Lecture 7-10: 25/10 - 10/11
Assessing 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
Assessing 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
