Pharmacology

DRUG_DRUG INTERACTIONS

I think the following will be useful to learn:

• Cisplatin can lead to renal damage which can therefore reduce the renal clearance of methotrexate
• If cisplatin is given before topotecan, exposue to topotecan increases, due to reduced renal clearance of topotecan

• Allopurinol reduces the metabolic inactivation of 6-mercaptopurine and increases its toxicity.
• Penicillins, Probenacid and sulfonamides and NSAIDs reduce the renal clearance of Methotrexate. Compete for the tubular secretion pathway

• If Carboplatin/Cisplatin are administered simultaneously with paclitaxel there is less myelosuppression compared to when platinum preceeds paclitaxel.
• There is increased neurotoxicity when cisplatin ans paclitaxel are administered together. This interaction is worse when paclitaxel infusion has along duration.

• Methotrexate can be displaced from Albumin by 1.sulphonamides 2.tetracycline 3.chloramphenicol 4.phenytoin 5.NSAIDs. This will increase the plasma concentration, causing more side effects such as mucositis and myelosuppression

RANDOM PHARM

• MESNA binds acrolein (metabolite of ifosamide) that is irritant to urothelium
• Dexrasone iv is used with anthracycline extravasation
• Epirubicin and Doxorubicin are a red solution and can cause urine and sweat to appear pink after treatment.
• Methotrexate is yellow
• Mitomycin C is a light blue solution
• You can give vincristine, bleomycin and gemcitabine on day 8 as they have less myeloosuprresive effects on the pre-cursor cells.
• Gemcitabine and Fludarabine have synergy with cisplatin by inhibiting the repair of cisplatin adducts (by NER)
• 5-FU as a BOLUS affects RNA metabolism
• 5-FU as an INFUSION affects DNA metabolism

Irinotecan is a popular question and I think it is well worth learning as much as you can about it. It has an interesting pharmacology, so lots can be asked about it.

DRUG DEVELOPMENT

Overall View

1.      Identify Molecular Target

-        Involved in cancer growth/development

-        Promise ‘Lead’

2.      Find/Screen/Design a product to interact with target (inhibitor/activator)

3.      Optimisation and Formulation

4.      Pre-clinical studies

-        ‘proof of principle’

-        Animal models for proof of concept and safety data 

5.      Clinical Studies  Phase 1 à 4

e.g. Imatinib (Gleevec)

-        Identify Target: Chromosome Transolcation t(9,22), BCR-ABL fusion protein

-        Lead Compound was found to have Kinase Inhibition, from screening of high throughput screening

-        Optimisation to enhance bioavailability and target specificity

-        Pre-clinical testing demonstrated proof of principle

-        Phase I  to III trials

Screening for Useful Compounds

•       High Throughput –millions of compounds (libraries) exposed to cell cultures and levels of apoptosis measured
•      Cominatorial Chemistry- synthetic molecules created
•            Natural products
•      ‘In-silico’ approach – virtual computer screening, selecting compounds binding based on knowledge of target structure

• 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%

I found for pharmacology it was useful to read the product information literature from the drug companies. They are normally comprehensive and give a lot of detail on the pharmacology, especially interactions and side effects.

I recommend doing this for the drugs the FRCR seem to commonly ask about.

The links are as follows:

• Capecitabine (Xeloda®) link
• Herceptin® link
• ADRIAMYCIN® (Doxorubicin)link
• Epirubicin (Pharmorubicin®) link
• Docetaxel (Taxotere®) link
• Paclitaxell  (Taxol®)
• Irinotecan (Campto®)link