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In Depth Notes on Drug Discovery and Manufacture

Drug Discovery Process

  • Definition: The process by which new candidate medications are identified and developed. It includes several stages from basic research to drug approval.

  • Purpose: To create new drugs for various diseases (chronic conditions, infections, genetic disorders).

Importance of Drug Discovery

  • Implications for Human Health:

    • Develops medicines to cure/manage diseases.

    • Improves quality of life and life expectancy.

  • Challenges:

    • Complex, expensive, and lengthy process (10–15 years, billions of dollars).

Key Players in Drug Discovery

  • Major Pharmaceutical Companies:

    1. Johnson & Johnson (USA)

    2. Merck Frosst (Canada)

    3. Pfizer (USA)

    4. Apotex (Canada)

    5. GlaxoSmithKline (UK)

    6. Roche (Switzerland)

    7. Sanofi-Aventis (France)

    8. Novartis (Switzerland)

    9. AstraZeneca (UK)

    10. Abbott Laboratories (USA)

    11. Merck (USA)

    12. Wyeth (USA)

    13. Bristol-Myers Squibb (USA)

    14. Eli Lilly (USA)

  • Types of Pharmaceutical Companies:

    • Research and Development (R&D): Focus on drug discovery, development, commercialization (e.g., Pfizer, Merck).

    • Generic Companies: Produce lower-cost, generic versions post-patent.

    • Contract Manufacturing Organizations (CMOs): Manufacture drugs for other companies.

Stages of Drug Discovery

  1. Target Identification and Validation

    • Identifying biological molecules involved in disease (drug targets).

    • Validate effectiveness of targeting molecule using methods like Genetic Knockdown (RNAi or CRISPR).

  2. Hit Discovery

    • Screening compounds to find "hits" that interact with targets.

    • High-Throughput Screening (HTS): Automated testing of diverse chemical libraries.

  3. Lead Discovery and Optimization

    • Testing identified hits for potency, selectivity, and stability.

    • Only 5 out of 10,000 hits typically reach human testing.

  4. Preclinical Development

    • In Vitro Testing: Laboratory tests on cells and enzymes.

    • In Vivo Testing: Animal studies to assess pharmacokinetics (absorption, distribution, metabolism, excretion).

    • Pharmacology Testing: Effects of the drug on the body, including pharmacodynamics.

    • Toxicology Studies: Identify risks, evaluate toxicity (acute and chronic), reproductive toxicity, carcinogenicity.

  5. Clinical Trials

    • Phase 1: Safety and dosage testing in healthy volunteers (20-100).

    • Phase 2: Efficacy and safety testing in patients (100-300).

    • Phase 3: Larger populations (1,000-3,000) to confirm efficacy and monitor side effects.

  6. Regulatory Review and Approval

    • Data submitted to regulatory bodies (FDA, EMA) for evaluation.

    • NDA filing post-trials; FDA review period typically 1-2 years.

  7. Post-Marketing Surveillance (Phase 4)

    • Ongoing monitoring after market approval for long-term side effects.

Challenges in Drug Discovery and Manufacture

  1. High Failure Rates: 90-95% of drug candidates fail due to efficacy/safety issues.

  2. Drug Resistance: Increasing antimicrobial resistance complicates drug discovery.

  3. Cost and Time: Average drug development cost is $2.6 billion; takes 10-15 years.

  4. Regulatory Hurdles: Stringent requirements can cause delays.