PK – Half-life

Master answer

Definitions

Half life: Time taken for a reduction in one half the total ammount of drug from the body.

Half time: Time taken for a reduction in one half the plasma concentration of a drug

Simplified equation for half life

• Where
  • Vd is volume of distribution of a drug
  • Cl is its clearance
  • ln(2), the natural log of 2, can be approximated as 0.693

Pharmacokinetic factors

Absorption

• Minimal impact on T_1/2
• If initial plasma concentration saturates its metabolic pathway, clearance will become zero-order and rate of elimination will be independent of drug concentration

Distribution

• In the multi-compartment pharmacokinetic model,
  • Drug initially entering the central (plasma) compartment will redistribute to other compartments (tissues), decreasing the amount remaining in the central compartment.
  • As V_d increases, the ammount redistributing to other tissues increases → increased distribution away from central compartment → T_1/2α (Distribution half time) decreases.
  • This reduction in plasma concentration will decrease the concentration of drug reaching its metabolic organs (unless plasma metabolism) and prolong the elimination half-life.
  • Drugs with high volumes of distribution display context-sensitive half time
• Protein binding of drug increases half life
  • Prevents glomerular filtration

Metabolism and elimination

• Clearance is the volume of plasma completely cleared of drug per unit time
• Total body clearance is a sum of renal clearance (via metabolism or elimination), hepatic clearance (via metabolism, biliary secretion) and other mechanisms (such as lung metabolism, plasma cholinesterases etc.)
• As drug metabolism and elimination increases, T­_1/2β decreases

Zero-order kinetics

• As elimination of drug is independent of drug concentration, half life is not constant and progressively shorten by half
  • E.g. 100mg of drug in body eliminated at 10mg/hr hour
    • Half life from 100mg (to 50mg) would be 5 hours
    • Subsequent half life (from 50mg to 25mg) would be 2.5 hours etc.

Sakurai 2016

Answer by Sakurai