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I&I SC2 > Animal models: other > Flashcards

Animal models: other Flashcards

1
Q

What are the reasons for the use of animal models in TB drug and regimen development? (2)

A
  • In vitro systems cannot address crucial component
  • DS-TB: safe and highly effective treatment regimens are already available for active/latent infection
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2
Q

Which crucial components of can in vitro systems not address in TB drug and regimen development? (5)

A
  • Safety and tolerability of drugs/compounds
  • Pharmacokinetic properties of drug and drug-drug interactions
  • Bacterial susceptibility to drugs in vivo
  • Selection of in vivo drug resistance mechanisms
  • Treatment duration
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3
Q

What are the common animal models for TB treatment? (5)

A
  • Mice
  • Guinea pigs
  • Rabbits
  • Zebrafish
  • NHP
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4
Q

Why are guinea pigs, rabbits and zebrafish difficult model systems for TB?

A

They have drug metabolism, tolerance and toxicity issues –> cannot tolerate long durations of drug testing

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5
Q

Which animal models have housing requirements that make it difficult to conduct statistically robust experiments? (3)

A
  • Guinea pigs
  • Rabbits
  • NHP
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6
Q

Why is a mouse model the preferred model system for TB?

A

No other animal model has demonstrated equivalent or superior predictive value for translation to human clinical studies

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7
Q

What is the fundamental goal of an animal model for TB?

A

To have a model of TB treatment with translational value that provides critical information to inform the design of (human) clinical trials

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8
Q

What are NOT the goals for designing an animal model for TB? (2)

A
  • Finding treatments for mouse TB
  • Mimicking human disease
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9
Q

What are factors to consider when selecting a TB mouse model? (2)

A
  • PK studies conducted in uninfected mice (M/F)
  • PD and PK/PD studies conducted in female TB infected mice
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10
Q

Why do you need to consider PK studies conducted in uninfected mice (M/F) when selecting a mouse model for TB? (4)

A
  • Before testing in humans: to understand drug exposure in mice
  • After testing in humans: to mimic exposure levels in humans
  • Detect potential drug-drug interactions
  • Identify PK differences between M/F mice
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11
Q

Why do you need to consider PD and PK/PD studies conducted in female TB infected mice when selecting a mouse model for TB? (4)

A
  • To evaluate anti-TB activity and correlate with drug exposure
  • To identify PK differences between infected and uninfected mice
  • To define pharmacological parameters that drive activity
  • To identify good companion drugs and characterize regimens
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12
Q

Before selecting a model, have a very well-defined research question. What factors do you need to consider in the research question? (5)

A
  • M.Tuberculosis strain
  • Mouse strain
  • Primary outcomes
  • Inoculation regimen
  • Timelines
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13
Q

What factors do you need to consider when choosing an M.Tuberculosis strain? (3)

A
  • Origin
  • Virulence of the strain in mice
  • Drug susceptibility
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14
Q

What are the most common M.tuberculosis strains used for TB treatment studies? (3)

A
  • H37Rv (lab)
  • Erdman (lab)
  • Beijing lineage (clinical isolate)
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15
Q

What factors do you need to consider when choosing a mouse strain for TB experiments? (3)

A
  • Susceptibility
  • Course of infection and TB disease
  • PK differences between mouse strains
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16
Q

What are the most common mouse strains used for TB treatment studies? (3)

A
  • BALB/c
  • C3HeB/FeJ
  • Nude
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17
Q

What is special about the BALB/c mouse strain in TB research?

A

Immunocompetent –> possible to control infection

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18
Q

What is special about the C3HeB/FeJ mouse strain in TB research?

A

Caseous necrotic lung lesions & cavity formation –> human-like pathology

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19
Q

What is special about the nude mouse strain in TB research?

A

Lacking mature T cells –> immunocompromised

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20
Q

How do we quantify the primary outcome of TB treatment experiments? (2)

A
  • Bactericidal activity
  • Sterilizing activity
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21
Q

What is meant with bactericidal activity?

A

Change in lung bacterial load (CFUs) during treatment

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22
Q

What is meant with sterilizing activity?

A

Proportion of mice that are culture negative 3-6 months after stopping treatment

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23
Q

What does an altered bactericidal activity indicate in TB treatment experiments?

A

Speed and magnitude of killing

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24
Q

What does the sterilizing activity indicate?

A

Relative duration of treatment needed to eliminate the infection

25
Q

Which two models exist for the inoculation regimen in TB treatment experiments?

A
  • Acute/sub-acute model
  • Chronic model
26
Q

How does the acute/sub-acute inoculation model work?

