New drug development
Chemical modification of known active
- Usually begins w/
o Discovery or synthesis of potential new
drug
o Elucidation of a new drug target
- Synthesized or extracted from a natural source
- Understanding drug’s interactions w/ biologic
targets
- Repeated application leads to related
compounds w/ increased safety, potency, and
selectivity
- In vivo studies in animals before human drug
trials
o Relevant biologic effects
o Drug metabolism
o Pharmacokinetic profiles
o Relative safety of the drug
- Human testing for regulatory approval and
approval for general use – 3 phases
- 4th phase – data gathering and safety monitoring
- Highly toxic drugs are nevertheless valuable in
lethal diseases and approved for restricted use
- In vitro studies
o Biologic compounds; chemical
synthesis, optimization  Lead
compound
o 2 years
- Animal testing (preclinical)
o Efficacy, safety, mechanism
o 2 years
o Apply for Investigational New Drug
(IND)
- Clinical testing
o Drug metabolism, safety assessment
o Phase 1-3
o 4-6 years
o Apply for New Drug Application (NDA)
- Marketing
o Phase 4 – postmarketing surveillance
o 11 years (year 20)
o Patent expires 20 years after filing of
application
 Generics become available
Drug discovery
- Most new drugs/drug product discovered or
developed in the ff approaches
1. Screening for biologic activity of
 Large no. of natural products
 Banks of previously discovered
chemical entities
 Large libraries of peptides,
nucleic acids, and other organic
molecules
2.
molecule  “me-too” analog
3. Identification/elucidation of a new drug
target
4. Rational design of new molecule based
on biologic mechanisms and receptor
structure
Drug screening
- Assays to define pharmacologic profile – activity
and selectivity
- Type and number of screening depends on
pharmacologic & therapeutic goal
- Eg, anti-infective drug
o Tested against infectious organisms
- Hypoglycemic drugs
o Tested for ability to lower blood sugar
- Mechanism of action and selectivity of the drug
- Reveal expected and unexpected toxic effects
- Compound optimization
o Further chemical modification to achieve
more desirable pharmacokinetic or
pharmacodynamic properties
- Lead compound
o Desired result after screening
procedures, ie, leading candidate for a
successful new drug
Preclinical Safety and Toxicity Testing
- Candidate drugs that survived initial screening
(lead compound)
o Evaluated for potential risks before and
during clinical test
- No chemical is certified completely “safe”
- Only estimate the risk associated with exposure
to the drug candidate
- Goals of preclinical toxicity studies: identify
potential hu man toxicities, define toxic
mechanisms, predict most relevant toxicity to be
monitored
- Safety tests:
o Acute toxicity test
 Determines no-effect dose –
max dose that has no toxic
effect
 Maximum tolerated dose
 Median lethal dose (LD50) –
dose that kills approx. half of
animals
o Subacute/subchronic
 2 wks – 3 mos before clinical
trial
 Determines biochemical,
physiologic effects
PHBS 2A (Pharmacology I & Therapeutics)
Tecson, 2018
 o Chronic
 When drug is to be used in
humans for prolonged periods 3. Subject and observer bias and other factors
 Run with clinical trials o Placebo response
 Same as subacute  Positive responses as many as
o Effects on reproductive performance 30-40%
(Test for capability to induce congenital o Subject bias
diseases)  Quantitated and minimized by
 Animal mating behavior, single-blind design
reproduction, parturition, o Observer bias
progeny, birth defects, postnatal  Minimized by double-blind
dev’t design
o Carcinogenic potential (test for o Compliance/adherence
carcinogenicity)  Necessary element to consider
 When drug is to be used in Clinical trials
humans for prolonged period
 Determine gross and histologic - Phase 1
pathology o Safety; pharmacokinetics (absorption,
o Mutagenic potential (test for half-life, metabolism)
mutagenicity) o 20-100 subjects – healthy volunteers
 Effects on genetic stability and o In research centers
mutations on bacteria or - Phase 2
mammalian cells o Efficacy (proof of concept)
 Dominant lethal test o Dose
 Clastogenicity in mice o Single-blind
- Sulfanilamide  death (Federal Food, Drug, and o 100-200 patients
Cosmetic Act of 1938) o In special clinical centers, eg, university
- Thalidomide  phocomelia (Kefauver-Harris hospitals
Amendment of 1962) - Phase 3
- Hormone replacement therapy  breast cancer o Double-blind; crossover technique
- Celecoxib  heart problems o Minimize errors caused by placebo
o 1 000-6 000 patients
Evaluation in Humans - New Drug Application (NDA)
- Less than 1/3 survive clinical trials - Biologic License Application (BLA)
- Confounding factors in clinical trials
1. Variable natural history of diseases
o Take into account the natural history by
evaluating a large enough pop’n
o Crossover design
 Alternating periods of
administration of test drug,
placebo, and standard treatment
 Protects against errors in
interpretation caused by disease
fluctuations
2. Presence of other diseases
o May alter pharmacokinetics
o Avoided by crossover technique and
proper selection and assignment of pt to
each study group

PHBS 2A (Pharmacology I & Therapeutics)

Tecson, 2018