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DMPK > Overview of PK/PD > Flashcards

Overview of PK/PD Flashcards

1
Q

Draw the porfile for Pharmacokinetics-Pharmacodynamics and both parameters (Pk/PD)

A
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2
Q

Biomarkers are indicators of a biological state. Mention 3 indicators that biomarkers characteristics measure and evaluate acts as

A
  • Normal biological status
  • Pathogenic process
  • Pharmacological responses to a therapeutic intervention
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3
Q

What should be an ideal biomarker?

A

An ideal biomarker is sensitive, specific and accurate in reflecting
disease burden

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4
Q

How biomarker can be quantitative?

A

Can be quantitative by link between quantity of the marker and disease or by
link between existence of a marker and disease.

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5
Q

Why study PK/PD?

A

*Relate in vitro data to in vivo data
* Translate animal model to human therapy
* Understand determinants of in vivo drug action
* Explain variability in response
* Identify and increase confidence in biomarkers
* Aid dose/regimen selection through clinical trial simulatio

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6
Q

Why should be understand for determinants of in vivo drug action?

A

-Time course of pharmacological response
– Relationships between dose and response
– Delays, tolerance, sensitization

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7
Q

What are the 3 most common models to relate [Drug] to effect?

A

-Linear model
– Log-linear model
– (Sigmoidal) Emax model

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8
Q

What is summarised as Target Product Profile (TPP)?

A

Integration of the required PK and PD effects can be summarised as a Target Product Profile (TPP)

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9
Q

What should be considered for a Target Product Profile?

A
  • Should consider the desired properties of the eventual clinical candidate
    Route of administration
    Dosing frequency
    Optimal efficacy
    Duration of action
    Safety profile (related to disease)
    Metabolism
    Tissue penetration
    Storage
    Cost
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10
Q

What do we mean by PK/PD?

A
  • Preclinical or clinical experiment that involves
    Concentration, effect (and time)
    Design, analysis, modelling & simulation
  • Mechanistic biomarker studies
    Design, analysis, modelling & simulation
  • Quantitative systems pharmacology modelling
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11
Q

What are the three pillars of society from improving chances to progress to Phase III

A
  • Exposure at the target site of action
  • Binding to the pharmacological target (target engagement)
  • Expression of functional pharmacological activity
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12
Q

What are the desirable features of biomarkers? (Antecedent, screening, diagnostic, graded, prognostic)

A

Antecedent: Identify the risk of developing an illness
eg amyloid plaques start forming before the symptoms of AD appear
Screening: Identify subclinical disease
eg abnormal lipid profile is a screening marker for heart disease
Diagnostic: Recognise overt disease
eg diagnostic kits for various diseases
Graded: Categorize disease severity
Prognostic: Predict the future disease course, including recurrence and response to therapy and monitoring efficacy of therapy

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13
Q

Describe the linear model to describe PK/PD

A
  • Drug effect is directly proportional to drug concentration
  • Pharmacodynamically, can be described by:
  • Features
    Applicable at low [drug] only
  • Precludes prediction of maximum effect
    Doesn’t allow comparison of EC50/ED50 or Emax values
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14
Q

Describe the Emax model

A
  • Low abundance of drug target lead to capacity-limitations in most responses
  • Incorporates the observation known as the law of diminishing returns
    An increase in [drug] near maximal pharmacological response produces disproportionally smaller increase in response
  • After Emax is reached, no further increase in response is observed with increasing [drug]
  • Mimics hyperbolic profile of pharmacological
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15
Q

Explain how a graph would show the relationship between exposure profile (PK) and subsequent response profile (PD)?

A

Short acting, not very potent = not much response
Long acting, same potency = better response

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16
Q

Why are most drugs not directly associated with CP?

A
  • The effect is not immediate
    Signal transduction effects or active metabolite
  • Indirect effect of the drug
    Time needed for turnover of endogenous substances or for cell maturation
  • Distribution of the drug is the rate limiting step
  • Slow association and dissociation of drug to/from targets
17
Q

What are the mechanisms that cause clockwise hysteresis?

