Clinical studies to measure Pharmacokinetics

Question 1

What is pharmacokinetics?

Answer 1

Movement of drugs within the body.

Question 2

What is the relationship between PK and PD?

Answer 2

PK : 
- Drug
- Concentration in Blood 
This links to PD: 
- Drug Receptor Interaction 
- Effect 
- Clinical Outcome

Question 3

Why is PK necessary to study?

Answer 3

Ensures the best conditions of efficacy and safety is used.

Allows dosage and dosing schedule to be administered.

Question 4

What is the importance of plasma concentration?

Answer 4

Important predictor of drug effect.

Question 5

What are the key determinants of plasma concentration?

Answer 5

Absorption
Distribution
Metabolism
Excretion

Question 6

How is clearance brought about?

Answer 6

Metabolism and Excretion added together.

Question 7

During clinical trials, where is the PK information summarised?

Answer 7

In the Investigator Brochure (known as IB)

Question 8

What is the physiology affected by pharmacokinetics?

Answer 8

GI tract ( A and M )
Liver ( M and E ) 
Kidneys ( M and E) 
Blood / Blood Flow ( D )
Skin
Blood - Brain Barrier

Question 9

What is the effect of ageing on the pharmacokinetics?

Answer 9

• Decreased first pass metabolism / protein binding / hepatic and renal excretion.
• Increase in volume of distribution.

Question 10

What is the effect of intestinal disease on pharmacokinetics?

Answer 10

Impaired absorbance.

Question 11

What is the effect of kidney function on pharmacokinetics?

Answer 11

Decrease in elimination and protein binding.

Question 12

What is the effect of liver disease on pharmacokinetics?

Answer 12

Decrease in 1st pass metabolism and elimination.

Fluid retention too.

Question 13

What is the effect of congestive heart failure?

Answer 13

Decrease in GI absorption.

Altered volume of distribution.

Question 14

What is the speed of fate affected by?

Answer 14

Determined by distribution.

Question 15

What is the rate and extent of distribution dependent on?

Answer 15

Blood Flow
Diffusion (Lipid Solubility and Size)  
Active Transport
Plasma Protein (Mostly Albumin)
Tissue Binding
Disease.

Question 16

What is the distribution of the plasma?

Answer 16

5% proportion of total body fluid.

Question 17

What is the distribution of the interstitial fluid?

Answer 17

15% proportion of total body fluid.

Question 18

What is the distribution of the intracellular fluid?

Answer 18

35% proportion of total body fluid.

Question 19

What is the distribution of the intracellular fat?

Answer 19

20% proportion of total body fluid.

Question 20

What is the aim of drug metabolism?

Answer 20

Decrease drug activity

Convert lipid soluble drugs to more polar / water soluble metabolites in order to be excreted in bile or urine.

Question 21

Why are lipid soluble drugs not easily cleared by the kidney?

Answer 21

Largely reabsorbed in the proximal tubule.

Question 22

Where does drug metabolism usually take place?

Answer 22

In the liver as Phase I and II reactions.

Question 23

What is metabolism Phase 1?

Answer 23

Phase One: Cytochrome P450 Enzymes are involved (IN THE LIVER).

• Oxidation
• Reduction
• Hydrolysis

Question 24

What other enzymes are used in metabolism phase I?

Answer 24

Monoamine Oxidase

Alcohol Dehydrogenase

Question 25

What is metabolism Phase 2?

Answer 25

Further increases water solubility.

Question 26

What are the processes which occur in metabolism Phase 2?

Answer 26

Glucuronidation Sulphation Acetylation Methylation

Question 27

Do only some drugs undergo Phase II metabolism?

Answer 27

Yes.

Question 28

What are the 3 main routes of excretion?

Answer 28

Renal (Kidney) Biliary (Liver) Sweat / Breath / Breast Milk

Question 29

Explain Renal Excretion.

Answer 29

Glomerulus : Glomerular Filtration Proximal Tubule Proximal and Distal Tubules.

Question 30

Explain Liver Excretion.

Answer 30

Involves active transport and secretion. Conjugated compounds which are water soluble are excreted in the bile. Bacteria hydrolyses the conjugated drug by glucuronidase. Enters the ENTEROHEPATIC CIRCULATION.

Question 31

What are the plasma concentration parameters?

Answer 31

Descriptive Parameters = Cmax / Tmax / AUC / t1/2. | Conceptual Parameters = Clearance (CL) / Bioavailability (F) / Volume of Distribution (Vd).

Question 32

What is the significance of the area under the curve?

Answer 32

Signifies the total amount of drug exposed for the entire time course.

Question 33

What is the conceptual PK parameter?

Answer 33

Clearance = Bioavailability = Volume of distribution

Question 34

What are the factors which affect bioavailability?

Answer 34

Pharmaceutical Preparation Physiochemical Interaction Patient Factors 1st Metabolism

Question 35

What does Clearanc (CL) mean?

Answer 35

Volume of blood cleared of drug per unit time. (L/hr).

Question 36

What is the maximum clearance?

Answer 36

Maximum blood flow to that organ.

Question 37

How do you work the elimination rate?

Answer 37

clearance X plasma drug concentration

Question 38

What does the elimination rate equal?

Answer 38

Maintenance dose rate. (MDR)

Question 39

How do you work out the maintenance dose rate?

Answer 39

clearance X steady state plasma drug concentration

Question 40

How do you work out the volume of distribution?

Answer 40

Total amount of drug in the body = plasma concentration.

Question 41

What does the volume of distribution rely on?

Answer 41

Size of molecule Plasma protein binding Lipophilic

Question 42

What is a high volume of distribution?

Answer 42

Very lipophilic and very small sized molecules. | Achieves a steady state plasma drug concentration much MORE quickly.

Question 43

What is a low volume of distribution?

Answer 43

Not very lipophilic | Plasma protein binding and large molecules.

Question 44

What does t1/2 determine?

Answer 44

Duration of action after a single dosage. | *In multiple dosages = Time take to reach steady state of drug concentration*