Lecture 4 Clinical Trials

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21 Apr 2012
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Lecture 4 PHC320 Clinical Trials: Pharmacokinetics, Pharmacodynamics, and Drug
metabolism
Considerations and potential biases in Lipinski’s rules
Pre/Post 1997
Criteria dependent on # of Lipinski rules considered
Post 1983, most small molecule screening libraries follow Lipinski’s rules
Drug metabolism
Body regards drugs as foreign substances, not produced naturally, “xenobiotics”.
Body has “goal” of removing such xenobiotics from system by excretion in the
urine.
The kidney is set up to allow polar substances to escape in the urine, so the body
tries to chemically transform drugs into more polar structures.
Phase 1 metabolism involves the conversion of nonpolar bonds (e.g. C-H bonds) to
more polar bonds (e.g. C-OH bonds)
A key enzyme is the cytochrome P450 system, which catalyzes this reaction (in the
liver): 75% of total metabolism
RH + O2 + 2H+ + 2e- ROH + H2O
Oxidation/reduction/hydrolysis most common mode of detoxification
e.g. steroids (hormones), antidepressants
Phase 2 metabolism (liver) links the drug to still more polar molecules to render
them easier to excrete
oConjugation reactions: methylation, sulphation, acetylation, glutathione
Secondary assays: preclinical ADME-PK
Adsorption and metabolismL solubility, stability, permeability
Caco-2 cells, derived from large intestine carcinoma
Other approaches
MDCK – kidney
BBB methods
Hepatocytes
Microsomes – mainly cytochrome P450s
In vivo testing (1-2 years): animal models
ADME-PK, mostly animal models, considerations:
Expense
Suffering
Don’t necessarily know target/mechanism
Result (may be) difficult to interpret
Works in an in vivo system
Submission to FDA: IND (investigational new drug)
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Permission to legally test drug on human subjects; based on pre-clinical data that
shows the drug is safe enough to be tested in humans.
Often, the “new” drugs that are submitted are not NMEs, but old medications that
have been modified.
Clinical pharmacology/toxicology
Chemical composition, stability, manufacturing, controls
IND investigator or sponsor initiated followed by approval IRB (institutional review board)
for clinical trials.
1. Patent NME
2. Use Patent (issue of gene patenting)
3. Target patent (must include more than target, assay, etc.)
4. IND from FDA
5. Clinical protocols: detailed protocols, safety, information on qualification of
clinical investigators.
Clinical trial
Biomedical or health-related research studies in human beings that follow a pre-defined
protocol
1. Interventional
2. Observational
Types of clinical trials
Treatment
Screening Diagnosis
Prevention
Supportive care
Quality of life/Fast track
Phases of clinical trials
Phase O
Phase I
Phase II
Phase III
Phase IV
Clinical Trials
Pre-clinical trials
oIn vitro studies and trials on animal populations.
oWide ranging doses of compounds used to obtain preliminary efficacy and
toxicity information to assist decisions regarding further development of the
test compound.
Phase O
oEstablishing whether agent behaves in healthy human subjects as
anticipated from preclinical studies. Involves subtherapeutic doses to a
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