ADME Flashcards
Definition of Pharmacokinetics
What the body does to the drug
- relationship between dosage and plasma levels
Definition of Pharmacodynamics
What the drug does to the body
- relationship between plasma levels and therapeutic effects
Why do we use plasma concentrations instead of tissue concentration?
Tissue concentration is very difficult to obtain from a live patient, and not pleasant. plasma can easily be measured
Relationship between pharmacokinetics and pharmacodynamics?
A dosage/regimen is designed to reach a particular plasma concentration (PK), which is needed to produce a particular response in the patient (PD)
Importance of pharmacokinetics?
to know the extent of distribution of the drug across tissues, to see the degree of the response produced
What is ADME?
Absorption
Distribution
Metabolism
Elimination
ADME model?
Drug dose absorbed into the blood (systemic circulation), then reaches target tissues. Drug lost from the blood by metabolism and elimination at the same time.
The purpose of metabolism of drugs?
Change the structure of the molecule so that it can be excreted more easily in bile/kidneys. some drugs are eliminated unchanged
Definition of absorption?
All processes from the site of administration to the site of measurement
Definition of bioavailability?
a measure of the extent of absorption of unchanged administered compound
Definition of distribution?
Reversible transfer of substance between site of measurement and other sites within the body
Definition of metabolism?
irreversible loss of unchanged substance by chemical conversion
Definition of excretion?
Irreversible loss of unchanged substance
Definition of elimination?
Irreversible loss of unchanged substance from site of measurement
What is pharmacokinetics a function of?
- physicochemical and structural properties of the drug
- dosage form
- route of administration
- physiology of the body
Result of poor pharmacokinetic properties of a drug?
limited clinical application - as not taken up correctly
What physiological factors can impact pharmacokinetics?
genetics, size, age, disease, co-administration, environmental factors e.g. smoking - affect on transporters etc
What are the components of pharmacokinetics?
data: used to describe PK processes (e.g. plasma conc/time data, or deerived e.g. cumulative amount excreted)
models
Types of PK models used for ADME processes?
- Single equation: C = CoE(-KT) or differential
rate constant - used to calculate drug conc at a given time - Kinetic compartmental models - data driven, used for fitting sparse clinical data (all individuals data fitted together to get an idea of PK). empirical - used to describe the data
- PBPK models (physiologically based) - major tool for predicting in vivo PK from in vitro data
What is the one compartment kinetic compartment model?
drug enters and absorbed –> drug in central compartment (blood) –> elimination
What is the two compartment kinetic compartment model?
drug enters and absorbed –> drug in central compartment (blood) –> elimination
from central compartment - reversibly enters peripheral compartment via distribution (must be supported by data)
Single compartment model of drug absorption and elimination?
Drug at absorption site -> drug in body -> then excreted OR metabolised -> metabolite in body -> eliminated metabolite
Equation relating dose and pharmacokinetics?
dose = amount at absorption site + amount in body + amount excreted + amount metabolised
Equation showing rate of change of drug in body?
rate of absorption - (rate of excretion + rate of metabolism)
What is the therapeutic window?
the plasma concentration window at which the drug has a therapeutic effect
Determinants of efficacy and toxicity of a drug?
Exposure: permeability and transport, metabolism, route of administration
Intrinsic biological effects (wanted and unwanted)
Elimination: metabolism and excretion by liver and kidneys etc
PBPK modelling: physiological/system parameters considered?
tissue volumes and blood flow, tissue composition, intestinal pH, transit times, emzyme and transporter abundance
PBPK modelling: population and external factors considered?
age, gender, race, disease status, genetic status, smoking, diet
PBPK modelling: Drug dependent parameters to consider?
LogP, pKa, molecular weight, permeability, solubility, particle size, Clearance
Benefits of PBPK modelling?
allows simulation of drug plasma and tissue concentration time profiles after iv and oral administration
Role of PBPK modelling in pharma?
early development: ‘learn and confirm’, simulate the profile then use the clinical data to verify
late development: confidence that the model can predict profiles, for special populations e.g. paeds - can guide clinical studies
Definition of disposition?
Elimination and distribution
