Summary
Samenvatting Les 7-10 'Assessing Drug Safety'
- Course
- Institution
This document includes the summary of Lesson 7-10 (info slides with notes) of the “Preclinical drug research” course.
[Show more]
Seller
Follow
evagoormans
Content preview
Lecture 7-10: 25/10 - 10/11Assessing drug safety
Overall objec,ves
• ICH: non profit organiza0on with the guidelines that are accepted per region
o Accepted by FDA, by EMA and the Japanese FDA
§ Most of the regions accept these guidlines
o When you perform the study based on this guidelines the drug will not only
be approved by Europa but also by US
• Animal welfare guidelines
o Most of the 0me na0onal guidelines
o Europe guidelines
§ FELASA
ICH M3 guidline
• Overall guidelines for clinical studies
• Next to the M guidelines you have the S guidelines = safety guidelines
• We don’t need to learn them by hard
• Guidelines are not rules. There may be validate reasons why you deviate from
them.
• Some drug cause phototoxicity. Some have a cause on the IS.
Phases of preclinical safety assessment
• First 0me in man
o You need the toxicological studies, safety pharmacology and genotoxicity
o Reproduc0ve tox if you already include women of child birth poten0al in
phase 1
• MAA
o Marke0ng authoriza0on applica0on
General overview toxicity evalua,on
1. General toxicity
• Single-dose: dose range finding
• Repeated-dose: dose-related toxic effects, long-term pharmacological effects
2. Safety pharmacology -> core baYery
• Central nervous system
• Respiratory
• Cardiovascular
3. Genotoxicity
• Mutagenicity
• Chromosomal damage
4. Reproduc0on toxicology (when can change a liYle bit)
• Fer0lity before phase 3
• Fetal development before phase 2
• Peri- and postnatal development before marke0ng
5. Carcinogenicity
,General toxicity
Single-dose (acute) toxicity
• In rodent and non-rodent
• 4 groups
• Doses se`ng; high, low and middle
o High dose should shown some toxic signs
o It is possible that is doesn’t work and then we come to the maximal feasible
dose
§ Some0mes 2g/kg per day, but mostly 1g/kg
Repeated-dose toxicity
• One month tox study for the first 0me in man. Then you will go for the phase 2: 3- 6
month and then the long term are 6 in the rat and 9 months in the dog
• All the studies should be under GLP
• Do clinical observa0ons
o Aggressions -> clinical observa0on for the drug
o Are they breathing normally?
o Cardiovascular effects?
• Try do the observa0ons at the 0me you have the maximal concentra0on of the drug
in the blood because then you have the maximal effect
• You always need a longer dura0on in the animals than in the clinical situa0on
• All people of the study need to assigne the protocol
o If you deviate from the protocol that need to be documented
Repeated-dose toxicity, test substance iden<fica<on
• Physicochemical characteris0cs
o Chemical form (acid, base)
o Purity & homogeneity
o Stability – storage condi0ons
o Solubility
• Pharmacological characteris0cs
o CNS
o Gastro-intes0nal
o Oncology
• Pharmaceu0cal characteris0cs
o Appropriate solvent for projected dose levels
o Analy0cal method
Repeated-dose toxicity, dosing groups
• Low dose needs to be above the therapeu0cal concentra0on
, • 10 fold safety marge in the high dose, ideally even more
Repeated-dose toxicity, animal studies
• Depending on the dura0on you will increase the number of animals because there is
a risk that the animals will drop out
• Recovery is also important
o Off dose -> liver problem is solved -> lower NOAEL
o Off dose -> liver problem s0ll present -> problem
Repeated-dose toxicity, in vivo observa<on
1. Mortality: dose group, sex-related, species-related, accidental
2. Clinical observa0ons:
• General: behaviour, movement, ...
• CNS: excita0on, seda0on, ...
• Cardiovascular: vascular injec0on, oedema, ...
• Respiratory: dyspnoea, hyperpnoea, ...
• Gastrointes0nal: diarrhoea, cons0pa0on, ...
3. Opthalmology: in the dog only
• Before and at 1, 3, 6 and 9 months
• Use of atropine sulphate (1%) for mydriasis induc0on
• Check: conjunc0va, sclera, cornea, anterior chamber, lens, iris, fundus
4. ECG: in the dog only
• Before and at 1, 3, 6, 9 months immediately after dosing
• Standard Einthoven derivations (I, II and III)
• Parameters:
o PQ-interval
o QRS-complex
o QT-interval
o R-top amplitude
o heart-rhythm
5. Body weight:
• Animals will have a lower weight in the end after treatment
• Daily for dose determination – weekly as parameter
• Important: 10% weight loss = toxic effect !
6. Feed uptake
The benefits of buying summaries with Stuvia:
Guaranteed quality through customer reviews
Stuvia customers have reviewed more than 700,000 summaries. This how you know that you are buying the best documents.
Quick and easy check-out
You can quickly pay through credit card or Stuvia-credit for the summaries. There is no membership needed.
Focus on what matters
Your fellow students write the study notes themselves, which is why the documents are always reliable and up-to-date. This ensures you quickly get to the core!
Frequently asked questions
What do I get when I buy this document?
You get a PDF, available immediately after your purchase. The purchased document is accessible anytime, anywhere and indefinitely through your profile.
Satisfaction guarantee: how does it work?
Our satisfaction guarantee ensures that you always find a study document that suits you well. You fill out a form, and our customer service team takes care of the rest.
Who am I buying these notes from?
Stuvia is a marketplace, so you are not buying this document from us, but from seller evagoormans. Stuvia facilitates payment to the seller.
Will I be stuck with a subscription?
No, you only buy these notes for $10.23. You're not tied to anything after your purchase.
Can Stuvia be trusted?
4.6 stars on Google & Trustpilot (+1000 reviews)
74534 documents were sold in the last 30 days
Founded in 2010, the go-to place to buy study notes for 14 years now