism of ActionMechanism of Action
Dezemtje VO, Guchelaar HJ, et al. Annu Rev Clin Cancer Res. 2009;15:15-21.
CYP 2D6 polymorphismCYP 2D6 polymorphism
Patient enzyme activity identified by Patient enzyme activity identified by probeprobe
Patients separated in to four groupsPatients separated in to four groups Poor, intermediate, extensive, or ultra-Poor, intermediate, extensive, or ultra-
rapid metabolizersrapid metabolizers
Higher rates of recurrence in poor Higher rates of recurrence in poor metabolizersmetabolizers
Dezemtje VO, Guchelaar HJ, et al. Annu Rev Clin Cancer Res. 2009;15:15-21.
SummarySummary Majority of studies conducted failed to account Majority of studies conducted failed to account
for tumor grade and prognostic factorsfor tumor grade and prognostic factors
Only one of the major studies accounts for the Only one of the major studies accounts for the use of other CYP2D6 inhibitorsuse of other CYP2D6 inhibitors
Recent studies showing some “negative data” Recent studies showing some “negative data” publishedpublished
AmpliChip CYP450 test is an FDA approved testAmpliChip CYP450 test is an FDA approved test
CYP 2D6 polymorphismCYP 2D6 polymorphism
Food and Drug Food and Drug Administration Administration
Endocrinology and Metabolic Drugs FDA Endocrinology and Metabolic Drugs FDA Advisory Committee Advisory Committee
October 16October 16thth, 2006, 2006
Package insert updated for tamoxifenPackage insert updated for tamoxifen
““Increased risk of breast cancer recurrence Increased risk of breast cancer recurrence in postmenopausal estrogen receptor positive in postmenopausal estrogen receptor positive patients who are CYP2D6 poor metabolizers”patients who are CYP2D6 poor metabolizers”
Patients can benefit from Patients can benefit from preemptive testingpreemptive testing ASCO & NCCN endorsement for ASCO & NCCN endorsement for K-RasK-Ras testing testing
K-RasK-Ras Testing and Testing and Economic ImplicationsEconomic Implications
BRAF and K-RasBRAF and K-Ras
Nicolantonio FD et al. J Clin Oncol 26:5705-5712
Study Conclusions Demonstrated a 30% frequency of the K-
Ras mutation in the patients analyzed
The BRAF V600E is has negative implications on EGFR monoclonal antibody therapy, progression free survival, and overall survival
Sorafenib restored sensitivity to the EGFR monoclonal antibody therapies
BRAF BRAF and and K-RasK-Ras
“So what exactly do we want to take away from the information presented this morning?”
ConclusionsConclusions
Pharmacogenomic sampling Pharmacogenomic sampling continues to be focus of researchcontinues to be focus of research TPMT, UGT1A1, DPD, TS, TPMT, UGT1A1, DPD, TS, K-RasK-Ras, and , and
most recently most recently BRAF BRAF impact drug impact drug efficacy and toxicityefficacy and toxicity
Drug dosing guidelines based upon Drug dosing guidelines based upon pharmacogenetics will continue to pharmacogenetics will continue to emergeemerge
Pharmacogenomics: Pharmacogenomics: Clinical Application and Clinical Application and
Effects on Drug Effects on Drug
MetabolismMetabolism Rodney J. Hunter, Pharm.D.Rodney J. Hunter, Pharm.D.
Assistant ProfessorAssistant ProfessorTexas Southern University College of Pharmacy and Texas Southern University College of Pharmacy and
Health SciencesHealth SciencesSNPhA Regional Conference District III, IV, & VSNPhA Regional Conference District III, IV, & V