Pharmacokinetics Variables

Volume of distribution, Vd

Clearance, Cl

Bioavailability, F

Elimination rate constant, Ke

Half-life, t1/2

  • The apparent volume into which a drug disperse in order to produce the observed plasma conc.
  • Theoretical volume necessary for the total amount of drug to produce conc. similar to plasma conc.

Salt factor, S

Creatinine clearance, CrCl

Elimination rate, K

Zero-order

  • The fraction of an administered dose of unchanged medicine that reaches the blood stream/systemic circulation.
  • IV injection ➡ F = 100%
  • The percentage of fraction of total molecular weight of a salt formulation that represent active drug
  • Drugs formulated in salt form:
    • can be fully ionized in water
    • improve the extent & rate of absorption
    • rapid therapeutic effect
  • Eg. Valproic sodium & Metformin hydrochloride

Compartment models

  • Drug ➡ Blood ➡ Target ➡ Therapeutic effect


  • Compartment models illustrate the distribution phase of drug.

  • Different organs take up drug with different rate & different extend.
  • More compartments are involved, PK calculation more complex.
  • Generally, assume drug distribute as Compartment model 2
  • But, different drug behave differently, some hv significant accuracy in model 3.

In two-compartment model:

  1. IV injection/bolus


    • 100% drug directly enter plasma compartment
    • sudden increase plasma conc. ➡ slowly be distributed
    • Distribution phase - drug reduces until reaches equilibrium between plasma and tissue
    • Elimination phase starts after equilibrium is achieved

  2. IV infusion


    • Infusion: continuous introducing drug - distribution & elimination at the same time
    • Firstly - Rate infusion > Rate elimination
    • Plasma conc. increasing during drug infusion & slowly reached steady-state level
    • Steady-state conc. - Rate infusion = Rate elimination

Vd is the theoretical volume (not real)

  • depends on size of compartment / BW
  • Large compartment - drug widely distributed to other tissues ( ⬆ Vd)
  • Small compartment - drug confined to plasma conc.
    Vd is inversely proportional to drug plasma conc.
    Vd is needed to calculate loading dose

Population Vd

  • population parameter to estimate the patient Vd

Loading dose

  • Dose required to achieve desired plasma conc. in order to reach therapeutic range
  • to produce rapid onset

Factors influenced Vd

  1. Timing of measurement
  2. Pharmacokinetic models
  3. Free vs Total drug levels
  4. Molecular size
  5. pKa
  6. Lipid & water solubility
  7. pH
  8. Body water volume
  9. Protein levels
  10. Age
  11. Gender
  12. Pregnancy
  13. Oedema
  14. Ascites / effusion

Incremental loading dose

  • Dose administered to bring the plasma level to therapeutic range rapidly.
  • Use when plasma level far below therapeutic range
  • When normal maintenance dose may not increase or slowly increase
  • Example case:
    • non-adherence to chronic medication
    • exceptionally large Vd
  • The hypothetical volume of plasma or other biological fluids form which the drug is totally and irreversibly removed per unit time.
  • The intrinsic ability of body to remove the drug
  • Represent theoretical volume of plasma which drug is completely cleared in time

Needed to calculate maintenance dose
Unit: L/hr ➡ mL/min (x60/1000)

Factors influenced Cl

  1. Body surface area
  2. Body weight
  3. Plasma protein binding
  4. Cardiac output
  5. Drug-drug interactions
  6. Extraction ratio
  7. Genetics
  8. Hepatic functions
  9. Renal functions

Unit: L

  • Drug eliminated through kidney may hv Cl similar to CrCl
  • Some drug assume Cl = CrCl
  • Unit: mL/min
  • The fraction of total amount of drug in body is removed at any time interval / per unit time.
  • Unit: L/day or L/hour - hr-1
  • Elimination rate is constant
  • independent of plasma conc.

First-order

  • Elimination rate depends on plasma conc.
  • ⬆ plasma conc. ⬆ elimination rate
  • But, the fraction of drug being eliminated per unit time remained constant.

Time required for the total amount of drug in body or the drug plasma concentration to reduce by one-half.
t1/2 = 0.693/Ke [Unit: hr]

Factors influenced t1/2

Patient-specific variables

  1. age, gender
  2. blood circulation
  3. diet
  4. excessive fluid or low fluid
  5. medication history
  6. kidney function
  7. liver function
  8. obesity
  9. pre-existing condition // comorbidity
  10. race / ethnicity
  11. smoking
  12. hemodialysis

Drug-specific variables

  1. drug formulation - modified release
  2. drugs behavior - kinetics orders
  3. route of administration
  4. route of elimination
  5. drug accumulation in fats or tissues
  6. protein-binding
  7. metabolites
  8. drug properties - size, charge, pKa
  9. Vd
  • t1/2 ⬆ by ⬆ Vd
  • t1/2 ⬆ by ⬇ Cl
  • Disease state (renal failure) - Vd ⬆ Cl ⬇ ⛔ t1/2
  • Doubling dose will ⬆ duration of action by ONE t1/2
  • First-order kinetic elimination: t1/2 is constant regardless conc.

Steady-state - Rate of administration = Rate of elimination
IV infusion - Plasma conc remain constant at SS unless change in rate of infusion