Preclinical pharmacokinetics Flashcards
Purpose of preclinical PK
to assess safety/toxicology and for preclinical optimisation of doses in animal studies
Will look at microsomal stability, CYP inhibition, permeability, metabolite profiling, species comparison of CL, in vivo PK parameters, bioavailability, etc…
In 1990, PK was the primary reason for drugs failing in drug development. now it is not a major cause anymore.
Log P
A parameter that determines if a neutral compound is able to dissolve in lipids and water. the logarithmic partition coefficient: [organic]/[aqueous]
implication is if the solubility is low there would be altered bioavailability. high accumulation in fat may occur if there is high log P. low log P identifies high affinity for aqueous phase
Molecular weight
Molecules over 500g/mol do not easily cross the cell membrane. would affect oral absorption.
Solubility
the maximum amount of substance that can be dissolved in an aqueous solvent at a certain temp.
poor solubility leads to poor oral bioavailability. also dependent on the pH of GIT and the pKa of the compound
Intrinsic clearance
the intrinsic ability of the compound to be cleared without the influence of blood flows or plasma protein binding
high clearance indicates poor metabolic stability, rapid clearance, and a subsequent short duration of effect
Apparent permeability
estimates permeability across the intestinal epithelium - e.g., Caco2 cell lines
identifies the absorption and the influence of efflux/uptake transporters. can also identify permeation into different tissues
a < 10^-6 Caco Papp identifies 0-20% permeability,
10^-6 - 10^-7 identifies 20-70% absorption
> 10^-7 identifies 70-100% absorption
Plasma protein binding
PPB and lipophilicity often correlated. drugs bound to plasma proteins often cannot cross the cell membrane.
PPB can increase t1/2
should also assess the PPB of metabolites.
PPB-mediated DDIs do not tend to occur with drugs that have < 85% PPB
Inhibition constant
the inhibition constants of the drug at enzymes and transporters.
if less than 10 micro molar, then high risk
Preclinical PK and its application to human studies
defines the expected levels of active drug in the target compartment. important as dose dependency of drug action - quantified in AUC, Cmax, and t1/2
The choice of animal in the in vivo studies is dependent on the similarities to human biology. interspecies differences should be accounted.
As clearance is related to the bodyweight of an animal, human clearance can be predicted based on the clearance rat attained in other species (normally 3 or more used). normally gives within 2-fold prediction.
These predictions are poorer in drugs that have low clearance rates.
