Pharmacology 101: Drug Development

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Questions and Answers

What is usually the form of biologic drug formulation?

Capsule

Solution for injection (correct)

Oral Suspension

Tablet

What is the outcome of preclinical studies on a drug candidate?

Establishing safety and efficacy (correct)

Determining the marketing strategy

Finalizing the drug formulation

Determining the dosage regimen

What document contains information about the drug's chemical structure and formulation?

Marketing Authorization

IND document (correct)

New Drug Application

Clinical Development Plan

What is the primary role of the Project Manager in an IND review team?

Coordinating the review team's activities Signup and view all the answers

At what stage does a drug candidate become an Investigational New Drug (IND)?

After preclinical animal testing Signup and view all the answers

What is a critical aspect of small molecule formulation development?

Selecting the final form Signup and view all the answers

What type of information is typically included in the Clinical Development Plan (CDP)?

Initial protocols for planned investigation Signup and view all the answers

What is the primary purpose of an IND application submission?

To initiate clinical trials Signup and view all the answers

What is a primary characteristic of a therapeutically useful chemical?

It can distribute to the target tissue Signup and view all the answers

Which of the following is NOT a Lipinski rule for small drug molecules?

Being highly hydrophilic Signup and view all the answers

What is the primary goal of drug development?

Finding a dose range that is efficacious and safe Signup and view all the answers

Which of the following is an example of a rational design approach in drug development?

Development of captopril from ACE active site analysis Signup and view all the answers

What is the main purpose of acute studies in the preclinical phase?

To investigate possible toxic effects for 2 weeks Signup and view all the answers

What is the primary focus of the nonclinical or preclinical phase of drug development?

Generating an idea for a new drug candidate Signup and view all the answers

What is the primary goal of toxicological studies?

To determine safety and identify potential toxic effects Signup and view all the answers

Which of the following drugs is an exception to the Lipinski rule?

Cyclosporine Signup and view all the answers

What is the primary objective of pharmacological studies in drug development?

Evaluating the efficacy of a drug candidate Signup and view all the answers

What type of study is used to investigate drug effects on fertility and possible teratogenic effects?

Reproductive cycle studies Signup and view all the answers

Which of the following is a characteristic of a safe drug candidate?

It is non-toxic and has an acceptable risk of adverse effects Signup and view all the answers

What is the purpose of a Clinical Development Plan (CDP)?

To guide Phases I to III clinical studies Signup and view all the answers

What is the NOAEL?

No Observed Adverse Event Level Signup and view all the answers

What type of study is used to investigate the mutagenic potential of a drug candidate?

Mutagenesis (Ames test) Signup and view all the answers

What is the ideal characteristic of a drug candidate in terms of safety?

A large therapeutic index Signup and view all the answers

What document contains detailed information about how a drug is used?

Drug label Signup and view all the answers

Study Notes

What is a Drug?

A therapeutically useful chemical must be able to:
- Be absorbed into the body
- Distribute to the target tissue
- Be stable enough to act on the target tissue for a desired amount of time
- Be reversible in its action (biodegradable and excreted from the body)
- Be safe (not cause adverse effects, non-toxic)

Lipinski Rules

Drug-like molecules should:
- Have less than 5 hydrogen-bond donor atoms
- Have a molecular mass of less than 500
- Have relatively high lipophilicity
- Have a sum of oxygen and nitrogen atoms less than 10 (hydrogen bond acceptors)

Starting Point for Search for a New Drug

Natural products:
- Opium → Morphine
- Cinchona officinalis → Quinine
- Penicillium crysogenum → Penicillin
Rational design approach:
- ACE active site analysis → Captopril
- HIV protease → Nelfinavir
Older drugs:
- Penicillin → Ampicillin
- Cocaine → Procaine

Exceptions to Lipinski Rule

Cyclosporine:
- MW around 1200
- Highly hydrophobic
- More than 10 hydrogen bond acceptors and donors
Digoxin:
- MW around 800
- More than 10 hydrogen bond acceptors and donors

Drug Development Objective

Finding a dose or dose range of a drug candidate that is both:
- Efficacious (improves or cures the target disease condition)
- Safe (has acceptable risk of adverse effects)

Drug Development Process

Nonclinical or preclinical phase:
- Idea!
- Clinical design should be for single dose treatment
Drug formulation:
- Biologic: usually administered as a solution for injection
- Small molecule: variety of formulations may be possible
- Effect of formulation on drug disposition has to be determined
- Most suitable formulation for the required dose and dosing regimen has to be found
- Final form may be: injectable, tablet, capsule, oral suspension or solution, etc.

Premarketing Clinical Development

If after preclinical animal testing, a drug candidate is deemed to be safe and efficacious, it can enter the clinical phase
From this point on, the drug candidate becomes Investigational New Drug (IND)
IND application is submitted to the regulatory authority (e.g. FDA in the USA)

IND Document

Contains:
- Name and description of the drug (chemical structure, other ingredients)
- How the drug is processed during chemical manufacturing and formulation
- Any information regarding the safety of the drug from preclinical studies
- Forecast about marketing of IND
- Past experiences for the certification of the drug in other countries
- The Clinical Development Plan (CDP) including signed statements from the investigators and initial protocols for planned investigation

Toxicological Studies

Preclinical phase:
- Acute studies: single dose administered, possible toxic effect investigated for 2 weeks
- Subacute studies: repeated dose regimen for 30 to 90 days
- Chronic studies: repeated dose regimen for greater than 90 days
- Reproductive cycle studies: used to determine drug effects on fertility
- Mutagenesis (Ames test): Salmonella typhimurium testing
Criteria for toxicological effect can be varied, examples:
- Functional: e.g. neurological effect, changes in enzyme levels, failure to thrive, weight loss, etc.
- Anatomical: e.g. cell damage, anatomical abnormality during development, etc.

Aim of Toxicological Studies

To determine safety:
- An ideal drug candidate has a large TI (therapeutic index), i.e. there is spatial separation between dose-response and dose-toxicity curves
- This is referred to as Safety

Final Outcome of Toxicological Studies

NOAEL (No Observed Adverse Event Level) for the drug candidate
- Helps determine safe dosing regimens in clinical studies
- Guidance as to what type of adverse events to be expected in human studies

Getting Ready for Clinical Phase

Clinical Development Plan (CDP):
- At early stages of drug development (preclinical phase), a CDP should be drafted
- Guides Phases I to III studies
- Draws on a draft drug label document
- A drug label is a document that contains detailed information about how a drug is used, including:
  - Target patients
  - Dose
  - Dose regimen
  - etc.

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Description

Learn about the key characteristics of a therapeutically useful chemical, including absorption, distribution, stability, and safety. This quiz covers the basics of drug development, including Lipinski rules for small drug molecules.