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PHRX 3002: bioorganic chem > EXAM 4 - "Late Stage" Drug Development > Flashcards

EXAM 4 - "Late Stage" Drug Development Flashcards

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1
Q

Why is early stage ADMET screening important during “late stage” drug development?

A

We have to think about these factors to make sure we want to proceed with the compound as a drug.
* or design the drug based off what we find during ADMET screening

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2
Q

What are the different screens during early stage ADMET screening?

A

Absorption
* water solubility: LogP
* intestinal absorption: Caco-2 cell monolayer

Metabolism
* Stability to CYP45o metabolism
* in vivo metabolic stability
* major metabolites: active/inactive?

Toxicity
* general cytotoxicity studies: ATP measurement, MTS, enzyme release

Side-effects
* hERG potassium channel inhibition: arrhythmias
* drug-drug interactions (usually metabolism related)

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3
Q

List the different avenues of drug absorption.

A
  • Passive uptake (paracellular, transcellular)
  • active uptake (carrier-mediated)
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4
Q

Explain why P-gp is screened during drug development.

A

P-gp mediates efflux
* if the compound is a P-gp substrate –> it gets effluxed out of circulation
* We will have to design the drug around the fact that it is going to get effluxed by P-gp

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5
Q

How can we test to see if the drug is a P-gp substrate?

A

You can incubate the drug with a P-gp inhibitor substrate.
* if the drug is a P-gp substrate –> more drug will enter the basolateral chamber.

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6
Q

Explain what Caco-2 cells are.

A

Colon cancer cell line that contains all of the uptake and efflux mechanisms of drug absorption.

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7
Q

Explain the process of screening for intestinal absorption using Caco-2 cells.

A
  • Caco-2 cells are grown as a single layer
  • 2-chamber model –> (apical - small intestine) chamber inside another chamber (basolateral - blood)
  • Drug is added to the apical chamber
  • Amount of drug that is isolated in basolateral chamber gives idea of drug permeability
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8
Q

The liver is the major organ responsible for metabolism. What is the primary method to screen for metabolism of potential drugs?

A

The primary method is through use of microsomes - subcellular fraction of digested liver
* Consists of ER
* Phase 1 (CYP450 and FMO) enzymes only
* easier to use
* contain pooled fractions that have multiple microsomes from multiple people

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9
Q

What is the secondary method used to screen for drug metabolism?

A

Secondary method (used after microsomes) is use of hepatocytes - the majority of cells in the liver
* isolated from animal and used as intact cell
* contain entire range of metabolic enzymes (phase 1 and 2)
* harder to grow and use

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10
Q

Describe the method of testing drug metabolism using microsomes and hepatocytes.

A
  1. Add chemicals into 96-well plate.
  2. Add hepatocytes or microsomes.
  3. Incubate plate.
  4. Extract plate.
  5. LC-MS analysis.
  6. Quantification of parent compound disappearance
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11
Q

What does screening for CYP450 inhibition tell you about the drug?

A
  • Determines drug’s ability to inhibit/induce CYP450.
  • Drug’s effect on metabolism of other drugs (drug-drug interaction)
  • Drug’s effect on digestion of food (drug-food interaction)
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12
Q

How can we test to see if the potential drug inhibits/induces CYP450?

A
  • Add chemicals and hepatocytes to a chamber
  • add P450 substrate
  • quantify production of metabolites.
  • each P450 is tested to see which enzyme the drug inhibits/induces
    (If the drug is inhibiting CYP450 –> there will be slower production of metabolite)
    (If the drug is inducing CYP450 –> ther will be faster production of metabolite)
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13
Q
A

B) 30 mins, 15 mins
* inhibitor –> more time needed
* inducer –> less time needed

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14
Q

Describe how toxicity of a drug is quantified at ealy stages.

A

Hepatocytes - used as model system
* measured as hepatocyte viability in the presence of the drug
* if we give the drug to hepatocytes –> will they survive?

FIbroblasts - used as model of ‘normal’ cells
* connective tissue that is easy to grow
* if fibroblasts are able to grow –> not toxic

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15
Q

Explain what enzyme release tells us about cytotoxicity.

A

When cells get damaged –> loss of membrane integrity –> enzymes released from cell
* Kits can be purchased to quantify amount of enzyme activity.
* increased enzymatic activity = increased cell death

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16
Q

Side-effects: Explain effect of hERG channel inhibition.

A

hERG potassium channel is the major protein responsible for conducting K+ iond out of the heart muscle cells.
* When the hERG channel gets inhibited –> leads to arrythmias or death
* if a compound is a hERG inhibitor, it can be designed to not inhibit it

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17
Q

Can a compound be a good drug if it is a hERG channel inhibitor?

A

Yes. There are major drugs that are hERG inhibitors.
* fluoroquinolones - antibacterial
* terfenadine - antihistamine

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18
Q

Why do we test compound genotoxicity?

A

It tells us if the potential drug is mutagenic.
* single test sufficient for phase 1
* multiple tests required to progress to phase 2

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19
Q

How do we test for compound genotoxicity?

A

Cheap, fast, and reliable
* Tube 1: suspected mutagen is incubated with liver extract in culture of His- salmonella
* Tube 2: control (only liver extract) incubated in culture of His- salmonella
* If there is growth of His+ salmonella –> compound is a mutagen
* If there is no growth of His+ salmonella –> compund is not a mutagen

20
Q

What preclinical studies are needed in order for the FDA to approve for progression to clinical trials?

