Drug Discovery and Development

Six current approaches in searching for new drugs (leads): Identification of new?

Drug targets

Six current approaches in searching for new drugs (leads): Rational drug design of?

A new drug based on biologic mechanisms, receptor and drug structure.

Six current approaches in searching for new drugs (leads): Chemical modification of?

A known molecule

Six current approaches in searching for new drugs (leads): Screening for large collections of?

Natural products, previously identified chemical compounds, or extensive libraries of peptides, nucleic acids, and other organic molecules for biological activity.

Six current approaches in searching for new drugs (leads): Biotechnology and recombinant DNA techniques to produce?

Peptides, proteins and information useful astargets, drugs or diagnostics

Six current approaches in searching for new drugs (leads): Combinations of known drugs to obtain?

Additive or synergistic effects or a repurposing of a known drug for a new therapeutic use

What are the two methods for further development of chosen lead compound(s)?

Compound-based approach and Target-based approach

Describe the compound-based approach

The chemical is initially identified, and its biological profile is further investigated. Based on the findings from these studies, its structure may be modified as needed to enhance its activity.

Give three types of compounds that undergo the compound-based approach

Naturally occurring products, purely synthetic drugs, and drug metabolites

Compound-based approach: Naturally occurring products

Usually the product is associated with a biological activity, and the main challenge is to isolate and purify the compound.

Give an example of a naturally occurring product that was formed via the compound-based approach

Digoxin

Compound-based approach: Purely synthetic drugs

It may involve structural analysis and modifications of an existing drug with specific biological activity or a broad chemical screening of structures using computer-assisted comparisons with current drug therapies

Give an example of a purely synthetic drug that was formed via the compound-based approach

Hycamptin from camptothecin (slides 5-6)

Compound-based approach: Drug metabolites

Involves testing drug metabolites of current drug therapies

Give an example of a drug metabolite drug that was formed via the compound-based approach

Allegra (fexofenadine) that is a metabolite from Seldane (terfenadine), which was withdrawn from the market in 1998 (slides 7-8)

Describe the target-based approach

The biological target is known, and a chemical is designed to interact with it. While most drug targets are receptors and enzymes, other targets can include ion channels and various molecules involved in biochemical processes.

Further divide the target-based approach into its sub-methods

Systematic approach and screening methods

Name two methods in the systematic approach that allow you to identify drugs suitable for drug targets

Knowing mechanisms of disease and the life processes of pathogens

How can you utilize the systematic target-based approach by knowing the mechanism of disease or the life process of a pathogen?

You can identify the targets of that disease and then synthesize compounds that bind to those targets. A hypothesis is often developed related to a drug target and then a decision is made if the drug should either activate or inactivate the target

Give an example of the systematic approach to creating new drugs via the HIV virus

The HIV virus relies on protease enzymes to produce functional proteins essential for its development in the body. By inhibiting these protease enzymes, the progression of HIV can be halted.

Describe the screening method in the target-based approach

In this approach many chemicals are synthesized and then screened for their biological activity on the target of interest.

Name the three aspects of the screening method that allow you to identify drugs suitable for drug targets

Combinatorial chemistry, high-throughput screening, and computer-aided drug design

Describe combinatorial chemistry and how it can develop new drugs suitable for certain drug targets

The first part of the screening method. It uses a small number of precursor molecules to make a large number of derivatives with variable but similar structures.

Describe high throughput screening and how it can develop new drugs suitable for certain drug targets

It uses robotic automation to rapidly evaluate which of the synthesized chemicals (from combinatorial chemistry) might have biological activity

Results of high-throughput screening are the ________ _________ in drug design

starting point

What is the key lab ware for high throughput screening?

The microtiter plate

Describe the process behind high throughput screening

96-well plates contain multiple reaction wells, each holding a test item. Test molecules are then added to these wells, and the reactions that occur are monitored. This allows for quick, automated analysis of many reactions simultaneously.

Describe computer-aided drug design

Uses computers to predict which molecules might work as drugs. It involves creating 3D models of disease-related targets, designing potential drug molecules that fit these targets, and virtually testing them to identify promising candidates. This approach speeds up the drug discovery process by focusing on molecules most likely to be effective

Name two studies used to screen for the activity of chosen leads

In vitro and In vivo studies

In vitro screening

This involves testing compounds in a controlled environment outside a living organism, such as in test tubes or petri dishes, to assess their biological activity

What is a consequence of in vitro screening/studies?

It has a high potential for false positives or negatives due to functional selectivity

Why are more complicated cell-based systems better for in vitro studies compared to simple cells?

They will more accurately mimic the complex environment of living organisms

In vivo screening

This method tests compounds in living organisms (such as animals) to evaluate their effectiveness and safety within a whole biological system

Give the main characteristics of a good therapeutic agents

Effective, selective in activity, delivered to site of action, good pharmacokinetics, no side effects in all types of patients, and good physicochemical properties

Name the six stages of new drug development in chronological order

In vitro studies, animal testing, clinical trials I, II, and III, and marketing

3 multiple choice options

In vitro and animal testing studies are grouped into what category?

Preclinical studies

How long do in vitro studies normally last? Animal studies?

