Pharmacogenetics & Pharmacogenomics Personalized Medicine

Drugs and Genes Pharmacogenetics: –Study of the genetic factors that influence an organism's reaction to a drug Pharmacogenomics: –Development of drug therapies to compensate for genetic differences in patients

Genotype: –The genetic makeup of an organism Phenotype: – An organisms’ observable traits Review of Genes

Human Genome is Variable

Contains 3x10 9 base pairs of DNA –3 billion! Between 2 people (except identical twins) the rate of genetic variation (individuality) is about 0.1% [0.1% of 3 billion = 3 million base pair differences]

The most common cause of genetic variation SNPs occur on average every 1000 bases Understanding SNPs has shown promise for improving disease detection and treatments Single Nucleotide Polymorphism Polymorphism “Poly” Many “Morphe” Form General Population 94% Single Nucleotide Polymorphism 6%

Examples of SNPs and Disease SNPs in Beta-globin Sickle Cell Anemia SNPs in BRCA1 Predisposed for breast cancer

Protein Single Nucleotide Polymorphisms Regulatory SequenceCoding Region Coding SNP: changes amino acid sequence (function) Outside gene Linked SNPs Non-coding SNP: changes amount of protein Causative SNPs

SNPs Can Change Drug Response Pharmacokinetic: changes in drug metabolism Pharmacodynamic: changes in drug targets –enzymes, receptors, or transporters Genetic Polymorphisms Pharmacokinetic AbsorptionDistributionMetabolismExcretion Pharmacodynamic ReceptorsIon ChannelsEnzymesImmune System

SNPs and CYPs Cytochrome P450 enzymes are commonly found with SNPs

Drug Metabolism PolymorphismSubstrate CYP2B6 doxorubicin, nicotine CYP2C9 warfarin, doxorubicin CYP2C19 diazepam, proton pump inhibitors CYP2D6 beta-blockers, anti-depressants, codeine, tamoxifen CYP3A4 erythromycin, HIV protease inhibitors

Effects of SNP in CYP2D6 1: Normal enzyme activity 2: Decreased enzyme activity Extensive Metabolizer Plasma Level of Drug Time Poor Metabolizer

Pharmacokinetics of Tamoxifen

Mutations Impact Treatment Outcome No Polymorphisms on CYP2D6 Polymorphisms on CYP2D6 Clin Pharmacol Ther January; 83(1): 160–166. Extensive n=115 Decreased n=65 Relapse-free Survival (%) P=0.007

Metabolism of Alcohol… 2 Steps

Genetic Polymorphisms and Differences in Alcohol Metabolism

ADH Polymorphism Metabolism Rate Populations with High Prevalence ADH1B*1Slow Most populations, including most Caucasians, Mexican Americans, and Native Americans Heavy drinkers ADH1B*2Fast Most Asians, 25% of Jews, and some Hispanics ADH1B*3Fast African-Americans and 6% of Mission Indians (S. West California) Genetic Polymorphisms and Differences in Alcohol Metabolism

23andMe

Better Drug Discovery with Pharmacogenetics & Pharmacogenomics Increase drug efficacy Eliminate adverse drug reactions Ensure success for drug approval in clinical trials Increase efficiency of clinical trials

Drug Treatment Available Drugs Drug 1 Drug 2 Drug 3 Drug 4 No response Adverse side effect Weak response Strong response Currently best treatment determined by trial and error. Future genomics may enable us to pick the right drug the first time.

Yesterday’s Medicine

Tomorrow’s Medicine

Personalized Medicine The right dose of the right drug for the right indication for the right patient at the right time.

Personalized Medicine: Cancer Many factors contribute to tumor formation.

Breast Cancer is a Perfect Model

Pharmacogenomics: Gene Candidate to Drug Treatment Human epidermal growth factor receptor-2 (HER2) in breast cancer cells

Herceptin in Clinical Trials

Cancer Results from a Combination of Genomic Changes

Drug Discovery

The Clinical Trial Process Safe in humans? Does the treatment work? Better than current treatment? More info on the approved treatment File NDAFile IND

Less than 1 in 10 Drugs in Clinical Trials Obtain a NDA In a study of 14 clinical trials, 20-75% of subjects got no benefit

Streamlining of Clinical Trials is the Future

Pharmacogenetics and Pharmacogenomics Summary 1.SNPs in coding and non-coding regions can alter the function or expression of an enzyme that metabolizes drugs 2.Pharmacogenetics impacts the kinetics and dynamics of drugs. 3.Personalized medicine will help treat patients according to their genetic profile, increase drug efficacy, and reduce side effects 4.Designing clinical trials based on SNP profiles can reduce FDA approval time for drugs

Concept Map Pharmacogenomics Pharmacodynamics Pharmacokinetics Gene SNPs Haplotype Phenotype Genotype CYPs Drug