Pharmacokinetics & Biopharmaceutics Course PD-712

Biopharmaceutics-II Course Outline

• Course code: PD-712
• Professor: Dr. Hafiz Muhammad Arshad
• Department: Pharmaceutics
• Faculty: Pharmaceutical Sciences
• College: Dow College of Pharmacy
• University: Dow University of Health Sciences, Karachi

Introduction to Pharmacokinetics

• Determination through plasma drug level studies
• Application of Pharmacokinetics in clinical situations

Concept of Compartment Models

• Compartmental and non-compartmental method of analysis
• One compartment open model
• Two compartments open model

Biological Half-Life and Volume of Distribution

• Concept and methods of determination

Drug Clearance

• Mechanism, determination
• Relationship of clearance with half-life

IV Infusion and Multiple Dosage Regimen

• Included in the course outline

Clinical Pharmacokinetics

• Included in the course outline

Recommended Books

• Leon Shargel, Applied Pharmacokinetics and Biopharmaceutics
• Robert E. Notari, Bio-Pharmaceutics and clinical Pharmacokinetics
• Malcolm Rouland, Thomous N. Tozer, Clinical Pharmacokinetics and Pharmacodynamics
• Milo Gibaldi, Bio-Pharmaceutics and Clinical Pharmacokinetics

Learning Objectives

• Introduction to Pharmacokinetics and its importance
• Kinetics analysis of data (Order and rate constants)
• Kinetics of Drug transport (movement of drug through membranes)
• Model independent vs compartment model pharmacokinetic analysis
• Compare and contrast variable, constant and parameters
• Describe pharmacokinetic parameters: apparent volume of distribution, elimination half-life, first-order elimination rate constant, clearance
• Determine pharmacokinetic parameters from plasma or urinary data

Pharmacokinetics

• Mathematical subject dealing with quantitative conclusions (dose or concentration of drug in fluids)
• Quantitative study of drug movement in, through and out of the body
• Magnitude of response depends on drug concentration at the site of action

Applications of Pharmacokinetic Studies

• Define time course of drug and metabolite concentrations in plasma and other fluids
• Bioavailability measurements
• Effects of physiological and pathological conditions on drug disposition and absorption
• Dosage adjustment in disease states
• Correlation of pharmacological responses with administered doses
• Evaluation of drug interactions
• Individualizing drug dosing regimens to optimize therapy

Study of Drug(s) Over Time

• Gut to liver
• Drug in plasma and proteins
• Drug in metabolized form
• Drug in tissue reservoirs
• Drug to site of action (receptors)
• Drug in Excretory organs (kidney)

ADME

• Drugs enter the body through various routes
• Distribution by blood to site of action
• Cellular and intracellular transport
• Biotransformation to different compounds
• Excretion from the body (kidney or other routes)
• Quantification of these processes is pharmacokinetics.

Plasma Level-Time Curve

• Blood-plasma serum level demonstrate concentrations upon drug administration
• Generated by obtaining drug concentrations in plasma samples at intervals
• Plasma concentration is plotted against time on a graph
• Drug reaches systemic circulation causing plasma drug concentration to rise
• Absorption is generally faster than elimination

Elimination Half-Life

• Elimination half-life (t_1/2) is time required for plasma concentration to decrease to half its initial concentration
• Graph of log C versus t
• Secondary parameter (depends on clearance and volume of distribution)

Zero Order Reactions

• Constant rate, independent of concentration
• Rate = k
• Units of k are M/sec

First Order Reactions

• Rate proportional to reactant concentration
• Rate = k[A]
• Units of k are sec^-1

Second Order Reactions

• Rate proportional to the square of one reactant or product of two reactants
• Rate = k[A]² or k[A][B]
• Units of k are M^-1sec^-1

Units of Rate Constants

• For zero order k= (moles/liter)/second
• For first order k= 1/second
• For second order k = 1/ (liter.second.moles)

Applications of Pharmacokinetics

• Understanding drug absorption, distribution, metabolism, and excretion (ADME) and effect on biological response
• Determining plasma drug concentrations and establishing more accurate dosage regimens
• Evaluating drug interactions and risk of toxicity
• Designing and developing new drugs with appropriate dosage regimens

Pharmacokinetic Models

• Generalized and simplified methods
• Methods for the quantitative analysis of kinetic processes
• Model Approach: mathematical description and the relationship
• Model-Independent (Non-compartmental Analysis): Analysis of statistical moments and statistical parameters

Types of Pharmacokinetic Models

• Compartment models
• Physiological models
• Distributed parameter models

Compartment Model Approach

• Body represented as a series or parallel compartments
• Each compartment has characteristic fluid levels
• Drugs are considered to be quickly distributed in the compartment as it is well mixed
• Rate constants used to represent rate of entry and exit from the compartment

Assumptions for Compartment Models

• One compartment
• Rapid mixing
• Linear model

Two Compartment Model

• Has a central compartment and a peripheral compartment
• Drug moves between compartments with first-order kinetics
• Defines parameters like V₁ (central compartment volume), V₂ (peripheral compartment volume), k₁₀, k₂₁, k₁₂

Three Compartment Model

• Has a central compartment and two peripheral compartments
• Similar structure to Two Compartment Model with added complexity
• Introduces additional constants/parameters for drug movement within the compartments

Elimination Rate Constant

• Calculating the slope of the linear portion of the log C versus time graph
• Used for calculating rate of elimination
• Units of the constant are in hr^-1

Area Under the Curve (AUC)

• Total exposure of a drug over a particular time interval using various methods like trapezoidal rule
• Calculated from the graph of C vs t
• Used to determine total clearance
• Units: mg. hr/mL

Volume of Distribution (Vd)

• Ratio of amount of drug in the body to plasma drug concentration
• Hypothetical volume required to dissolve total amount of drug found in blood
• Apparent volume in drug calculation; differs from actual
• Factors affecting Vd: blood flow rate in tissue, lipid solubility of drug, binding of drug to tissue, plasma proteins, and pH

Biological Half-Life

• Time for plasma (or total body) concentration to reduce to half of initial concentration

Classification of Drugs based on Half-life

• Ultra-fast (UFD) - Half life less than 1 hr.
• Fast (FD) - Half life 1 to 4 hrs.
• Medium (MD) - Half life 4 to 8 hrs.
• Slow (SD) - Half life 8 to 24 hrs. or more than 24 hrs.

Non-Compartmental Analysis

• Based on statistical moments of drug concentration vs time
• Model-independent methods
• Calculation of key parameters like MRT, CL, V_ss, half-life

Total Body Clearance (Cl_T)

• Relates dosing rate of a drug to its steady-state concentration
• Determined after IV dose administrations
• Calculated based on dose & AUC₀₋∞
• Cl_T = Dose / AUC₀₋∞

Mean Residence Time (MRT)

• Average total time drug molecules stay in the body
• Can only be determined after instantaneous administration

Mean Absorption Time (MAT)

• Measures the fraction of an oral dose reaching systemic circulation
• Ratio of AUC after oral administration to AUC after IV administration
• Used to estimate absorption rate

Other Important Calculations

• Parameters like V_ss (volume of distribution at steady state), %F (% bioavailability), etc. can be calculated.

Numerical Example

• Numerical example for calculation of clearance, V_ss, and MRT is given.