Pharmacokinetic variability

Question 1

Why is PK variability important in the use of drugs?

Answer 1

Because exposure of a drug determines its safety and efficacy.
Understanding and controlling the factors that influence exposure can limit the range achieved.

Question 2

Therapeutic window

Answer 2

A drug should exceed the minimum effective concentration for as long as the dose time as possible. (try to keep within the upper and lower bounds of the window

Question 3

Why is PK variability important in the design of PK studies?

Answer 3

The effectiveness of a clinical PK study design is based on the power to detect differences in the PK parameters of interest (Cmax, AUC, tmax)

The 4 main determinants of power are:

Level at which a difference will be considered statistically significant (p<0.05)

Variability among subjects

The number of subjects studies

The magnitude of difference you are able to detect

Question 4

How is variability in drug PK calculated?

Answer 4

The variability can be described by the coefficient of variation - CV(%) - CV = SD/mean

Question 5

Outline the potential sources of pharmacokinetic variability how to assess their impact

Answer 5

Intrinsic (factors inherent to the individuals)

Extrinsic (factors from the environment)

Intra-subject (within the same individual over time). *intra-subject bariability is generally lower than inter-subject variability in clinical trials

Inter-subject (between indivudals)

Assessing intrinsic and extrinsic factors

They can be assessed by specific studies; which aim to standarize all other sources of variability as much as possible (usually in a healthy volunteer population, can also be done as an intensive sampling day in a phase 2 study)

or population pharmacokinetic studies; considers all sources of variability in parallel usually in the intended population (applied to phase 2 and phase 3 studies)

Question 6

Examples of intrinsic factors

Answer 6

Age

Question 7

Examples of extrinsic factors

Answer 7

Effects of food

Effects of co-administered drugs

Question 8

How is variability managed in drug PK?

What to do if the variability of a drug in clinical usage breaches the therapeutic window?

Answer 8

Dose adjustment or prohibition for definied population

Dosing by weight

Therapeutic drug monitoring (TDM) by drug concentration or by pharmacodynamic effect