8 – Intro to Clinical PK Flashcards
3 options when deciding drug dose and regime
- Follow drug label (MOST OFTEN)
- Look at a research paper
- Individualize treatment for specific patient (usually more ‘extreme’ circumstances)
Pharmacodynamics
- Dose is NOT proportional to effect
- Often when increase dose=not get a better effect and just get closer to the toxic effect
Therapeutic window
- Range between minimum EFFECTIVE and minimum TOXIC plasma concentrations in an INDIVIDUAL
Therapeutic range
- Plasma concentration range in POPULATION likely to produce a desired effect
Clinical limitations of PK data
- 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)
Penicillin for UTI
- Works well because the kidneys get rid of it so much, so there is ton in the urine!
Tulathromycin: plasma vs. tissue drug concentration
- Much higher in the lung than the blood plasma
- Also drops off more slowly
- *may be good for treating pneumonia
Drugs (ex. moxidectin): thin vs. fat animals
- Stays in the fat=last longer in the body
If you were to get a toxic effect, when would it be?
- Cmax = early on!
o Then concentration drops of in a ‘curve’ - Some drugs: need to give them slowly to not get a toxic effect
AUC
- Area under the curve
- Measure of drug and drug time in the body
If you infuse a drug at a constant rate
- Concentration will rise logarithmically to reach a steady state
- Final concentration is related to RATE OF INFUSION
How long does it take to reach steady state?
- Based on half-life of the drug
- Ex. ~7 half-lives
Can you get the drug concentration to steady state faster?
- Loading dose
o Rapid IV bolus followed by sustained infusion
Loading dose equation
- =desired concentration x volume of distribution
Volume of distribution
- =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
When you give a drug any other route than IV…
- 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
Route of administration affects
- Absorption phase
- Bioavailability
- Sustained release
Bioavailability: IV vs oral (flunixin)
- Elimination rate does NOT change
- Bioavailability(F) = AUC oral / AUC IV
- *how much of the drug gets into the blood
Sustained release (ex. penicillin)
- 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
Flip-flop kinetics
- 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
Dosage interval more frequently than half-life
- 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
Dosage interval at same time as half-life
- A little bit of accumulation, but more variation between Cmax and Cmin
Dosage interval less frequently than half-life
- 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
When can you change the dose?
- 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
When can you change the dose interval?
- Based on therapeutic drug monitoring (ex. phenobarb for seizures)
- Based on likely changes in drug clearance (ex. renal or hepatic failure)
Drug formulation is optimized based on
- Pharmacokinetics
- Pharmacodynamics
*both need to be well known
Knowing which drug is ‘better’
- PK parameters do NOT indicate safety or efficacy
Limitations of PK data: volume of distribution
- Just a RATIO
- Don’t know what tissues the drug may be in
- Higher does NOT mean it works better
Limitations of PK data: half-life
- Elimination half-life
- Longer does NOT mean better
- Elimination from tissues may not be the same as in the plasma
Limitations of PK data: plasma concentrations
- May not be relevant to tissue drug concentrations
Limitations of PK data: PK/PD models
- Highly variable between studies
- Numbers are NOT absolute
- Only PREDICTIVE
o Need to have a randomized controlled clinical trial
Summary of PK for vets
- 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
