Welcome

I've just got started with this blog. Give it time and I hope to create a really helpful resource for everyone out there sitting the exam. Please feel free to e-mail suggestions and 'killer' revision notes. Thanks. I would love to hear from you about this blog. Please post a comment.

A little disclaimer: I am doing this blog to hopefully help you when revising due to the very little available information about this exam. I am not affiliated with any organisation in doing this, completely unfunded and not being sponsored. I can not guarantee the accuracy of the information, but will do my best. If you think something is incorrect please let me know so we can all learn. Thanks

Monday 30 May 2011

DRUG DEVELOPMENT 2


  • Phase 1 : Human Pharmacology, (Dose finding)
  • Phase 2 : Therapeutic Exploratory (? anti-tumour activity)
  • Phase 3: Therapeutic action Confirmed and compared to standard
  • Phase 4 : Post launch
For classical Cytotoxics
  1. Dose escalation Phase 1 to determine Dose Limiting Toxicity (DLT) & Max Tolerated Dose (MTD)
  2. No-randomised Phase 2 to determine efficacy
  3. Phase 3 - for comparative effficacy
DLT -for example
  • neutrophil count <0.5 for 5 days associated with fever or infection
  • Platelet count <10 or bleeding
  • Other Grade 3 toxicity
MTD
  • Dose at which < or = 33% patients experience an unacceptable toxicity
Characteristics of a Phase 1 trial
  • Usually in patients with an advanced malignancy, refractory to standard therapies
  • Patients usually otherwise well
  • Start with a very cautious dose as determined from pre-clinical studies.
  • Starting dose (mg/M2) 1/10th of the LD10 (dose at which 10% of rodents die)
  • 1/3rd of minimal toxic dose in large animal studies
  • Minimise number of patients treated with sub-therapeutic doses. Escalate dose quickly if toxicity absent. Escalate slowly if toxicity present.
  • Example: Treat 3 pts with safe starting dose (as described above), increase dose if no toxicity. If toxicity in 1 patient add 3 more. Stop escalation when more than 33% pts have an unacceptable toxicity.
  • Modified Fibomaci Scheme: Start at 1/10th of LD10, then increase by 100% then 67%, then 50%, then 40%, then 33% thereafter (100--67--50--40--33). If the LD10 is accurate, should be 5-6 dose incriments.
  • PURPOSE: Estimate the recommended dose for later trials, study drug metabolism, elimination and side effects
  • LIMITATIONS: Chronic/cumulative toxicities not well assessed, uncommon toxicities missed, dose for Phase 2 may be conservative as Phase 1 patients often heavily pre-treated.
PHASE 1 ETHICS
- Pt benefit is not the primary goal, but the trial dose need to have a therapeutic intent
- Low probability of response expected - approx 5%

No comments: