PK Concepts

PK: drug absorption, distribution, elimination kinetics, predict disposition

PD: interaction b/w [drug] and receptor response

PK-PD model: drug intensity over time

Drug binds protein, work better with plasma

Bigger therapeutic window, easier dosing control, less toxic side effects

Mathematical model and stats: estimate drug dose/efficacy over time

PK parameter: constant for a drug

PK function: relate ind to dep (i.e. time to [drug])

3 models categories:
Empirical: no mech explained; simple ([plasma] vs. body weight)

Physiological: need sample tissue, monitor drug flow; ideal but need data

Compartmental: if know tissue [drug], binding; used most

1st order: drug metabolized in liver

0 order: drug metabolism is saturable (or aspirin, phenytoin with xs)

If VD > Cp, drug leaving fast, no drug found in tissue

Double dosage doesn’t mean double duration time

Cl rate is not constant, but can be expressed as constant (=k)

IV bolus
- Not useful for treatment

- Can avoid large spike in conc

- Avoid drug rxns like pH, solubility issues

- Give massive dose at first to overcome distribution phase

- Drug instantly in circulation

Urinary extraction data lim

- Need to have some unmodified drug in urea

- No intf in quantification assay

- Frequent, empty bladder

- Wait 7 t1/2

- pH of urine

1 compartment model: only worry elimination, ignore distribution

2 compartment model
- Non-linear distribution: diff rates in diff tissues

- Plasma: central comp, rapid EL

- Tissues: peripheral comp, varied EL rates

- Drug slowly end up in tissues

- Elimination mostly from central, act like 1 comp (drop in same rate)

Residual method to find A, B, α, β, k, k12, k21

- Plot Cp vs time in log scale

- Extend linear part to find y-int (log B)

- Sub data from linear, find β

- For non-linear, find Cp’

- Find Cp - Cp’, plot over time (line a)

- Find A, α with same method

- Find k values

β: elimination from central

- Drug declines more slowly, β < k

- K is true elimination constant

- Use t 1/2 β to find dose

3 compartment model

IV infusion
- Precise control of Cp

- Infusion 0 order, constant rate

- Slow rate over long time

- Rate in = out

- Reach SS if elimination 1st order, approach SS if 0 order

- 4.23 half lives required for SS

> 1 compartment
- Double infusion rate, double Cp

- SS indep on: t, R

- Dep on: half life, VD, Cl

- If right DL selected, reach SS faster

> 2 compartment
- Can’t get to SS instantly

- VD not constant

- Assume Cp = C body at SS

- a: normal, no loading dose

- c: fast infusion

- b, d: with loading dose

Drug (oral)
- Fat soluble: passive diffusion

- Bind carrier protein: active transport

- Exposed to liver first

- Water soluble: pass aq channel - Might be metab b4 reach rest of body