WITHDRAWN AND BBW DRUGS

safety studies required before use in humans of an investigational new drug (IND)

• safety pharmacology (e.g. vital organ fxn)

• ADME

• single dose in 2 mammalian species

• repeated dose toxicity

• genotoxicity

• immunotox

phase IV of clinical development

drug on the market → ADRs?

• if yes, monitor freq, severity, and balance w/ effectiveness

  • if cost>benefit = withdraw

  • if benefit > cost = BBW

major tox types assoc w/ drug withdrawals

• CV

• hepatic

• hematological

importance of dose

• no problems w/ lower doses, as dose increases risk increases

• once you get to a very high dose this is where drug starts to bind to off target things = more ADRs

• every drug is toxic if the dose is high enough***

black box warning drugs (BBW)

• drugs that we need to fulfil a certain therapy, but come at some acceptable risk

• e.g. clozapine

  • AP used for tx-resistant schiz

  • major risk: agranulocytosis

  • creates lots of reactive metabolites

  • must be enrolled in monitoring registry specific to manufacturer of brand being dispensed; must monitor WBC count weekly for ~18wks

reactive metabolites

• can be good:

  • enzyme inhibitors

  • compounds containing “covalent warheads’ or targeted covalent inhibitors

  • there are ~100 compounds in this category

  • e.g. ASA - enzyme inhibitor → takes enzyme and kills it

can we reduce BBW toxicity/risk?

• combo therapy (research needed)

• screening for human leukocyte Ag genotype

  • Review and Consensus Pharmacogenomic Testing in Psychiatry - review recommends using PGx for care during therapy and hope to get to screening

• ML/AI tools