A
  • proof of prinicple in most appropriate animal model
  • acute and chronic toxicity studies
  • safety pharmacology (respiratory, CVS, CNS)
  • ADME
21
Q

Name the two in vivo toxicity assays.

A

Acute toxicity and chronic toxicity

22
Q

Explain the purpose for conducting in vivo toxicity assays.

A

Study the relationship between the drug exposure and animal models and provide reliable evidence to explain/predict potential toxicities for later clinical trials.

23
Q

Describe acute toxicity assays.

A

Method: one large dose or several large doses given over short period of time (2 weeks)
* dose is outside therapeutic window

Why?: to determine obvious side effects and/or tissues affected at toxic level

24
Q

Describe chronic toxicity assays.

A

Method: lower dose levels tested over longer period of time (>2 weeks, length of clinical trial or longer)
* dose given is same as regular therapeutic dose

Why?: to determine if toxicities develop over long period of time after exposure to drug

25
Q

What organism is used to test toxicity assays?

A

For both acute and chronic toxicity assays, animals are sacrificed and tissues are studied for damage.

26
Q

Identify the two different types of species that must be used during toxicity testing.

A

Must test at least two different species: one rodent and one non-rodent
* rodent - rat or mice
* non-rodent - rabbit, dog, or nonhuman primate

27
Q

What route of administration has to be tested during toxicity assays?

A

Drug must be through at least two different routes of administration.
* one must be actual route of thearaputic administration
* unless route of administration is IV –> then only IV needs to be tested

28
Q

Define LD50.

A

Dose required to kill 50% of animal group.

29
Q

Define ED50.

A

Dose required to have a therapeutic effect on 50% of animals/participants.

30
Q

Define therapeutic index.

A

LD50/ED50

31
Q

What is the typical comparison/experiment done in clinical trials?

A

New drug vs. Placebo/current treatment on the market

Less common:
* use of already marketed drug for new indication
* change in dose, significantly higher

32
Q

How many phases are there in a clinical trial?

A

4 phases

33
Q

What is the objective of phase 1 trials?

A

To provide inital pharamcologic and pharamcokinetic data and to determine the maximum tolerable dosage (MTD)
* given to 10-20 healthy volunteers
* also studies food-drug interactions

34
Q

Define MTD.

A

Maximum tolerable dose = max dose associated with acceptable levels of toxicity.

35
Q

Describe what occurs during phase 2 trials.

A

Objectives:
* to establish if the drug is effective in the targeted patient base
* determine short term safety of drug
* identify dosing regimen
* one location - one clinic

2 subphases: 2a and 2b

36
Q

Explain the difference between phase 2a and 2b.

A

2a - limited number of patients to identify any therapeutic valie and obvious side effects (>10 patients)
2b - larger population (10-100)
* double-blind placebo-controlled studies
* placebo patients will still get treated (bc they can’t just go untreated if they’re in the placebo pool)
* new drug is compared to the standard care/typical drug given

37
Q

Describe what occurs during phase 3 trials.

A

Objective: to determine clinical effects over a much broader population at various/diverse centers nationally and internationally.
* identify rare, but important side effects based on population differences
* placebo-controlled double-blind studies
* measure effects over long period of time (~3 years)
* patient base - broad and matched (gender and race)

38
Q

Describe what occurs at phase 4 trials.

A

Objective: After the drug gets approved to enter the market, continued monitoring of safety and effectiveness.
* AKA post marketing surveillance trials.

39
Q

Describe characteristics of a patent.

A

Gives company the exclusive right to produce and sell the drug.
* lasts for 20 years after filing for patent
* usually the patented drug is only on the market for 10-15 years because companies file for patent before drug is ready for the market.

40
Q

Describe characteristics of a patent.

A

Gives company the exclusive right to produce and sell the drug.
* lasts for 20 years after filing for patent
* usually the patented drug is only on the market for 10-15 years because companies file for patent before drug is ready for the market.

41
Q

Describe the two patentable categories.

A

Composition of Matter - patent to protect the structure of the drug
* specific 3D structure
* strongest patent - hard to get

Method of Use - repurpose an already patented drug
* weaker patent - hard to enforce
* ex: patented as dye –> but want to newly patent as anti-inflammatory drug

42
Q

What are the 4 main criteria for patentability?

A
  1. Novelty - drug must be new compared to what is on the market prior to filing date.
  2. Inventive step - drug must not be obvious to a person “skilled in the relevant art” of drug development, prior to filing date.
  3. Enablement - application must clearly describe how the drug can be used by a person “skilled in the art”
  4. Support - the claims made (drug efficacy) must be justified by the descriptions in the patent.
43
Q

What happens after a drug goes off patent?

A

Generic drugs can be made and distributed

44
Q

Describe the characteristics of a generic drug.

A

Identical to the name brand “in all ways that matter”
* bioequivalent - works the same
* same API (active pharmaceutical ingredient)
* specific similarities are a moving target - dosage form, route of administration, performance, intended use
* costs much less bc generic manufacturer has not put in the time and money to develop the drug
* differences allowed: color, size, shape, additives, binder, filling agents

45
Q

What are the two strategies for generic drug before name brand goes off patent?

A
  • Lawsuit challenging brand name drug’s patent
  • Brand name company marketing generic drugs

PHRX 3002: bioorganic chem (27 decks)

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