week 6 Flashcards
Over the years, what does the industry tend to do?
Compartmentalise activities
How do we adopt a more integrated thinking approach?
Understanding concentration at the active site
e.g. CNS
What is pharmacodynamics?
Both efficacy and safety
all part of the same biological continuent
Define pharmacokinetics
- The study of the effect of the body on the drug
2. medicinal chemistry
Define pharmacodyanmics
- The study of the effect of the drug on the body
2. biology - good and bad
What impacts half life that drives dose regimens?
- Volume of distribution
2. Clearance
What defines the oral bioavailibility?
- Clearance
2. Absorption for oral drugs
What are the key questions for integrated thinking?
- Can we detect?
- Are we achieving?
- Can we observe?
- Can we measure?
- Can we demonstrate
- Does all this translate to a disease response?
What is an example of the key questions for integrating thinking?
- Expression of the target and/or activity of the pathway
- Active blood or tissue concentrations
- Activity on the desired molecular target
- modulation of the desired biochemical pathway
- Achievement of the desired biological effect
- Disease response
Where do we live in?
- one-click world
- Everything is instant
- we order instantly
- get decisions instantly
What is important in biology and also designing the safety study?
- look for a patient response
2. can I get signal efficacy in a week? or is it up to 6 months of dosing?
What is the biological turnover rates of Structure or Functions?
- Electrical signals (msec)
- Neurotransmitters (msec)
- Chemical signals (min)
- Mediators, Electrolytes (min)
- Hormones (hr)
- MRNA (hr)
- Proteins/enzyme (hr)
- Cells (days)
- Tissues (months)
- Organs (year)
- Person (Century)
What does the pharmacodynamics look at?
- Biological effect over time
2. concentration vs effect - represented in a simple sigmoidal E-max response
What does pharmacokinetics look at ?
- Integration of concentration over time
What do we need to have an understanding of in terms of PK/PD study?
How the magnitude and time scale of biological effect relates to drug concentration in a biophase which is blood/plasma for convenience
What can PK/PD modelling and stimulation be used an?
- Applied science tool to provide answers on efficacy and safety of new drugs faster and at a lower cost
where can PK/PD modelling be used in?
preclinical phase through all clinical phases of drug development
What does optimal use of PK/PD modelling and stimulation lead to?
- Fewer failed compounds
- Fewer study failures
- Smaller number of studies needed for registration
How can PK/PD modelling fulfil its potential in drug development?
It needs to be embraced across the industry and regulatory agency
more education on this topic is required
What is PK/PD model?
combines two classical pharmacologic disciplines of pharmacokinetic and pharmacodynamic
- it integrates both these into one set of mathemathical expression that allows decription of time course of effect intensity in response to administration of a drug dose
when can we utilise PK/PD modelling and stimulation?
models should be developed early in programme development
during the preclinical phase
such models are continously updated and refined as more data becomes available
when can PK/PD modelling offer the greatest value?
if preclinical data can be modelled in combination with existing clinical data on related compounds
what are potential benefits of modelling in preclinical phase?
- selecting the optimal compound
- predicting clinical potency estimates (EC50)
- providing the guidance for the dose range to be tested in early clinical trials
- providing guidance for optimal sampling
- predicting oral bioavailibility
- predicting hepatic clearance
- assessing the potential for drug-drug interactions
what should PK/PD model include?
- rate-limiting component from the mechanism of action
2. e.g. receptor binding, protein synthesis
What affects a model predictivity?
- protein binding
- receptor occupancy (species difference)
- Active metabolites
- Competitive endogenous ligands
What is prediction of PK/PD?
look at human efficacy and dose based on data
What is comparison of PK/PD?
simple at in-vitro level comparing IC50 across a range of compounds
What is PK/PD?
Funneling approach
look very early on a simple IC50 in a cellular expression system
or simple whole blood system
what are the four basic attributes to characterise PK/PD models?
- link between measured concentration and the pharmacologic response mechanism that mediate observed effect, direct vs indirect response
- the response mechanism that mediates the observed effect, direct vs indirect response
- the information used to establish link between measured concentration and observed effect
- time dependency of involved pharmacodynamic parameters
e. g. time variants vs time invariant
define disposition
What happens to the drug after it enters the body, including distribution and elimination process
What is biosignal?
Any signal in human being that can be continually measured and monitored e.g. ECG
What is sensitivity analysis?
determines how different values of independent variable affect a particular dependent variable under a given sit of assumptions
What is done in a healthy male volunteers?
Studies for a small molecule thats being delivered orally
What is the cornerstone of drug registration package?
- clinical outcome
- response
- biomarkers that drive response
- defining clinical therapeutic index
what is PK/PD?
Interdisciplinary effort
What is pre-clinical PKPD?
- development of mechanism based models
- Evaluation of in-vivo potency vs intrinsic activity
- Identification of bio/surrogate markers of efficacy
What is Translational PK/PD?
- extrapolation of preclinical data to humans
- prediction/understanding of therapeutic concentration
- prediction of human pharmacokinetics
- Prediction of clinical dose and dose regimen
What is clinical PK/PD?
- characterise dose/concentration effect relationship
- understand clinical risk vs benefit
- define clinical therapeutic index
- support drug registration
What drives pharmacodynamics?
pharmacokinetics
what drives drug-drug interactions?
Huge margins
What does a lot of data suggest?
The greater the dose the greater the drug-drug interaction
what is the PK parameters?
- Allometric modelling
- physiological scaling
- In-vitro (mics, s9, heps)
- simCYP/Gastroplus
- pb/pk modelling
what does predicted concentration and dose in man impact?
- impact on TI
- safety
- hERG
- DDI and reactive metabolites
- MABEL
- impacts on CoG
- impacts on tablet size
What is CNS penetration broken down into?
- Permeability
- P-gp liability
- Free concentrations
How is CNS commonly measured?
- Caco2
- LLC-PK1
- MDCK cells
What is used for CNS drugs?
Papp > 150-200 nm/s (optimal)
What is P-gp liability?
Efflux transporters in drug transport in many organs
What is essential for P-gp liability?
P-gp Efflux index < 2.5-3
Free concentrations
- in blood
- in brain
link with efficacy
Rat brain:blood ratios
Intravenous infusions for about 3-4 hours so that the concentration of blood and brain are at a steady state
When looking at cascades what do we need to consider?
In-vitro potency and selectivity and screen all that and put some functional assays –> developed ability assay
What is a classical animal model?
Collagen induced arthritis model in a rat
how do we define what is needed for a compound?
you need 75% receptor occupancy at target coverage
What will reduce during drug discovery?
Therapeutic index
What are the candidate selection criteria?
- Where do we need the compound to get to
- How fast do we need it to get there
- How long do we need to keep it there
- How much do we need
- Can we do it safely
What 3 fundamental element need to be demonstrated for a development candidate to have a potential to elicit the desired effect over period of time?
- Exposure at target site of action over a desired period of time
- Binding to the pharmacological target as expected for its mode of action
- Expression of pharmacological activity
Exposure at the target site of action
Demonstration of free drug exposure at the target site of action at a level that exceeds pharmacological potency over desired period of time
drug exposure is measured using blood samples
Binding to the pharmacological target
The highest level of confidence and direct evidence at site of action required levels of target binding
What is stated in the literature?
The industry is very poor for selecting drug targets to work on
What treats a small number of patients with cystic fibrosis with a G551D mutation?
Drug Caladako
Why has the value of animal experiments for predicting effectiveness of treatment strategies in clinical trials remained controversial?
- recurrent failure of interventions to translate to the clinic
How can translational failure be explained by?
- methodological flaws in animal studies
- lead to systematic bias and thereby inadequate data
- incorrect conclusions and efficacy
What may aid the selection of the most promising treatment strategies for clinical trials?
- systemic review
2. meta analysis of animal studies
What is Ceff?
the drug concentration or that exposure on which the compound is predicted to be unequivocally efficacious
What should Ceff provide?
near maximal clinical efficacy
clinically differentiated profile
What are examples of understanding the drive which drives the critical decisions?
- doses for preclinical safety studies
- Therapeutic index
- predicted first in human doses
- drug-drug interaction potential
- drug delivery factors
Where is there no pre-clinical model for?
Alzheimer’s disease
What is the default to no-regrets approach?
- maintain 80-90% target engagement at C-trough (antagonist) sometimes even higher (chemokines)
- Understanding pharmacology and concentration vs response is essential
- majority of compounds are well described by a sigmoidal Emax model
What obeys a sigmoidal condition?
- Safety
2. Efficacy
What is Rheumatoid Arthritis?
Chronic autoimmune disease affecting the joints
swelling of the synovial membrane
What does RA affect?
1% of the population
reduces life expectancy by 10 years
What is SoC of RA?
pain – NDSAIDs, steroids
disease modifying: sulfasalazine, methotrexate, anti-TNF’s (Embrel,
Humara)
What is Janus Kinases (JAK’S)?
soluble cytokines play a major role in controlling immune
response and inflammation
JAKs (1,2,3 and TYK2) critical components of cytokine
mediated effects via the JAK-STAT (Signal Transducers and
Activators of Transcription) pathway
selective interruption of this signalling could be beneficial
- “shut down the immune system”
What was CP-690550: toacitinib developed as ?
immune suppression
shuts down immune system to prevent tissue rejection
What is CP-690550 selective and non-selective for?
- It is very selective for JAK1/3 with IC50 = 56nM
4. It Is very non-selective for JAK2/2 – It is a pathway you do not want to interfere with
what is ARC70 score?
you want 70% of response in patient population
What drives the effect?
Average concentration
What is the problem with Tofacitinib?
it is more efficacious at more higher dosage
What is proof of concept?
- Appropriate patient group identified
- Correct dose used
- Appropriate endpoints measured
What is proof of mechanism? (PoM)?
- Incontrovertible and conclusive proof of target engagement
- Defined dose response: safety and efficacy
