Pharmacokinetics: Bioavailability and Dosage Studies

Absolute Bioavailability

• The systemic availability of a drug administered orally is compared to its intravenous (IV) administration
• It is denoted by the symbol F
• The formula is Dose (IV) x AUC (oral) / Dose (oral) x AUC (IV) x 100

Relative Bioavailability

• The systemic availability of a drug after oral administration is compared to that of an oral standard of the same drug
• It is denoted by the symbol Fr
• e.g. comparison between Amoxicillin capsules and Amoxicillin suspension

Single Dose Studies

• Used to determine the rate and extent of drug absorption after a single dose
• Advantages:
  • More common
  • Easy
  • Less tedious
  • Less drug exposure
• Disadvantages:
  • Difficult to predict steady state characteristics

Multiple Dose Studies

• Used to determine the rate and extent of drug absorption after multiple doses
• Advantages:
  • Accurate
  • Easy to predict the peak and valley characteristics of the drug
  • Few blood samples required
  • Ethical
  • Small inter-subject variability
  • Better evaluation of controlled release formulations
  • Can detect non-linearity in pharmacokinetics
  • Higher blood levels due to cumulative effect
  • Eliminates the need for long washout periods between doses
• Disadvantages:
  • Poor subject compliance
  • Tedious and time-consuming
  • More drug exposure
  • More difficult and costly

Plasma Level-Time Studies

• Most common type of human bioavailability studies
• Based on the assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of action
• The method is based on the assumption that two dosage forms that exhibit superimposable plasma level-time profiles in a group of subjects should result in identical therapeutic activity.
• Requires collection of serial blood samples for a period of 2 to 3 biological half-lives after drug administration
• The data is plotted in a graph of concentration versus time

Bioavailability Parameters

• Cmax (Peak plasma concentration): The maximum concentration of the drug obtained after administration of a single dose
• tmax (Time of peak plasma concentration): The time required to achieve peak concentration
• Area under the curve (AUC): The area under the plasma concentration-time curve

Methods of Measuring AUC

• Planimeter: A mechanical instrument used to measure the area
• Counting the squares: Total number of squares enclosed in the curve are counted

Urinary Excretion Studies

• Measure the amount of unchanged drug excreted in the urine
• Assumes a direct correlation between urinary excretion and plasma concentration
• Useful when sensitive analytical techniques are unavailable to measure drug concentration in plasma

Elements of a Bioequivalence Study Protocol

• Title
• Study objective
• Study design
• Study population
• Inclusion/exclusion criteria
• Restrictions/prohibitions
• Clinical procedures
• Ethical considerations
• Facilities
• Data analysis
• Drug accountability
• Appendix

Single Dose Bioequivalence Studies

• Involve determining relative bioavailability after a single dose of test and reference formulations
• Performed in fasting, young, healthy, adult male volunteers to ensure homogeneity

Statistical Interpretation of Bioequivalence Data

• Analysis of variance (ANOVA): Used to test data for differences between treatment and control groups
• Confidence interval approach: Used to demonstrate if the bioavailability from the test product is too low or high in comparison to the reference product

Methods for Enhancement of Bioavailability

• Pharmaceutical approach: Changing formulation, manufacturing process, or physicochemical properties of the drug
• Chemical approach: Modification of the chemical structure of the drug to increase its solubility and/or permeability
• Pharmaceutical Approach Detail:
  • Particle size reduction:
    • Micronization: Reducing particle size to less than 1 μm
    • Nanosuspension: Using specialized techniques to create nano-sized particles of drug
  • Crystal modification:
    • Polymorphs: Different crystalline forms of the same drug with different physicochemical properties
  • Salt formation:
    • Increased solubility of drugs
  • Solid dispersions:
    • Dispersion of drug into a carrier substance
  • Complexation:
    • Formation of complexes with cyclodextrin
  • Hydrotropy:
    • Addition of a hydrotrope to increase the solubility
  • Alteration of pH of the drug microenvironment:
    • In situ salt formation
    • Addition of buffers
  • Use of amorphs, anhydrates, solvates, and metastable polymorphs:
    • Amorphs are more soluble than metastable polymorphs
    • Anhydrates are more soluble than hydrates
    • Solvates are more soluble than non-solvates
  • Precipitation:
    • Drug is dissolved in an organic solvent and then rapidly mixed with a non-solvent
  • Selective adsorption on insoluble carriers:
    • Adsorbent clays like bentonite can enhance dissolution rates
  • Solid solutions:
    • A binary system comprising a solid solute molecularly dispersed in a solid solvent
    • Also called molecular dispersions or mixed crystals
  • Solid dispersions
    • Dispersion of the drug in an inert carrier substance
  • Eutectic mixtures
    • Mixtures of two components that melt at a lower temperature than either component alone

This quiz explores the concepts of absolute and relative bioavailability, including the comparison of drug administration methods and their systemic availability. It also covers single and multiple dose studies, their advantages and disadvantages, to understand drug absorption better.