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LSM4221 > L3: Preclinical testing > Flashcards

L3: Preclinical testing Flashcards

1
Q

what is GMP?

A

good manufacturing practice. a quality system to cover MANUFACTURE & TESTING OF ACTIVE PHARMACEUTICAL INGREDIENTS, diagnostics

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2
Q

what is GLP?

A

good lab practice. a system to manage and control lab and research organisations to ensure consistency and reliability of results

eg. system of documentation to be sent to regulators to check

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3
Q

what is GCLP?

A

good clinical lab practice. framework for a quality system in analysis of clinical trial samples, ensure GCLP compliance overall

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4
Q

is data from lead optimisation GLP/GMP?

A

no. they are non-GLP/GMP

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5
Q

is checking formulation and stability GLP/GMP?

A

no, this done during lead optimisation

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6
Q

is impurity analysis GLP/GMP?

A

no, done during lead optimisation

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7
Q

is identifying which in vivo disease models to use GLP/GMP?

A

no, in vivo disease models is on animals/cell culture, not on humans hence in lead optimisation

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8
Q

is ADME profiling GLP/GMP?

A

yes and no. brief data like oral bioavailability and metabolism, PK profile can be done during optimisation. comprehensive ADME should be done during GLP/GMP.

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9
Q

State the 4 broad categories of data from Lead optimisation that are non-GLP/GMP

A
  1. preliminary CMC [chemistry, manufacture and control]
  2. benchmark in vivo models
  3. ADME profiling
  4. preliminary toxicology
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10
Q

state the 3 broad categories of data gained from initial pre-clinical stage [GLP/GMP]

A
  1. detailed preliminary CMC
  2. comprehensive ADME
  3. GLP Toxicology package
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11
Q

Aim of chemical development [CMC]

A
  1. improve synthesis to reduce cost and increase output, safety and quality
  2. find best salt for stability and ease of formulation based on chosen route of administration
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12
Q

under CMC, chemical development is ____, chemical manufacturing is ______.

A

non-GMP; GMP

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13
Q

how is ADME profiled?

A

first need to optimise analytical methods so that we can demonstrate exposure levels and determine starting doses

  1. biologics [proteins/antibodies etc] -> use ELISA which can definitively show molecular structure
  2. small molecules -> use HPLC/MS
    - does not show structure nor activity, only use binding as endpoint

then assay needs to be validated for use in GLP studies

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14
Q

examples of GLP assay validation methods

A
  • extraction technique recovery [how well can you recover drug from biological samples]
  • linearity of standard curve [if its curved, need to ensure linear range when detecting drug]
  • intra and inter assay precision [how repeatable is our assay?’
  • benchtop and freeze/thaw stability
  • sensitivity
  • establishing quality control (QC) standards
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15
Q

state the 2 non-GMP/GLP methods when doing ADME profiling

A

HPLC/MS for small molecules
ELISA for biologics eg. proteins and antibodies

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16
Q

for ADME profiling, why do we have to do in at least 1 rodent and 1 non-rodent species?

A
  • identify metabolites that may be formed during metabolism. [presence may be good or bad]
  • allow us to do inter species scaling to improve human PK predictions and better design dosage
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17
Q

what is NOAEL?

A

No observed adverse effect level. the conc of drug before you even get ANY MINOR adverse effect

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18
Q

state the 3 methods of testing genotoxicity/mutagenicity, in increasing order of complexity

A
  1. in vitro non-mammalian cell system eg. Ames test using Salmonella
  2. in vitro mammalian cell system eg. Chinese Hamster Ovarian (CHO) cells
  3. in vivo mammalian system: eg mouse micronucleus assay
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19
Q

explain the principle behind AMES test

A

drug added into media w minimal histidine [nutrient for salmonella] + salmonella. if got high number of revertants aka become can produce histidine, means drug is mutagenic and potentially dangerous

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20
Q

explain principle behind chinese hamster ovarian cells test for genotoxicity/mutagenicity

A

treat cells w drug and look for chromosomal aberrations. determine % chromosomal aberration across a range of drug conc.

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21
Q

explain principle behind mouse micronucleus assay

A

immature mice treated w mutagen for period of 2-4 weeks. Normal: RBCs kick out nucleus when maturing, but when exposed to mutagen, will retain nuclei. observe RBCs under microscope and observe for increased % of micronuclei

22
Q

compare pros and cons of in vitro and in vivo genotoxicity tests

A

In vitro:
+ easy, cheap, fast
- overly sensitive

In vivo:
+ more accurate
- requires trained mouse researcher and more costly

23
Q

how to test carcinogenicity (GLP)?

