Pharmacology 101: Drug Development

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.