Drug Development

Question 1

Describe the 3 main stages of drug development.

Answer 1

1. Drug discovery - candidate molecules chosen, high-throughput screening of large compound libraries, lead optimisation
2. Preclinical development - non-human studies, toxicity testing, pharmacokinetic analysis of ADME, formulation
3. Clinical development - volunteers and patients, efficacy testing, side-effects and potential dangers

Question 2

Describe the 4 stages of the clinical development phase of drug development.

Answer 2

• Phase I - safety and tolerability (maximum tolerated dose - MTD)
• Phase II - small scale efficacy/placebo controlled trial
• Phase III - large scale efficacy/randomised double-blinded trial
• Phase IV - post-marketing surveillance - long-term side-effects and efficacy monitored

Question 3

Explain the different types of angiogenesis, its normal functions and how it contributes to disease.

Answer 3

Developmental:

• Developmental vasculogenesis - organ growth in embryo

Normal functions:

• Normal angiogenesis - adult wound repair, placenta during pregnancy, cycling ovary

Disease:

• Insufficient vessel growth - stroke, MI, ulcerative disorders, neurodegeneration
• Excessive vessel growth - cancer, inflammatory disorders, pulmonary hypertension, blindness

Question 4

Explain the processes involved in tumour hypoxia.

Answer 4

• Hypoxia, < 1% O₂, is a strong stimulus for tumour angiogenesis
• Hypoxia increases with increasing distance from capillaries
• Hypoxia activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis

Question 5

Name 2 specific examples of pathological angiogenesis.

Answer 5

1. Kidney cancer/renal cell carcinoma - highly angiogenic and metastatic tumour
2. Wet age-related macular degeneration (AMD) -due to excess VEGF and leaky blood vessels

Question 6

Describe and explain the main processes involved in vascular endothelial growth factor (VEFG) signalling.

Answer 6

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Question 7

Describe the stages in the development of Avastin (bevacizumab).

Answer 7

• A4.6.1 - mouse monoclonal antibody that binds to human VEGF
• Humanisation of mouse antibody achieved by exchange of 6 complementarity determining regions (CDR) into human antibody scaffold
• Resulting “bevacizumab” was a humanised anti-VEGF antibody suitable for human clinical trials

Question 8

Explain the mechanism of action of Avastin.

Answer 8

• Avastin used as a monoclonal antibody
• Binds to VEGF and prevents VEGF from binding to vascular endothelial cell receptors
• VEGF signalling is inhibited and angiogenesis is inhibited