A

Inoculation with high dose of TB -> makes mice unable to control infection

27
Q

How does the chronic inoculation model work?

A

Inoculation with lower dose -> mice are able to control the infection (chronic, stable)

28
Q

What does/doesn’t the chronic model show?

A

Shows killing, but doesn’t show inhibition or slowing of growth (due to stable population)

29
Q

What is the timeline range of TB treatment experiments?

A

9 weeks - 1.5 years

30
Q

Why are female mice preferred for TB treatment experiments?

A

Can be housed together for long durations -> male mice harm/kill on another

31
Q

What is the current dose-finding regimen for antibiotics?

A

potency of a drug in vivo (MIC) - exposure to the bug in vivo (PK) –> antimicrobial efficacy of the drug –> effect on host

32
Q

What does MIC stand for? Why is this used?

A

Minimal inhibitory concentration –> in vitro characteristics of an antibiotic

33
Q

What is the optimal approach in case a high concentration of antibiotics is rapidly cleared?

A

Frequent dosing with lower doses

34
Q

How can you study the optimum dosing regimen of antibiotic X in patients? (3)

A
  • In vitro
  • In vivo in animals
  • In vivo in clinical trials
35
Q

What are the advantages of in vitro testing the optimum dosing regimen of antibiotic X in patients? (4)

A
  • Cheap
  • Simple
  • Fast results
  • Translational value is increasing
36
Q

What are the DISadvantages of in vitro testing the optimum dosing regimen of antibiotic X in patients? (3)

A
  • Often only studies a single dose
  • Artificial growth medium
  • Translational value unclear
37
Q

What are the advantages of in vivo (animal) testing the optimum dosing regimen of antibiotic X in patients? (3)

A
  • Relatively cheap
  • Fast results
  • Antimicrobial efficacy at specific body sites
38
Q

What are the DISadvantages of in vivo (animal) testing the optimum dosing regimen of antibiotic X in patients? (4)

A
  • Ethical concerns
  • Mouse is not man
  • Most human pathogens are non-pathogenic in rodents
  • Requires advanced personnel training
39
Q

What is the advantage of in vivo (clinical trial) testing the optimum dosing regimen of antibiotic X in patients?

A

In humans –> short time to implementation –> easy translation

40
Q

What are the DISadvantages of in vivo (clinical trial) testing the optimum dosing regimen of antibiotic X in patients? (3)

A
  • May be disadvantageous for volunteer/patients
  • Time consuming
  • Expensive
41
Q

Antibiotics: Which mouse model can be used to prevent interference from the immune system?

A

Neutropenic mice, thigh and lung infection

42
Q

Where can you measure local antibiotic concentrations?

A

Epithelial lung fluid (BAL)

43
Q

What is the standardized way to induce neutropenia?

A

Cyclophosphamide

44
Q

Antibiotics: How can the amount of mice be reduced?

A

By injecting 2 strains per mouse (1/thigh)

45
Q

Antibiotics: mice are sampled at different timepoints (q), depending on?

A

Expected half-life (t1/2)

46
Q

Which readout is used in antibiotic experiments?

A

Colony-forming unit (CFU)

47
Q

CFU can be used to determine the bacteriostatic dose. This can be used for which type of infections?

A

Treatment of milder infections

48
Q

CFU can be used to determine the 1 or 2 lof kill doses. This can be used for which type of infections?

A

Severe infections

49
Q

What does AUC stand for?

A

Area under the curve = total systemic exposure of drug

50
Q

What does Cmax stand for?

A

Highest concentration of the drug in blood

51
Q

How can the PK be defined in an equation?

A
  • PK = AUC/MIC
  • PK = Cmax/MIC
  • T > MIC
52
Q

What is the pharmacodynamic index?

A

Quantitative model to establish the relationship between pharmacokinetic and pharmacodynamic parameters

53
Q

The pharmacodynamic index can be divided into three categories:

A
  • Time-dependent
  • Cmax-dependent
  • AUC-dependent
54
Q

How can efficacy be described in the time-dependent pharmacodynamic index? What kind of dosing regimen is best?

A

q6 > q12 > q24 –> frequent dosing more effective

55
Q

How can efficacy be described in the Cmax-dependent pharmacodynamic index? What kind of dosing regimen is best?

A

q6 < q12 < q24 –> single high dose is more effective

56
Q

How can efficacy be described in the time-dependent pharmacodynamic index? What kind of dosing regimen is best?

A

q6 = q12 = q24 –> dosing fréquence is not of influence

57
Q

T1/2 is/is not the same between mice and man

A

Not the same

58
Q
A

I&I SC2 (11 decks)

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