A

lifetime exposure to drug in rats for 24-30mths

24
Q

methods for Reproductive toxicology (GLP) [3]

A
  1. Fertility and general reproductive performance => on RATS
    - dose males 60-80 days prior to mating
    - dose females 14 days prior to mating and during gestation and lactation
  2. Potential drug-induced embryotoxicity and teratogenicity => on rodent and non-rodent
    - 1 month of treatment in pregnant females during embryonic and fetal development
  3. late fetal development, labour, delivery, lactation and new born viability
    - in pregnant female rats/mouse in escalating dose
    - dosing is from last gestation day to end of weaning
25
Q

what does safety pharmacology core battery test for?

A

represent core organ systems. if affected, will also affect patients

26
Q

state the 3 main systems studied during core battery test

A
  1. CNS
  2. Respiratory
  3. CVS
27
Q

how is CNS assessed during Safety Pharmacology Core Battery test?

A

Irwin test

28
Q

what does the Irwin test for?

A

safety of drug effect on CNS. assess autonomic, neuromuscular, sensorimotor and behavioural aspect of nervous system [B.A.N.S)

29
Q

how is respiratory system assessed during Safety Pharmacology Core Battery test?

A

whole body Plethysmograph chambers in rats

30
Q

what does whole body Plethysmograph chambers measure?

A

tidal volume and resp rate before and after drug

31
Q

what does whole body Plethysmograph chambers measure?

A

tidal volume and resp rate before and after drug

32
Q

how is CVS system assessed during Safety Pharmacology Core Battery test?

A

observe ion channels and cardiac potential
- eg. QT interval prolongation mediated by inhibition of hERG ion channel(K+) can result in Torsades de Pointes (TdP) aka heart arrhythmia -> sudden cardiac arrest

33
Q

when recording K+ current to study toxicity effects of drug on the heart, we plot response (K+ or current) against drug conc. do we want the curve to be as right or left?

A

right. left means big response aka inhibition of ion channel at low dose => TOXIC. best if drug conc is in milli or micro molar range. should not be in nano molar conc.

34
Q

how do we find the dosage to give to humans from studies done on animals?

A

we need to find Max. recommended starting dose (MRSD)
- MRSD: NOAEL in animals -> find human equivalent dose (HED) via allometric scaling (Km)-> divide by safety factor of 10 to find MSRD

35
Q

do we do allometric or isometric scaling when finding MSRD? why?

A

allometric. allometric takes into account ratio of body weight and normalised by body surface area [aka lower metabolism of larger animals]; isometric only considers body weight w/o surface area which may overestimate human dosage or underestimate toxicity of given dose

36
Q

steps required to translate dosage in animals to humans

A
  1. find Km of species, animal and human. Km= body weight (kg) / BSA (m2)
  2. find Human equiv dose (HED): animal dose x (animal Km/ human Km)
  3. divide HED by safety factor of 10
37
Q

during toxicology evaluation, what are some examples of endpoints?

A
  • body weight
  • clinical observations
  • serum chemistry
  • hematology
  • organ weights
  • histology
  • drug exposure
38
Q

when identifying single dose (acute) toxicity, animals are observed for ___ days after dosing. does the dose increase?

A

14, yes dose increases to find MTD

39
Q

when identifying repeated dose toxicity, animals are observed for what duration? aim of this is to ____?

A

similar to how clinical trial for humans would be. aim: find the upper bound of time course for drug treatment [during clinical trial]

40
Q

NOAEL is found during GMP/GLP or non-GMP/GLP toxicity studies?

A

GLP

41
Q

describe the standard toxicology design (GLP)

A
  1. treat animal [w disease] with drug
  2. collect organs, target tissues and blood plasma and check for clinical endpoints [weight, survival, clinical signs], clinical pathology, histopathology, plasma drug analysis
42
Q

does carcinogenicity testing have long or short duration?

A

long, lifetime exposure for rats/mouse/hamster to see if prolonged exposure is carcinogenic

43
Q

what does whole body plethysmograph chambers measure? [2]

A

tidal volume and resp rate before and after drug

44
Q

describe how certain drugs can lead to heart arrhythmia [3]

A
  1. drug block HERG ion channel
  2. prolong action potential –> causes QT interval elongation
  3. can cause Torsades de Pointes (TdP)
45
Q

During pre-clinical testing, when evaluating toxicology, FDA guidance states to test dosing up to ___g/kg, if possible.

A

1 g/kg

46
Q

fertility and general reproductive performance toxicology tests are done on ____. does dosing increase?

A

rats only. no

47
Q

potential drug-induced embryotoxicity and teratogenicity tests are done on ___? does dosing increase? duration?

A

both rodents and non-rodents. yes. 1 month

48
Q

late fetal development, labour, delivery, lactation and newborn viability tests are done on ___? does dosing increase? duration?

A

female rodents ONLY. yes. from last gestation day to last day of weaning [feeding milk]

49
Q

if reproductive capacity of offspring is evaluated, study duration is ___.

A

5-6 months

50
Q

units for calculating dose for MRSD or HED

A

mg/kg

LSM4221 (13 decks)

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