Pharmacokinetics 1 + 2 Flashcards
what is pharmacokinetics (PK)?
what the body does to the drug (ADME)
what is pharmacodynamics?
what the drug does to the body i.e. mechanism of action
what are the stages to collecting and analysing PK data?
- drug is administered
- Blood sample is taken
- Analyse the blood via HPLC or LC-MS or Atomic absorption spectrometry
what are the main types of pharmacokinetic (PK) data analysis?
- Non-compartmental analysis
- Compartmental
- Population PK models
- Physiologically-based (PBPK) (bottom-up approach)
what is the straight line equation of PK drug elimination?
C = -k.t + Co C = Conc K = rate constant t = time Co = conc at time zero
(negative sign showing the loss of the drug with time (so a negative line gradient)
what is zero order process of drug elimination?
elimination of a constant amount of drug per unit of time, independent of drug concentration
what is first order process of drug elimination?
constant proportion of drug eliminated in a defined time period
what is absorption?
the transfer of an exogenous compound (i.e. drug) from site of
administration into the systemic circulation
what type of compounds cross cell membranes easier and are rapidly absorbed?
lipid-soluble compounds
what parameters are looked at when talking about absorption?
Cmax and Tmax
what is the trapecoid rule to calculate area under the curve?
the sum of the area of all the trapezoids using this equation: (C1+C2)/2 X (t2-t1) to work out the area of one trapezoid
what is bioavailability a measure of?
the extent of absorption after extravascular administration
how do we calculate bioavailability?
(% of parent drug in urine after oral dosing) / (% of parent drug in urine after IV dosing)
what determines the distribution of drugs into tissues from the blood circulation?
– Its ability to cross cell membranes (based on physiochemical properties)
– Blood flow to individual tissues
– Extent of its plasma protein binding
what effect does drug binding to plasma proteins have?
it increased the volume of distribution as if it’s bound to proteins it won’t be able to diffuse into tissues
how do we calculate volume of distribution?
(total amount of drug in body) / (conc of drug in blood)
what does a volume of distribution of <3L mean?
drug is mostly in plasma
what does a volume of distribution of ~40L mean?
even distribution of the drug throughout the body
how do we calculate half-life?
t1/2 = 0.693/K
where K= Clearance / vol od distribution
how many half-lives does it take usually for a compound to reach steady state?
5 half-lives
what are the features of a compartmental fit/model?
- use exponential equations to describe the curve
- accomplished by theoretical compartments and transfer rates
- Can be used for simulations (to an extent)
what is the one compartment model?
- assume it’s a linear process
- all tissues and organs are lumped into one compartment
what is the two-compartment model?
- assumes the body doesn’t conform to one compartment
- represent a group of similar tissues or fluids
- more flexibility
what is the ‘central’ or ‘peripheral’ compartment?
-a compartment including blood, heart, lungs, liver and kidneys
what are the features of population pharmacokinetic models?
- intensive and sparse sampling
- computationally intensive
- longer analysis time
- allows provision for PK/PD modeling
what are advantages of individual PK analysis methods?
- simple
- robust
- model-independent
- user-friendly
- rapid
what are disadvantages of individual PK analysis methods?
- assumes linear PK
- Single analysis - cannot address multiple doses
- study design often limits analysis
- model - independet
what are advantages of population PK analysis methods?
- robust
- provides structural model for PK/PD
- Any route of admin
- Linear and non-linear PK supported
- descriptive and predictive
- studies can be pooled
what are disadvantages of population PK analysis methods?
- less rapid
- less user-friendly software
- more expertise required for analysis
What is PBPK and how is it different from ‘traditional’
PK approaches?
- traditional PK approaches lump kinetically similar tissues together in a way that typically bears no relation to anatomical structure or physiology
- PBPK has compartments representing organs or tissues whose drug conc are assumed to be uniform
what can we use the PBPK model approach for?
- simulation of clinical trials without the need for clinical data
- estimation of tissue specific drug concentration
- assessment of potential for drug-drug interactions
what effect does a change in dose have on non-linear pharmacokinetics?
- causes a disproportionate change in AUC
- affects metabolism, transport(distribution) and absorption
true or false:
‘the rate of elimination is not proportional to the concentration or
to dose given’?
True
what is the role of pharmacokinetics in drug development?
to look at:
• In vivo (animal models)
• In man (phase I clinical trial – first in man)
• In clinic (several stages of clinical trial before
drug approval)
why can small animals tolerate relatively larger doses?
as they have a more rapid clearance rate.
what factors are considered when you individualise a dose?
– Renal function
– Hepatic function
– Genetics
what is used to help predict drug action/metabolism?
– Liver function tests
– Marker compounds
– Pharmacogenetics
what are you testing for in liver function tests?
-bilirubin levels
-liver function enzymes
(if these are raised, shows a sign of hepatic dysfunction)
what is Pharmacogenetics?
Study of how genetic variations affect drug response
in therapeutic drug monitoring, what is monitored in the clinical trials?
efficacy and toxicity
in therapeutic drug monitoring, what is monitored in the lab tests?
pharmacokinetics, pharmacodynamics and pharmacogenetics
what are the characteristics of drugs with a potential for therapeutic dose monitoring?
(i) variable or unpredictable relationship between dose and resulting plasma
drug concentrations
(ii) narrow therapeutic window
(iii) ability to correlate measured drug concentration with efficacy and/or
toxicity
(iv) availability of reliable and clinically feasible assays
what is ‘therapeutic window’?
- range of drug exposures that produce a therapeutic response without causing any significant adverse effect in patients (the range between minimum effective concentration and minimum toxic concentration)
