Lecture 2 PK modeling and parameters

Question 1

Physiologically Based Pharmacokinetic Model

Answer 1

• Blood-flow model, Perfusion models
• Uptake of drug into organs is determined by the binding of drug in these tissues.
• Based on actual anatomic tissues, their ability to accumulate drug and their respective blood flow.
• The actual tissue volume is used i.e determined physiologically rather than mathematically.
• A good PBPK model can potentially predict realistic tissue drug concentrations.
• Missing information will lead to bias or error in the model.
• No data fitting is required.
• Describe drug distribution in animals, because tissue samples are easily available for assay.
• For some drugs, human data may be extrapolated (Sawada et al, 1985) because the mass of various body organs or tissues, extent of protein binding, drug metabolism capacity, and blood flow in humans and other species are often known or can be determined.
• Assumptions: Tissue samples are often not available for human subjects! Therefore, most physiological models assume an average set of blood flow for individual subjects.

Question 3

Transcellular drug absorption

Answer 3

• Drug movement across the cell
• Movement is inhibited by
  
  • cell membrand characteristics
  • Efflux pumps, transporters

Question 4

First Order Process

Answer 4

1. Rate constant= k unit is time-1, hr-1, min.-1
2. Represents the fraction of drug eliminated per unit time.
3. Rate is proportional to the amount/ concentration of the drug.
4. Curvilinear.
5. Concentration dependent.
6. K=0.29 hr-1 it means that 29% of the drug present will be eliminated.

Question 5

The Volume of Distribution (Apparent Volume of Distribution)

Answer 5

• hypothetical volume in which the drug is assumed to be uniformly distributed in
• called apparent as it has no true physiological meaning.
• Apparent implies that the volume determined has the appearance of being true but is not a true volume.
• should be considered in estimating the drug dose regimen.
• It correlates the concentration of drug in the body to the administered dose.
• drug property not a biological system property.
• constant for a given drug
• Drugs with high affinity to tissues will have higher distribution into tissues and thus will have high VD.
• Drugs with high plasma protein binding will have higher plasma concentration and thus low VD.

Question 6

Zero Order process

Answer 6

1. Rate is a constant.
2. k0 is the zero order rate constant with a unit of mass/time e.g mg/hr mghr-1 or Concentration/Time= mg/mL.h
3. Independent of the drug concentration (i.e. concentration independent).
4. Amount of drug eliminated is constant.
5. Linear
6. Examples are:

• controlled release dosage forms administration.
• Intravenous infusion drug administration.

Question 7

Paracellular movement

Answer 7

• Drug movement between cells
• Movement inhibited by
  
  • Decrease surace area between cell- narrow path
  • Tight Junctions

Question 8

Carrier Mediated Transport

Answer 8

• Specificity
• Saturation and competition
• Uptake transporters move drug molecules into the blood and increase plasma drug concentration ( influx)
• efflux transporters move drug molecules back into the gut lumen and reduce systemic drug absorption.

Question 9

Passive diffusion

Answer 9

• the process by which molecules spontaneously diffuse from a region of higher concentration to a region of lower concentration
• No external energy is expended
• Major process
• Conc. dependent, not saturable

Question 10

Elimination Half-life

Answer 10

• biological half life of a drug.
• time (days, hrs, min etc) required to eliminate 50% of the drug from the body.
• It is a constant for a drug.
• t 1/2 = 0.693 / k

Question 11

Why is a Pharmacokinetic model needed?

Answer 11

1. Predict (plasma, urine, tissue) concentrations with any dosage regimen.
2. Summarize or ‘compress’ data.
3. Describe how changes in physiology or disease affect the absorption, distribution, or elimination of the drug.
4. Correlate drug concentrations with pharmacologic or toxicological activity and explain drug interactions.
5. Optimize dosage regimen (Individualized Therapy).
6. Analyze differences in the rate or extent of availability between different formulations (bioequivalence).