Challenges to drug design

Did you know? Over 2 million people are hospitalized each year for adverse reactions to prescription drugs. Over 2 million people are hospitalized each year for adverse reactions to prescription drugs. Every year more than 100,000 people die from those reactions, making it the sixth leading cause of death! Every year more than 100,000 people die from those reactions, making it the sixth leading cause of death!

Pharmacogenomics Will allow: individualized medication use based on genetically determined variation in effects and side effects individualized medication use based on genetically determined variation in effects and side effects use of medications otherwise rejected because of side effects use of medications otherwise rejected because of side effects More accurate methods of determining appropriate dosage More accurate methods of determining appropriate dosage

Variations in drug response are hereditary Variations in drug metabolism Variations in drug metabolism Variations in drug inactivation and/or elimination Variations in drug inactivation and/or elimination Variations in target receptors Variations in target receptors

Some drugs are pro-drugs that need to be converted into their active form enzyme Pro drug drug

Some drugs are inactivated by enzymes, in order for them to be eliminated from the body drug enzyme

Some drugs act through binding to receptors Receptor Drug

Variations in drug metabolism can be caused by mutations: If the activating enzyme is non-functional, the prodrug accumulates as a prodrug If the inactivating enzyme is non-functional, the drug stays in the system too long and may be toxic If the receptor has an altered shape, the drug cannot bind and therefore does not work

EX) G-6PD Deficiency and Anti- malaria drug treatments The most common human enzyme deficiency The most common human enzyme deficiency X-linked inheritance X-linked inheritance Most common among African American men (also Mediterraneans) Most common among African American men (also Mediterraneans) Exposure to certain drugs, chemicals and foods can induce hemolytic anemia Exposure to certain drugs, chemicals and foods can induce hemolytic anemia First seen among AA soldiers in Africa who were treated for malaria First seen among AA soldiers in Africa who were treated for malaria

glucose-6-phosphate dehydrogenase deficiency Glucose-6-phosphate dehydrogenase causes red blood cells to break down prematurely. Red blood cells are destroyed faster than the body can replace them.

An estimated 400 million people worldwide have glucose-6- phosphate dehydrogenase deficiency. It affects 1 in 10 African-American males in the U.S. Hemolyzing RBCs

EX) Warfarin Discovered 60 years ago and one of the most widely prescribed drugs in the world anticoagulant Intended to prevent and treat thromboembolisms. – Formation in a blood vessel of a clot (thrombus) that breaks loose and is carried by the blood stream to plug another vessel. Significant increase in Rx’s over past 10 years especially in the elderly

Dosing of Warfarin is Complex Narrow therapeutic index Narrow therapeutic index – Small separation between dose-response curves for preventing emboli and excess coagulation Wide range (50x) of doses (2-112 mg/week) to achieve target INR of 2-3 Wide range (50x) of doses (2-112 mg/week) to achieve target INR of 2-3

DNA testing for Warfarin sensitivity The FDA Clinical Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical Sciences has recommended testing for variations in the CYP2C9 and VKORC1 genes in patients requiring warfarin therapy. Patients with CYP2C9 or VKORC1 variants may need lower doses of warfarin.

Mechanistic Basis of Dosing Large interindividual variability related to S-warfarin metabolism by CYP2C9 (genetics) – *1 (wild type), *2 and *3 (variant alleles) Genotype (N = 188) Prevalence % Enzyme Activity S/R Warfarin (mg/L) Weekly Doses (mg) Clearance/LB W (ml/min/kg) 2C9 *1/*1 63%100% 0.45 (0.11) 34.1 (19.5) (0.025) 2C9 *1/*X 31%50-70% 0.69 (0.28) 19.0 (10.8) (0.021) 2C9 *X/*X 6%10% 1.43 (0.63) 11.5 (7.2) (0.011) Herman et al, The Pharmacogenomics J 4:

Pharmacogenomics will most likely use “panels” of polymorphisms to calculate the relative risk–benefit ratio of a particular therapeutic course for an individual patient

SNPs Characterization of SNPs may help in identifying subsets of individuals at risk for specific diseases SNPs may predict drug responses/adverse reactions

“therapy with the right drug at the right dose in the right patient”