Pharmacology 4350A/B Study Guide - Panitumumab, Cetuximab, Cyp2B6

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Craig Venter diploid genome 2007
James Watson 2008
First human genome sequence completed in 2003
3 billion bases
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25,000 protein coding genes
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0.4% difference in DNA between individuals
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Polymorphism - DNA variation of a gene
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Allele - specific sequence variation of a gene
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Haplotype - chromosomal region which groups of alleles are more frequently inherited together
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Genetic variants on pharmacokinetic effects
Warfarin metabolized by CYP2C9 (genetic testing)
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Azathioprine -> 6-MP -> 6-TG
TPMT deficiency = hematopoietic toxicity
90% TPMT*1 = WT: 1/300 TPMT*3 = low enzyme activity
Genetic testing before dosing
Thiopurines (Treat leukemia + inflammatory bowel + organ transplant)
Irinotecan --> SN-38 (active) ---> SN-38G (inactive)
*28 is frequent in europeans + *6 is frequent in asians
UGT1A1*1 (normal) + UGT1A1*28 (AA change in TATA box) + UGT1A1*6
UGT1A1 deficiency = severe diarrhea + neutropenia
UGT 1A1 (UDP-glucuronosyltransferase)
Phase 2
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Genetic effects on pharmacodynamic
Overexpression = head/neck cancer
Deletion = brain cancer
Kinase domain mutation = lung cancer
EGFR (ERBB1)
Overexpression = breast cancer
Kinase domain mutation = lung cancer
HER2 (ERBB2)
RTK - proliferation + inhibit apoptosis + angiogenesis
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Monoclonal AB (trastuzumab + cetuximab) blocks receptor dimerization
Increase response to getfitinib in lung cancer patients with EGFR mutation/amplification
(lesser)
Getfitinib - increase response to getfitinib in lung cancer patients with kinase-domain mutation
ATP mimetics small molecules (getfitinib + erlotinib + lapatinib) blocks nucleotide binding
RTK inhibitors
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Genetic variant on toxicity effects
MHC chromosome 6 with 220 genes
Very polymorphic affecting MHC binding to antigen + T cell recognizing MHC
MHC molecules bind to antigen's cell surface peptide and is recognized by T cells
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Fever + rash + internal organ involvement
Reversible if drug stopped within 3 days
HLA-B*5701 + HLA-DR7 + HLA-DQ3 linked with hypersensitivity syndrome (delayed immune response)
Abacavir (HIV reverse-transcriptase inhibitor) (anti-viral)
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UGT - most common phase
2 enzyme
Best prediction of thyrosine inhibitor response in kinase -domain
Screen clipping taken: 22/04/2012, 3:10 PM
Lecture - Pharmacogenetics
April-22-12
2:07 PM
clinical pharm Page 1
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