PED2001 pharmacokinetics Flashcards
pharmacokinetics - what thew body does to a drug
absorption
distribution
metabolism excretion
what are clinical pharmacokinetics
the application of pharmacokinetic principles to individual patients
what is pharmacodynamics
what the drug does to the body
what is the general order of ADME
site of administration - absorption
plasma - distribution, metabolism/excretion
urine/faeces
what are the route of administration of drugs
intravenous
oral
intramuscular
subcutaenous
transdermal
inhaled
intrathecal
sublingual
rectal
vaginal
what are the ways of gathering drug administered data
oral
IV
what are the ways of gathering blood sample taken data
separation of plasma
ultrafiltration
derivatisation
what are the ways of gathering analysis data
HLPC - UV detection (microg/ml)
HPLC - fluorescence detection (ng/ml)
LC-MS - mass specific detection (pg/ml)
atomic absorption spectrometry
what is concentration-time profile
schematic representation of the relationship between drug exposure, toxicity and response
what are the main types of pharmacokinetics data analysis
non compartmental analysis
compartmental
population PK models
physiologically based
what are the PK terms of the straight line PK principles
C=-K.T + C0
- c = concentration
- t= time
- k = rate constant
- C0 = concentration at time zero
- negative symbol indicating loss of drug with time
what are elimination rates
most commonly need to predict how a drug concentration in the plasma with change with time
what is a zero order process
elimination of a constant amount of drug per unit of time (independent of drug concentration)
what is a first order process
involve a constant proportion of drug eliminated in a defined time period
ln c = ln c0 - K.T
What is included in absorption
- transfer of a exogenous compound from site of administration into systemic circulation
- in general lipid-soluble compounds cross cell membranes more easily and are more rapidly absorbed
what are the parameters of absorption
CMax - maximum concentration of compounds after administration
TMAX - time at which Cmax is reached
how do you calculate AUC
sum all the component trapezoid areas to obtain the total AUC
AUC = Ct/K
how can we calculate bioavailability (F)
AUC oral/AUC x dose i.v./dose oral
% in urine as parent compound after oral dosing/ % in urine as parent compound after intravenous dosing
what does distribution depend on
its ability to cross cell membranes
blood flow to individual tissies
extent of its plasma protein binding
what is the free drug hypothesis
only free drug can exhibit pharmacological effect
unbound drug is free to diffuse through membrane and interact with receptors
how does protein binding affect distribution
greater binding to tissue proteins will result in a larger volume of distribution
what is the distribution parameter of volume distribution
a dilution factor which represents the relationship between the amount of compound in the body and the plasma concentration
what is the relevance of Vd estimates for distribution
plasma protein binding = lower Vd
tissue binding = higher Vd
What is the equation for Vd
plasma volume of drug + apparent tissue volume of drug (fraction unbound in plasma/ fraction unbound in tissue)
how do physiochemical properties effect mechanism of elimination
volatile gases are eliminated by exhalation
water-soluble compounds are often eliminated to some degree unchanged in the urine
lipid-soluble compound typically undergo metabolism to more water-soluble metabolites that are then excreted in the urine and/or bile
how can we calculate clearance
total CL = hepatic CL + renal CL + all other CL
why is a half life an elimination parameter
it takes 5 half lives for a compound to reach stead-state after chronic exposure
what is the relationship between CL, Vd and t1/2
CL/Vd = K
t1/2 = 0.693/k
what is one compartment model
linear processes assumed
all tissues/organs lumped into one compartment
v= volume of distribution
k = elimination rate constant
what is 2 compartment model
assumes body doesn’t conform to one compartment
two compartment models do not represent specific tissues or fluid but may represent a group of similar tissues or fluid
processes of distribution and elimination
what is the central compartment
blood
heart
lungs
liver
kidneys
what are the features of population pharmacokinetic models
intensive and sparse sampling
computationally intensive
longer analysis time
allows provision for PK/PD modelling
what are the ads of individual PK
simple
robust
model-independent
user friendly software
rapid
what are the disadvantages of individual PK
assume linear PK
model-independent
single analysis, cannot address multiple doses
study design often limits analysis
what are the advantages of population PK
robust
provides structural model for PK/PD
any administratuion schedule/route
linear and non-linear PK supported
descriptive and predictive
studies can be pooled
what are the disadvantages of population PK
less rapid
less user friendly software
more expertise required for analysis
what is PBPK
composed of a series of compartments representing organs or tissues whose drug concentration are assumed to be uniform
what are the advantages of PBPK
can be used to extrapolate in vivo situations from in vivo or even animal data
allow estimation of drug time course in any organ/tissue of interest incorporated in the model
allow stimulation of different dosing regimens, large-scale clinical trials, drug interactions, parent and metabolite pharmacokinetics
what can the PBPK model approach be used for
stimulation of clinical trials without need for clinical data
estimation of tissue specific drug concentrations
assessment of potential for drug-drug interactions
what is the role of PK in drug development
idea
in silico
in vitro
in vivo
in man
in clinic
treatment
what is allometric scaling
small animals can tolerate relative larger doses due to more rapid drug clearance
longer half life in human equates to increased tissue exposure
limitations in terms of available volumes of blood for studies
what is PK/PD relationship
correlations investigated between [crizotinib] plasma and ALK/MET inhibition
rate limiting distribution of crizotinib from peripheral blood to target tumour
PK/PD model developed to provide EC50 values for ALK and MET inhibition
ALK is a better target
what are the beneficial characteristics for drugs with potential for TDM
variable or unpredictable relationship between dose and resulting plasma drug concentrations
ability to correlate measured drug concentrations with efficacy and/or toxicity
availability of reliable and clinically feasible assays
what are the clinical applications of TDM
cardiovascular disease
HIV/AIDs
epilepsy
infections/septicemia
respiratory disease
what is the rationale for TDM in oncology
narrow therapeutic window between systemic exposure for toxicity and response for most established anticancer agent
large degree of inter patient variability in drug disposition at a given dosage for vast majority of anticancer drugs
