Pharmacokinetic Models and Bioavailability (1)

System

whole patient, NOT an organ system.

Model

• simplified representation of a system

•  (often boxes + arrows; mathematical; validated by matching experimental vs theoretical data)

Process

 actions/functions that cause drug to “move” (ADME)

a. Parameter

b. example

a. measurable factor describing one aspect of a process

b. max drug concentration

a. Variable

b. example

a. the named/calculated value used for a parameter

b. Cmax

Absorption

drug entering the body

Distribution

drug moving/partitioning within the body

Metabolism

chemical change to the drug within the body

Excretion

 drug being physically removed from the body

≠ Absorption

Route of administration (e.g., PO)

difference between Route vs absorption

• Route delivers drug to a site; absorption is the movement across a membrane into systemic circulation

Models require…

samples that are representative of the system

Common sample types:

 Blood (whole blood, plasma, serum), urine, other fluids, tissues/biopsies

Whole blood

• Cells + dissolved stuff + fluid

We process whole blood to get…

plasma or serum

Plasma

• Dissolved stuff + fluid

• anticoagulated blood, then centrifuged →cells removed (the cells are no longer mixed in the liquid — they’ve settled to the bottom.), fluid layer retained (you keep the top liquid and pour/pipette it off.)

Serum

• Fluid

• allow blood to clot, then centrifuge → fluid remaining after clotting factors removed

What can make measured drug concentration wrong?

 Improper collection/processing

most drug concentrations measured in…

 plasma

Concentration vs time profile

X–Y graph: time on x-axis, concentration on y-axis

One-compartment model (1CM)

single “box” representing the patient/system with:

• Input arrow = Absorption

• Output arrow = Elimination (composite of metabolism + excretion; you cannot separate them with this simple model)

a. One-compartment model (1CM) is done for what? \

b. how accurate it is?

a. simplification

b. expected to be close, not perfect

Analytical sensitivity can do what?

can limit precision/rounding (significant figures)

dont do what when it comes to Analytical technique & significant figures

Don’t write more decimal places than the test can accurately measure.

AUC =

 area under the concentration–time curve; represents total drug exposure

how to calculate AUC?

Trapezoidal method

Trapezoidal method

• (concept + formula only; no calculations here):

  • Break curve into trapezoids between adjacent time points

  • Formula: AUC₀–n = Σ [ (Cᵢ + Cᵢ₊₁)/2 × (tᵢ₊₁ − tᵢ) ]

  • Exam flag: know what the method is doing even if they don’t make you calculate it

FDA definition: Bioavailability =

(F) rate and extent to which the active ingredient is absorbed from a product and becomes available at the site of action

Clinical proxy

(when site of action is hard to measure)

what to do if have Clinical proxy

 use systemic circulation exposure as the practical assessment

Bioavailability (F) is quantified using..

AUC ratios

 F is typically expressed as a

percent (dimensionless after unit cancellation)

Bioavailability equations (know which product goes where)

1. General dose-normalized ratio:

   1. A = comparator, B = reference

2. Absolute bioavailability (Fabs):

   1. Comparator = non-IV (commonly PO), Reference = IV

   2. Often referred as oral bioavailability

   3. Logic: IV is assumed 100% into systemic circulation → goes in the denominator

3. Relative bioavailability (Frel):

   1. Relative bioavailability (Frel):

      • Compare formulations (e.g., generic vs brand)

Interpretation flags (what F implies)

• F < 100% is common (incomplete absorption and/or first-pass metabolism, etc.)

• F > 100% is rare/unlikely → exam flag that your ratio is likely flipped