Non-Linear PK

Question 1

What factors don’t change PK parameters (t1/2, k, Vd, Cl)?

Answer 1

1. Different doses of the drugs are administered
2. When the drug is administered by different routes as a single or multiple doses

Question 2

What factors can change PK parameters?

Answer 2

The presence of certain disease states or DDIs

Question 3

What is a linear PK?

Answer 3

dose independent PK
PK of drug doesn’t change from dose or route of administration

Question 4

What kind of PK are a majority of drugs?

Answer 4

linear

Question 5

What is linear?

Answer 5

The plasma drug concentrations at a given time and the secondary acute PK parameters will change in the same directly proportion to the dose adminsitered

Question 6

What are the secondary acute PK?

Answer 6

AUC, Cmax, Cmin, Cavg

Question 7

What factors affect linearity?

Answer 7

All PK processes in drug disposition (distribution, metabolism, excretion) are first order processes therefore the PK parameters are constant and don’t change with changes in dose under normal circumstances

Question 8

What does it mean for a drug to be non linear?

Answer 8

1. Dose dependent
2. PK parameters depends on administered dose
3. Relationship between AUC and plasma concentration at a given steady state and the administered dose is no linear

Question 9

What are the factors that affect nonlinearity?

Answer 9

When one or more of the PK process (ADME) deviates from a first order process, and/or when a drug’s PK parameters change with dose

Question 10

When would non-linearity most commonly arise?

Answer 10

1. Drug concentrations is high enough to saturate an enzyme or another protein involved with ADME

Question 11

Describe examples of non linearity?

Answer 11

1. Extent of absorption of amoxicillin decreases with an increase in dose
2. Dose-dependent protein binding of valproic acid; saturable tissue uptake of methotrexate
3. Saturation of the metabolism of phenytoin and ethanol at higher doses
4. Dicloxacillin has saturable active secretion in kidneys resulting in a decrease in renal clearance as dose is increased

Question 12

What are mechanisms of non-linearity?

Answer 12

1. Auto-induction
2. Pharmacological or toxicological actions of a drug

Question 13

What is auto-induction?

Answer 13

Drugs like carbamazepine that induce their own metabolism, will display nonlinear PK until the induction process stabilizes which takes about 10-14 days

Question 14

Describe an example of non-linearity of toxicological actions of a drug?

Answer 14

The clearance of aminoglycosides can decrease with dose as a result of dose-dependent renal toxicity that aminoglycosides themselves cause