Animal models: other Flashcards
(58 cards)
What are the reasons for the use of animal models in TB drug and regimen development? (2)
- In vitro systems cannot address crucial component
- DS-TB: safe and highly effective treatment regimens are already available for active/latent infection
Which crucial components can in vitro systems not address in TB drug and regimen development? (5)
- Safety and tolerability of drugs
- PK properties of drug and drug-drug interactions
- Bacterial susceptibility to drugs in vivo
- Selection of in vivo drug resistance mechanisms
- Treatment duration
What are the common animal models for TB treatment? (5)
- Mice
- Guinea pigs
- Rabbits
- Zebrafish
- NHP
Why are guinea pigs, rabbits and zebrafish difficult model systems for TB?
They have drug metabolism, tolerance and toxicity issues –> cannot tolerate long durations of drug testing
TB: Which animal models have housing requirements that make it difficult to conduct statistically robust experiments? (3)
- Guinea pigs
- Rabbits
- NHP
Why is a mouse model the preferred model system for TB?
No other animal model has demonstrated equivalent or superior predictive value for translation to human clinical studies
What is the fundamental goal of an animal model for TB?
To have a model of TB treatment with translational value that provides critical information to inform the design of (human) clinical trials
What are NOT the goals for designing an animal model for TB? (2)
- Finding treatments for mouse TB
- Mimicking human disease
Which studies do you need to consider when selecting a TB mouse model? (2)
- PK studies conducted in uninfected mice (M/F)
- PD and PK/PD studies conducted in female TB infected mice
Why do you need to consider PK studies conducted in uninfected mice (M/F) when selecting a mouse model for TB? (4)
- 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
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)
- Anti-TB activity and correlation with drug exposure
- PK differences between infected and uninfected mice
- Pharmacological parameters that drive activity
- Good companion drugs and characterize regimens
Tuberculosis: What factors do you need to consider in the research question? (5)
- M.Tuberculosis strain
- Mouse strain
- Primary outcomes
- Inoculation regimen
- Timelines
What factors do you need to consider when choosing an M.Tuberculosis strain? (3)
- Origin
- Virulence of the strain in mice
- Drug susceptibility
What are the most common M.tuberculosis strains used for TB treatment studies? (3)
- H37Rv (lab)
- Erdman (lab)
- Beijing lineage (clinical isolate)
What factors do you need to consider when choosing a mouse strain for TB experiments? (3)
- Susceptibility
- Course of infection and TB disease
- PK differences between mouse strains
What are the most common mouse strains used for TB treatment studies? (3)
- BALB/c
- C3HeB/FeJ
- Nude
What is special about the BALB/c mouse strain in TB research?
Immunocompetent –> possible to control infection
What is special about the C3HeB/FeJ mouse strain in TB research?
Caseous necrotic lung lesions & cavity formation –> human-like pathology
What is special about the nude mouse strain in TB research?
Lacking mature T cells –> immunocompromised
How do we quantify the primary outcome of TB treatment experiments? (2)
- Bactericidal activity
- Sterilizing activity
What is meant with bactericidal activity?
Change in lung bacterial load (CFUs) during treatment
What is meant with sterilizing activity?
Proportion of mice that are culture negative 3-6 months after stopping treatment
What does an altered bactericidal activity indicate in TB treatment experiments?
Speed and magnitude of killing
What does the sterilizing activity indicate?
Relative duration of treatment needed to eliminate the infection
