8 – Intro to Clinical PK

Question 1

3 options when deciding drug dose and regime

Answer 1

1. Follow drug label (MOST OFTEN)
2. Look at a research paper
3. Individualize treatment for specific patient (usually more ‘extreme’ circumstances)

Question 1

Pharmacodynamics

Answer 1

• Dose is NOT proportional to effect
• Often when increase dose=not get a better effect and just get closer to the toxic effect

Question 2

Therapeutic window

Answer 2

• Range between minimum EFFECTIVE and minimum TOXIC plasma concentrations in an INDIVIDUAL

Question 3

Therapeutic range

Answer 3

• Plasma concentration range in POPULATION likely to produce a desired effect

Question 4

Clinical limitations of PK data

Answer 4

• Most studies are done on blood (plasma), but most drugs don’t work in the blood
  o Need to extrapolate from blood levels to tissue levels
• Not all drug use is systemic (ex. skin lesion, put drug on the skin)
• Studies done on small groups of similar animals (Ex. effects of age, gender, sex, body type, pregnancy, lactation)

Question 5

Penicillin for UTI

Answer 5

• Works well because the kidneys get rid of it so much, so there is ton in the urine!

Question 6

Tulathromycin: plasma vs. tissue drug concentration

Answer 6

• Much higher in the lung than the blood plasma
• Also drops off more slowly
• *may be good for treating pneumonia

Question 7

Drugs (ex. moxidectin): thin vs. fat animals

Answer 7

• Stays in the fat=last longer in the body

Question 8

If you were to get a toxic effect, when would it be?

Answer 8

• Cmax = early on!
  o Then concentration drops of in a ‘curve’
• Some drugs: need to give them slowly to not get a toxic effect

Question 9

AUC

Answer 9

• Area under the curve
• Measure of drug and drug time in the body

Question 10

If you infuse a drug at a constant rate

Answer 10

• Concentration will rise logarithmically to reach a steady state
• Final concentration is related to RATE OF INFUSION

Question 11

How long does it take to reach steady state?

Answer 11

• Based on half-life of the drug
• Ex. ~7 half-lives

Question 12

Can you get the drug concentration to steady state faster?

Answer 12

• Loading dose
  o Rapid IV bolus followed by sustained infusion

Question 13

Loading dose equation

Answer 13

• =desired concentration x volume of distribution

Question 14

Volume of distribution

Answer 14

• =total dose of drug / C max
• L/kg
  *gives you an idea of how drug distributes in the body
  Ex. if 0.6= in extracellular and intracellular fluid (60% of body is water)
  Ex. if more than 1=somewhere else in the body and not in the blood

Question 15

When you give a drug any other route than IV…

Answer 15

• It needs to be absorbed into the plasma
  o Typically happens relatively quickly (Cmax)
  o Tmax will not be 0
• ‘triangle’ at front of the curve
• Not all of the drug will get into the bloodstream

Question 16

Route of administration affects

Answer 16

• Absorption phase
• Bioavailability
• Sustained release

Question 17

Bioavailability: IV vs oral (flunixin)

Answer 17

• Elimination rate does NOT change
• Bioavailability(F) = AUC oral / AUC IV
• *how much of the drug gets into the blood

Question 18

Sustained release (ex. penicillin)

Answer 18

• Half life: 20mins = drops off very fast
• Procaine (salt) penicillin: ‘holds’ onto penicillin
  o Doesn’t spike as fast or as high
  o Eliminated, but it is slowly being released for SUSTAINED RELEASE
  *pseudo-infusion

Question 19

Flip-flop kinetics

Answer 19

• Describes situation where a ‘depot’ injection is SLOWLY absorbed over time
• Apparent elimination rate is controlled by the absorption rate from the depot
  *LONG ACTING DRUGS

Question 20

Dosage interval more frequently than half-life

Answer 20

• Drug will slowly increase over time (still considered steady state, 4 half-lives to get there)
• *those with a narrow window (want less variation between Cmax and Cmin)
• Ex. dog with epilepsy (slowly increase to reach a therapeutic level)
• ACCUMULATION WITH MINIMAL FLUCTUATION
• Missing one dose has minimal impact on plasma concentration
• May need a loading dose

Question 21

Dosage interval at same time as half-life

Answer 21

• A little bit of accumulation, but more variation between Cmax and Cmin

Question 22

Dosage interval less frequently than half-life

Answer 22

• Give the drug, it gets eliminated: REPEAT
• Not much accumulation
• Very massive spread between Cmax and Cmin
• Missing a dose greatly affects concentration
• Minimal lag time to achieve desired concentration
• Ex. penicillin

Question 23

When can you change the dose?

Answer 23

• If giving something orally, may increase dose as the bioavailability is reduced (use relative bioavailability)
• Kidney or liver disease
  o Enzyme inhibition=decrease dose
  o Increased clearance due to enzyme induction=increase dose

Question 24

When can you change the dose interval?

Answer 24

• Based on therapeutic drug monitoring (ex. phenobarb for seizures)
• Based on likely changes in drug clearance (ex. renal or hepatic failure)

Question 25

Drug formulation is optimized based on

Answer 25

• Pharmacokinetics
• Pharmacodynamics
  *both need to be well known

Question 26

Knowing which drug is ‘better’

Answer 26

• PK parameters do NOT indicate safety or efficacy

Question 27

Limitations of PK data: volume of distribution

Answer 27

• Just a RATIO
• Don’t know what tissues the drug may be in
• Higher does NOT mean it works better

Question 28

Limitations of PK data: half-life

Answer 28

• Elimination half-life
• Longer does NOT mean better
• Elimination from tissues may not be the same as in the plasma

Question 29

Limitations of PK data: plasma concentrations

Answer 29

• May not be relevant to tissue drug concentrations

Question 30

Limitations of PK data: PK/PD models

Answer 30

• Highly variable between studies
• Numbers are NOT absolute
• Only PREDICTIVE
  o Need to have a randomized controlled clinical trial

Question 31

Summary of PK for vets

Answer 31

• Can’t rely on them solely, NEED research
• Know where the drug is going, how it is eliminated and how long it sticks around
• Can help modify things when you need to