A
  • Tolerance (down regulation or desensitization of receptors)
  • Input rate
  • Disequilibrium between arterial and venous concentration
  • Active antagonistic metabolite
  • Indirect effect (-ve input or +ve output)
  • Feedback regulation
  • Time-dependent protein binding
  • Racemic drugs and stereospecific assays
18
Q

What are the mechanisms that cause anti-clockwise hysteresis?

A
  • Sensitization (upregulation of receptors)
  • Input rate
  • Distribution delay into the site of effect
  • Active agonist metabolite
  • Indirect effect (+ve input or -ve output)
  • Slow receptor kinetics
  • Time-dependent protein binding
  • Racemic drugs and stereospecific assays
19
Q

Mention an example of anti-clockwise hysteresis

A

Morphine
Slow entry into CNS due to poor lipid solubility

20
Q

Mention an example of anti-clockwise hysteresis

A

Morphine
Slow entry into CNS due to poor lipid solubility

21
Q

What is determined by Keo?

A

Keo determines magnitude of delay

22
Q

Mention some of the things that need to be considered when designing PK/PD studies

A
  • May need different time points for PK and PD measurements
    Time matched PK and PD samples not always necessary
  • Ideally measure concentration and effect in the same subject
  • Ideally need to measure multiple concentrations
    0, E20 and E80 (bounds linear portion of shape), E50 and Emax
  • Select times to identify hysteresis if present
    Quantify full PK time course
    Quantify full PD time course (including return to baseline conditions)
23
Q

What are PK/PD useful for?

A

PK/PD models are used to support simulations of clinical trials from FIH studies to Phase 3 pivotal trials

24
Q

What do we mean by PK/PD?

A

*Preclinical or clinical experiment that involves
– Concentration, effect (and time)
– Design, analysis, modelling & simulation
* Mechanistic biomarker studies
– Design, analysis, modelling & simulation
* Quantitative systems pharmacology modelling

25
Q

Give 3 characteristics for Log-linear model

A
  1. Applicable over an extended [drug] range
  2. Relationship between [drug] and effect is not
    linear and may be curvilinear, requiring log
    transformation
  3. The log [drug]-effect plot is roughly linear for 20-80 % max effect
26
Q

How log-linear model pharmacodynamically can be describe ?

A

𝐸 = 𝐸0 + 𝑆 ∗ 𝑙𝑜𝑔[𝑑𝑟𝑢𝑔]

27
Q

Give 1 advantage and 1 disadvantage for log-linar model

A
  • Advantages
    – Applicable over large concentration range
  • Disadvantages
    – Limited predictability outside of 20-80 % rang
28
Q

How Sigmoidal Emax model can be defined? ( Equation)

A
29
Q

How the slop (nH) can be influenced in the Sigmoidal Emax model ? Explain the meaning of nH > 1

A
  1. Slope (nH) is influenced by number of drug molecules
    bound to effector.
  2. nH >1 may indicate allosteric or cooperative effects
    – Cooperativity occurs when binding of ligand at one
    binding site affects the affinity of other binding sites to their substrates
30
Q

Give an example of cooperative effects.

A

O2 binding to haemoglobin

31
Q

What mean Hysteresis? explain clockwise and anti-clockwise response

A

Hysteresis happens when Identical [drug] can lead to different pharmacological response. Response is dependent upon whether the drug concentration is on ascending or descending phase of the loop.

  1. Clockwise: Response decreases with time.
  2. Anti-clockwise: Response increases with time.
32
Q

sketch clockwise hysteresis graph and give 1 example.

A

Examples:
* Benzodiazepines
– Loss of modulator binding site
* Amphetamine
– Exhaustion of mediators

33
Q

How can be model a delay response?

A

Can be modelled using ‘Effect
Compartment’
* Hypothetical PD compartment
that links to the plasma
compartment containing drug
* Transfer of drug from plasma to hypothetical effect compartment governed by a first order rate constant - keo
* Only free drug can diffuse into effect compartment
* Pharmacological response
depends on the rate constant keo and [drug] in effect compartment

34
Q

sketch Effect Compartment

A
35
Q

What are the Indirect influences for response profile?

A

Stimulation of synthesis rate
– CYP induction
* Inhibition of synthesis rate
– Warfarin inhibition of prothrombin
* Stimulation of degradation
– Insulin effect on glucose
* Inhibition of degradation
– DPP4 inhibitor decrease of GLP-1 C

DMPK (7 decks)

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