Non-Linear PK Flashcards
What are the characteristics of linear PK?
- PK parameters will not be expected to change with different doses or route of admin
- First order
- Dose-independent
What is linear?
If the dose changes, the plasma concentration, or AUC will change in the same proportion
What non linear PK?
- PK parameters may vary depending on the size of the administered dose
- One or more ADME processes may be something other than first order
- Relationship between the Css or AUC with the size of administered dose is not linear
How does nonlinerarity arise?
Different PK processes (ADME) involve saturation
How does amoxicillin show nonlinearity?
The extent of absorption of drug decreases with an increase in dose
How does disopryamide show nonlinearity?
Staurates plasma protein binding at therapeutic concentrations resulting in an increase in the Vd with an increase in dose of the drug
How does docloxacillin show nonlinearity?
Has saturable active secretion in the kidneys, an increase in dose results in a decrease in renal clearance
How does phenytoin show non-linearity?
Have saturable metabolism, which means an increase in the dose would result in a decrease in hepatic clearance and more than proportional increase in the AUCs
How does carbamazepine show non-lineraity?
Induces its own metabolism displaying non linear Pk unit the induction process stabilizes which takes 10-14 days
What is the most common source of nonlinearity?
Metabolism
What is another name for non linearity in drug metabolism?
- Saturable metabolism
- Michaelis-Menten
- Mixed orde kinetics
What is the principle of MM kinetics?
The rate of drug metabolism changes with respect to a change in drug concetration
Describe MM kinetics with a low concentration of drug?
- The concentration of available enzymes is much larger than the number of drug molecules
- When drug concentration increases, the rate of metabolism is increased proportionality (linear)
- To a certain point, high concentrations of drug will express non-linearity
Describe MM kinetics with a high concentration of drug?
- More drug relative to available enzyme concentration
- All enzymes are saturated
- Increase in drug concentrations will not change rate of metabolism (nonlinear)
How is the rate of metabolism calculated?
Describe the properties of drugs that have a therapeutic concentration greater than their Km during increased drug concentration?
- 1st order (Cp < Km)
- Mixed order (Cp > Km < Vmax)
- Zero order (Cp ≥ Vmax)
What occurs when Cp «_space;Km?
- Both Vmax and Km are constants (k+ Vmax/Km)
- MR = k *Cp (classical first order)
- MR is proportional to the drug concentration (linear)
What happens when Cp»_space; Km?
MR = Vmax (zero order)
Describe some of the relationships drug expresses due to nonlinearity?
- ↑ in dose results in a greater than proportional ↑ in AUC or Cp
- As elimination t½ is inversely related to CL
- Because the time to reach steady-state is dependent on the t½ and size of administered dose
Why is dose proportional to AUC and Cp?
CL of drug decrease with an increase in dose due to enzyme saturation
What is t1/2 inversely related to Cl?
t1/2 will be longer at higher doses or plasma concnetrations
Why is time to Css dependent on t1/2 and size of admin dose
- The higher the dose, the longer is the t½ and the longer it takes to reach time to steady-state.
- These characteristics are different from those observed for drugs with linear (first-order) kinetics where no change in clearance, half life, or time to reach steady state is expected as a result of a change in the dose.
What is the drug dosing rate (R0)?
What happens if a non-linear drug (phenytoin) was administered on in multiple dose?
The rate of metabolism at steady state is a function of Css
Elimination rate = drug dosing rate (Ro)
