NUSCTX 11, Final - UC Berkeley questions and answers

Preclinical Development 6-7 years of preclinical testing Manufacturer completes synthesis and purification of the drug and conducts animal testing Of 5000 compounds tested, ~5 will appear promising enough for a company to file an Investigational New Drug Application If the IND is approved, then the company can begin Phase I clinical trials Essential Pharmaceutics Structural characterization Impurity identification Solubility assessment Prototype formulation Stability testing Screening Efficacy In vitro models In vivo models Other Early ADME In silico profiling Develop simple analytical method Measure membrane permeability Plasma stability Early toxicology Off target screen In vitro cytotoxicity Preliminary AMES hERG binding ADME/PK Test materials with respect to absorption, distribution, metabolism, and excretion (ADME) Duration: hours to days Animals required: 2 species Safety Pharmacology To investigate any toxicity-use single dose with 2 species and test cardiovascular, respiratory, CNS effects Acute Toxicity Determine Maximum Tolerated Dose (MTD) and No Observable Effect Level (NOAEL) 14 days after single dose in 2 species Look at mortality, clinical pathology, necropsy, weight change, clinical observations Sub Acute Toxicity 14-28 days of repeated dosing in 2 species All of the above parameters and toxicokinetics, immunotoxicity Subchronic/Chronic Toxicity 30 days to 2 years in 2 species Carcinogenicity Testing tumorigenic potential in animals Duration: 12 months+ in mose or rate Test for tumor development, pathology Other Tests Genotoxicity Reproductive toxicity On-Target Toxicity Toxic effect due to the drug interacting with the intended therapeutic target Off-Target Toxicity Toxic effect due to the drug interacting with an unintended biological target or unintended tissue Idiosyncratic Drug Reactions Drug reactions that occur rarely and unpedictably Idiopathic Drug Reactions Cause unknown On- and Off-Target Toxicities Nearly 2 million patients in the US are affected by adverse drug reactions Results in approximately 100,000 fatalities, making adverse drug reactions the fourth leading cause of death in the US, not far behind cancer and heart disease Increase in safety requirements by the FDA have led to decreasing number of drug approvals and an increase in late drug discovery stage attrition rate Non-Steroidal Anti-Inflammatory Drugs All inhibit cyclooxygenases type 1 and 2 (COX1 and COX2) and reduce pro-inflammatory eicosanoids such as prostaglandins, prostacyclins, and thromboxanes. Nonselective COX1/COX2 inhibitors increase risk of gastrointestinal bleeding, because prostaglandins help to maintain the gut mucosal protective barrier (due to COX1 inhibition) Rosiglitazone Prescribed as an insulin sensitizer for diabetics by binding to PPAR receptors in fat cells Found to increase risk of heart attacks Caused on-target edema which can put people at risk for congestive heart failure-has been proposed to occur through reduced renal excretion of sodium and increase in sodium and water retention Rofecoxib (Vioxx) COX2-selective inhibitor with very little gastrointestinal side-effects Was found to be responsible for increased risk of heart attack and stroke