PC1320 W5 Lecture 5d_Pharmacokinetics_Parameters

Pharmacokinetics Parameters Overview

• Presenter: Robi Islam

• Institution: James Cook University, Australia

• Duration: Celebrating 50 years (1970-2020)

Basic Principles of Pharmacokinetics

• Key pharmacokinetic parameters:

  • Bioavailability

  • Volume of Distribution

  • Clearance

  • Half-life

  • Steady-state plasma drug concentration

• Importance of understanding PK parameters for drug dosing and management.

Pharmacokinetic Parameters: Bioavailability

• Definition: Bioavailability (F) refers to the proportion of the administered dose that reaches systemic circulation, ranging from 0 to 1.

• Stages of Absorption:

  • Fraction absorbed (Fa): Fraction of the administered dose that enters intestinal cells (enterocytes).

  • Intestinal bioavailability (Fg): Fraction of drug in enterocytes that escapes metabolism.

  • Hepatic bioavailability (FH): Fraction of drug that escapes metabolism during the first pass through the liver.

Example of Bioavailability Calculation

• Given a dose of 100 mg:

  • Absorption into portal circulation: 80 mg, Fa = 0.8.

  • Hepatic extraction: EH = 0.75; thus, 60 mg is extracted in the liver, leaving 20 mg to systemic circulation.

• Bioavailability Calculation:

  • F = fg * fH = 0.8 * 0.25 = 0.2 (20%).

  • Comparison of plasma concentration between intravenous (i.v.) and oral administration shows that oral bioavailability is often incomplete due to metabolism.

Pharmacokinetic Parameters: Volume of Distribution (Vd)

• Definition: The volume of distribution represents the volume of fluid required to contain the total amount of drug in the body at the same concentration as in plasma.

• Calculated using:

  • Vd = total amount of drug in the body (Q) / plasma drug concentration (Cp).

• Examples:

  • Ethanol: Vd ~ 0.5 L/kg (total body water).

  • Tricyclic antidepressants: Vd ~ 10-50 L/kg (lipid-soluble, low in plasma).

  • Warfarin: Vd ~ 0.14 L/kg (confined to plasma).

Measuring Volume of Distribution

• Example calculation:

  • A dose of 200 mg is administered. After sampling, an extrapolation shows an initial concentration (Co) of 10 mg/L, thus:

  • V = amount of drug in body / plasma drug concentration = 200 mg / 10 mg/L = 20 L.

Pharmacokinetic Parameters: Clearance (CL)

• Definition: Clearance is the volume of blood cleared of drug per unit time (L/hour).

• Represents the efficiency of irreversible elimination of a drug from circulation.

• Total clearance is the sum of renal and other clearances:

  • CLtotal = CLrenal + CLothers.

• Elimination Rate Calculation:

  • Elimination rate = Clearance (CL) * Plasma drug concentration (C).

  • For most drugs, elimination is first-order kinetics.

Pharmacokinetic Parameters: Half-life (t½)

• Definition: Half-life is the time it takes for plasma drug concentration to reduce by half.

• Graphical Representation: Shows decay of drug concentration over time; typically modeled as:

  • For first-order elimination:

    • t = 0: 100%,t = 1t½: 50%,t = 2t½: 25%, ...

• Factors affecting half-life include:

  • Clearance (CL): Larger CL = shorter t½.

  • Volume of Distribution (Vd): Larger Vd = longer t½.

Pharmacokinetic Parameters: Steady-state Concentration (Css) and Maintenance Dosing

• Steady-state is achieved after approximately 3-5 half-lives (t½).

• Maintenance dose rate (DR) required to maintain Css can be calculated using:

  • DR = CL * Css.

Pharmacological Objectives in Dosing

• Aim to keep peak concentrations below toxic levels and trough concentrations above therapeutic thresholds.

Tutorial Questions

1. Discuss the significance of plasma protein binding on drug effects and elimination.

2. Define the following and discuss their significance:

   • Elimination half-life

   • Bioavailability

   • Clearance

3. Analyze hypothetical Drug A (t½ = 8 hours) and Drug B (t½ = 50 hours) to determine appropriate dosing intervals and whether loading doses are necessary.