1-2 years; 1-2 years

Describe the process of determining toxicity in new drug development

Toxicity testing requires two years of study using a high toxic dose in two species (typically a rodent and a non-rodent disease model). The testing evaluates various toxicity measures, including acute dosing, chronic dosing, and the effects of a single overdose

In 2022, the FDA passed a new rule regarding what involving preclinical trials?

That animal studies are no longer required for some medications

If all the data obtained from the preclinical studies are promising, then all this information is submitted to the Food and Drug Administration (FDA) as an?

Investigational New Drug (IND) application.

How long does it take for an IND to be approved?

The FDA's Center for Drug Evaluation and Research (CDER) decides within 30 days whether or not an IND application will be approved.

Once the IND is approved, the drug developer is allowed to initiate?

clinical trials

What are clinical trials?

Experiments that use human subjects to see whether a drug is effective, and what side effects it may cause. There are three main phases

How long do clinical trials normally last?

More than 5 years

Describe phase one of clinical trials

Studies in 20-100 healthy volunteers ranging from 18-65 years old. The main focus is determining maximum tolerated dose, pharmacokinetics, and most importantly- SAFETY

How long does phase one of clinical trials last?

Up to 1 year

Describe phase two of clinical trials

Studies in 100-200 volunteers with the disease. The main focus is determining the effectiveness of the drug towards the disease and side effects

What is a common method used in phase two trials to determine the effectiveness of the drug?

Using the placebo effect with the control group (single-blinded studies)

How long does phase two of clinical trials last?

Up to 2 years

Who helps determine if clinical trials can be continued after phase two?

The FDA

Describe phase three of clinical trials

Studies in 1000-6000 volunteers with the disease at multiple randomized clinical sites. The main focus is determining the effectiveness of the drug towards the disease, to optimize dosing, determine side effects, and PK properites

What is a common method used in phase three trials to determine the effectiveness of the drug and reduce bias?

Double-blind studies

How long does phase three of clinical trials last?

Up to 4 years

All the data obtained from the clinical studies and previous studies are submitted to the FDA for a?

New Drug Application (NDA)

What is included in the NDA?

Manufacturing specifications, stability and bioavailability data, method of analysis of each of the dosage forms intended to be marketed, packaging and labeling for both physicians and consumers, and the results of any additional toxicological studies since the IND application

After approval of the NDA, the drug is then

Marketed

Describe post-marketing surveillance

Determines whether or not previously unrecognized adverse effects have occurred. The FDA may require additional clinical studies to clarify aspects of the drug's effects

On average, from about ________ compounds in the drug discovery stage, about ____ enter pre-clinical testing, about ____ proceed to clinical trials and potentially lead to ___ new approved drug.

5,000-10,000; 250; 5; 1

What is a patent?

Sole legal right to an invention and its profits

How long after the initial filling of an application for a new drug product does the patent expire?

20 years

What are priority drugs?

Evaluations may be expedited if the drug is considered a special medical need and there is an absence or shortage of other therapeutic agents to treat the disease

Describe fast track or accelerated review

A process designed to expedite the review of drugs to treat serious conditions and treat life-threatening diseases

A drug that receives fast track designation is eligible for?

More frequent communication/meetings with the FDA, accelerated approval or priority review, and rolling review

Rolling review

Components of a new drug application are reviewed as they become available and don't need to be completely finished before submission

Describe breakthrough therapy

A process to speed up the development and review of drugs for serious conditions when early clinical evidence suggests significant improvement over existing treatments on a clinically significant endpoint

What are clinically significant endpoint(s)

measurable outcomes in clinical trials that demonstrate a drug's effectiveness in improving a patient's condition such as irreversible morbidity or mortality

What is a surrogate endpoint?

A substitute measurement in clinical trials that predicts a drug's effect on outcomes like survival or disease progression, allowing faster assessment of effectiveness

A drug that receives breakthrough therapy designation is eligible for?

All fast track features, intensive guide on a development program, and organizational commitment involving senior managers

What are the two drug review times used by the FDA for detailed drug review?

Standard and priority review

What is priority review?

This designation prioritizes the review of drugs that offer significant improvements in safety, effectiveness, or prevention of serious conditions over standard treatments

Compare the time frame of standard and priority review

Standard: 10 months

Priority: 6 months

What are orphan drugs?

Drugs used to treat diseases that relatively affect very few people (<200,000 patients)

What are some incentives of orphan drugs?

Tax credits for qualified clinical trials, exemption from user fees, and potential seven years of market exclusivity

Do orphan drugs go through the same rigorous scientific review as other drugs?

Yes

When can a generic drug be formulated?

Once the patent for the brand name product expires.

What does the FDAs Office of Generic Drugs (OGD) ensure when it comes to generic drugs?

They have the same active ingredient, same strength, use the same dosage form, and have the same route of administration

Describe the abbreviated new drug application

Generic drug applications that are abbreviated because they don't need preclinical and clinical trials. Applications show the product performs the same as the brand drug.

What is one way generic drug manufacturers show their drug performs the same as the brand name?

They measure the time it takes for the generic drug to reach the blood stream (bioequivalence, rate of absorption) that is then compared to the brand name

For a generic drug to be approved, it must deliver?

The same amount of API into the patient's blood stream in the same amount of time as the innovator drug (have the same bioavailability)