Clinical studies to measure pharmacokinetics Flashcards
Why is Pharmacokinetics important in drug development?
Enables us to find out how safe and efficacious a drug is.
They also help determine drug dose and dosing schedules.
What is pharmacokinetics
the movement of drugs in the body.
What is the importance of pre-clinical studies?
used to predict safety and efficacy of drugs in animal studies.
What are the two disciplines of pre-clinical trials
Toxicology and general pharmacology
Why are pharmacokinetic studies important?
ADME parameters
safety and efficacy
Helps to determine the half -life of a drug (prediction of drug safety profile)
Why is plasma concentration important?
An important predictor of drug effect
What are the key determinants of plasma concentration?
Absorption
Distribution
Metabolism
Excretion
What is clearance?
metabolism and excretion
Where can PK information be summarised?
Investigator brochure
List the effects of PK on physiology (ADME):
GI tract (A,M)
Liver (M,E)
Kidneys (M,E)
Blood/Blood flow (D, protein binding)
what is the effect of decreased kidney function on PK?
Decreased elimination and protein binding
what is the effect of intestinal disease on PK?
Impaired absorption
what is the effect of liver disease on PK?
decreased first pass metabolism and elimination.
fluid retention
what is the effect of congestive heart failure?
decreased GI absorption and elimination.
altered volume of distribution
what is the effect of ageing on PK?
decreased first pass metabolism, protein binding, hepatic and renal excretion.
what does the rate and extent of distribution depend on?
Blood flow
active transport. diffusion
plasma protein binding (albumin) tissue binding
disease
what is the distribution of plasma?
5% proportion of total body fluid.
what is the distribution of interstitial fluid?
15%
what is the distribution of intracellular fluid?
35%
what is the distribution of intracellular fat?
20%
What is the aim of drug metabolism?
to decrease drug activity.
to convert lipid soluble drugs into more polar water soluble metabolites to be excreted in bile or urine.
where does drug metabolism take place
in the liver as phase 1 and 2 reactions
what drug is an exception to liver metabolism?
codeine
Gut wall have enzymes that contribute to metabolism (CYP450)
what is phase 1 metabolism?
converting molecules into simpler forms
what is phase 2 metabolism?
conjugation, making molecules more water soluble.
what enzymes are involved in metabolism phase 1?
monoamine oxidase
alcohol dehydrogenase
what are the routes of excretion?
kidney
Biliary
sweat/breath/breastmilk
what is renal excretion?
Glomerular filtration proximal tubule
proximal and distal tubules
what is biliary excretion?
active transport/secretion e.g. Rifampicin
Into Bile and Faeces
what are the parameters for plasma concentration?
Cmax = max conc.
Tmax = time taken to reach max conc.
t1/2 (half-life) = time taken for drug conc. to fall by 1/2
area under the curve
what does the area under the curve signify?
the total amount of drug the system is exposed to for the entire time course
what are the conceptual parameters?
clearance
bioavailability
volume of distribution
what is bioavailability?
proportion of drugs reaching systemic circulation
what are the factors influencing bioavailability
pharmaceutical preparation
physiochemical interaction
patient factos
1st pass metabolism
What is the investigator brochure?
a comprehensive summary of the preclinical and clinical pharmacology data for the investigational medicinal product (for first in human trial, there will be no clinical data available).
What is the investigational medicinal product dossier?
It contains information related to the quality, manufacture and control of the investigational medicinal product.
