Lec 1- Basic pharmacokinetics

Question 1

What is pharmacokinetics

Answer 1

• Pharmacokinetics can easily be defined as
• What the body does to the drug
• It defines the kinetic change in a drug in the body over time
• If the pharmacokinetics of a drug are poor, it can cause significant problems clinically

Question 2

How is it used

Answer 2

• Lead optimisation
• Pre-clinical optimisation (starting doses, toxcitiy, therapeutic window)
• Phase 1 FIM (starting doses, toxcitiy, therapeutic window)
• Phase 2,3 = large trials (variabiliy in populations, dosing frequency)
• Phase 4 = post market
• Pharmacokinetics is first applied during drug discovery and development, and primarily during clincial trials to design the correct starting doses for animal studies
• Which are then adjusted for first-in-man studies before being again used to propose a final dosing schedule for FDA submission and marketing

Question 3

Clinical application of pharmacokinetics

Answer 3

• Route of administration
• Dosage form
• Dosing intervals
• Food effects- flucloxacillin (bad with food), some anti-malarials (increase effectiveness when taken with food)
• Frequency of adverse effects
• Dose adjustments
• MUR’s

Question 4

Pharmacokinetics deffinitions

Answer 4

• Absorption- how does it get into the body
• Distribution- how does it move around the body
• Metabolism- will it remain intact
• Excretion- how fast is the drug being eliminated

Question 5

ADME- Absorption

• What is drug absorption
• What ways can you get a drug into a body
• Is it an easy or complex process

Answer 5

• When we talk about absorption we refer to the amount of drug reaching the part of the body what we can routinely sample during clinical trial (ie the blood)
• Absorption is a complex process think about what happens when you take a drug orally
• Absorption is a complex process, think about what happens when you take drug orally
• The rate (how quick) and the extent (how much) of absorption is important to pharmacokinetics and is described by 2 terms

1. Absorption rate (ka)- how fast drug gets into circulation
2. Oral bioavailability (F)- how much of the drug ends up in blood

Question 6

What could alter the absorption and hence the clinical outcome of a drug

Answer 6

• pH of stomach- through food, or other medicines (antacid)
  
  • This is a problem because it effects ionisation of the drug, the more ionised the drug the less is absorbed due to phospholipid membrane
• Drugs which effect peristalitc movement in small intestine which can effect absorption of the drug
• Salt forms= poorly soluble drugs can be made into a salt which decrease dissolution time and therefore increase absorption rate

Question 7

Pharmacokinetics- Distributio

Answer 7

• Poorly distributed drugs= mostly stay in circulation
• Well distributed drugs will spread to all tissues
• Sometimes the distribtion can be different in different tissues (e.g. brain tissue)
• Before you can expect to see a clinical response in a patient, te drug has to be able to leave the circulation (blood) and diffuse out into all of the tissues and organs
• This is a really key concept as not all of the drug we give to patients will reach the target tissue
  *

Question 8

Pharmacokinetic distribution- Distribution of a drug out of the circulation and into a tissue is affected by

Answer 8

• Organ flow (is it rapid or slow)- blood flow to brain is far quickier than to digits
• Organ barrier sites (is there a permeability barrier) e.g. blood brain barrier
• When we are thinking about clinical effects the time it takes for the drug to distribute out of the circulation and into the target site is important. This means 2 types of distribution effect
  
  • Perfusion limited
  • Permeability limited
• When we talk about distribution, the volume of distributio (Vd) is important in telling us how much a drug can distriute in the body and is VITAL in calculating target concentrations when choosing the right dose to give (loading dose)

Question 9

What could alter the distribution and hence clinical outcome of a drug

Answer 9

• Renal
• % of adipose tissue (bodyweight)
• Heart function
• Pregnant (blood volume increase)
• Amputee (Vd of a drug will be different- due to different volume)
• Aneamic
• Burns (due to loss of ability to maintain moisture leading to dehydration

Question 10

Pharmacokinetic metabolism

Answer 10

• A mechanism for destroying drugs, making them easier to remove from the body
• This is typically a pathway where the body removes toxins/Drugs Phase 1 and 2 process
• Typically in the liver and intestine
  
  • Mediated by drug metabolism enzyme (cP450)
  • Which metabolise drugs for eventual metabolism
  • Protective process (Endogenous function in the body
• Phase 1= put on polar groups
• Phase 2= conjugation
• CYPp3A4- one of the main enzymes responsbile for metabolism

Question 11

Pharmacokinetic elimination

Answer 11

• Remember all drugs (and toxins) are eventually removed from the body
• The process involves excretion of drug from the body through
  
  • Urine (kidneys)
  • Faeces (liver-small intestine)
  • Sweat
  • Tear fluid
  • Hair
  • Lungs
• When we talk about excretion there are 3 important terms to think about
  
  1. Half-life-
  2. Elimination rate-
  3. Clearance-

Question 12

What could alter the excretion and hence the clinical outcome of a drug

Answer 12

• Kidney and liver funtion
• Elderly (poor organ function)
• Alcoholic- liver cirrhosis
• Hepatitis

Question 13

Pharmacokinetic- graphically

Answer 13

• Clinical pharmacy-get information on drug concentrations (loading doses, through concentrations)
• Collect blood samples over set time periods
• When we work with pharmacokinetic data we are working from plasma concentrations collected over time
• Graphically, we present this data using concentration vs time graphs
• The shape of the graphs depends on the route of adminstration and tells us

Question 14

Pharmacokinetics and patients

Answer 14

• Pharmacokinetics is used to design dosage regimen in patients, this can be done during development of new drugs or in clinical setting (warfarin, Li, clonazepine, digoxin)
• How long is absorption
• Is distribution rapid
• How effective is elimination
• Do we see an effect (duration of action)
• Is it toxic (MTC- max therapeutic conc NB MEC= minimum effective conc)
• How do I maintain the duration of action
• Plasma concentration profiles are really important in understanding the impact of ADME on the clinical activity