Pharmacogenomics Data Pharmacogenomics Data Management and Management and Application In Drug Application In Drug Development Development Chuanbo Xu Senior Director, Bioinformatics San Antonio, TX. 13 January 2003 HL7/CDISC Work Group Conference - 200
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Pharmacogenomics Data Management and Application In Drug Development Chuanbo Xu Senior Director, Bioinformatics San Antonio, TX. 13 January 2003 HL7/CDISC.
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Pharmacogenomics Data Pharmacogenomics Data Management and Application Management and Application In Drug DevelopmentIn Drug Development
Chuanbo Xu
Senior Director, Bioinformatics
San Antonio, TX. 13 January 2003
HL7/CDISC Work Group Conference - 2003
Drug DevelopmentDrug Development
FutureTargeted Discovery, Predictive Medicine
Beyond Pharmacodynamics and Beyond Pharmacodynamics and PharmacokineticsPharmacokinetics
Drivers for Personalized MedicineDrivers for Personalized Medicine
“… We believe that the central issue is not whether PGt- or PGx-guidedDrug prescriptions will happen, but when and how.”
What Is PGt/PGx?What Is PGt/PGx?
Pharmacogenetics (PGt) studies the genetics basis of therapeutics and the individual reactions resulted from genotypes; originally, it studies the effect exerted on drug ADMET (absorption, distribution, metabolism, excretion, & toxicity) process by the human cytochrome family proteins.
Pharmacogenomics (PGx) is the extension and enhancement of the PGt studies in the molecular sequence context of the individual genetic structures of the whole genome.
What Constitutes PGx Data?What Constitutes PGx Data?
Key Components:
1. Gene, genomic structure (primary sequence and higher level organization) of the genes, subject DNA, protein, variation (SNP, INDELs, Haplotpyes, etc.), genotypes, gene expression profiling
Population Sample Constituted Using the Population Sample Constituted Using the Definitions of the U.S. Census BureauDefinitions of the U.S. Census Bureau
•Polyphred analysis
Sequencing data confirmed in both directions
Electronic trace analysisPhred Score >30
High-Throughput Quality Control of SNPs: High-Throughput Quality Control of SNPs: I. ElectronicI. Electronic
High-Throughput Quality Control of SNPs: High-Throughput Quality Control of SNPs: I. ElectronicI. Electronic
Hardy-Weinberg Equilibrium•Distribution frequency of heterozygotes:
must conform to frequency of individual alleles in ethnic group
•Example of frequencies: if 5% for an allele, then 10% heterozygotes and no homozygotes
Mendelian Inheritance •Polymorphisms are confirmed in the
reference families
Problems Picked Up:•Fixed heterozygosity /co-amplification•Allele drop-out /primer sits on SNP
p2 +2pq+q2=1
High-Throughput Quality Control of SNPs: High-Throughput Quality Control of SNPs: II. GeneticII. Genetic
•Collect blood samples (affects no. of genes & protocol)
•Genotyping ($$$)
•Statistical analysis (depends on all above)
•Validation
STRENGTHSTRENGTH((StStatin atin RResponse esponse EExamixaminned by ed by GGeneenettic ic HHAPAP™ Markers)™ Markers)
Prospective, multicenter, open-label Age 18 to 75 Type IIa or IIb hypercholesterolemia Patients failed 6-week AHA Step I/II diet 4 week washout prior anti-hyperlipidemic
medications
~150 patients per each drug specific arm
pravastatin simvastatin atorvastatin
STRENGTH Genes and Clinical EndpointsSTRENGTH Genes and Clinical Endpoints