Bioavailability and Bioequivalence Notes

Bioavailability and Bioequivalence Notes

Big Picture

  • Bioavailability and bioequivalence studies are essential in understanding how drugs are absorbed and utilized in the body.
  • These studies inform the development and approval of both brand-name and generic medications.

Bioavailability

  • Definition:
    • Bioavailability is the relative amount of an administered dose that reaches the general circulation and the rate at which this occurs. (American Pharmaceutical Association, 1972)
Bioavailability Studies
  • Purpose:
    • Assess how changes in drug formulation or manufacturing affect bioavailability.
    • Investigate whether the oral bioavailability of drug X differs between various formulations, e.g., capsule vs. tablet.
  • Key Considerations:
    • Equality of content does not ensure equality of response.
    • Excipients and manufacturing methods can significantly influence bioavailability.
Types of Bioavailability

  • Absolute Bioavailability:

    • Refers to the systemic availability of a drug after extravascular administration compared to intravenous (IV) administration.
    • Calculated by comparing the area under the curve (AUC) or amount excreted (Ae,∞) over a specific time frame:
    • F=AUC<em>extravascularAUC</em>IV (F = 1 for IV)F = \frac{AUC<em>{extravascular}}{AUC</em>{IV}} \text{ (F = 1 for IV)}
    • Plasma and urine methods assume that clearance (CL) and fraction excreted (fe) remain constant regardless of route.

  • Relative (Comparative) Bioavailability:

    • Assessed by comparing AUCs or Ae,∞ of a drug in different dosage forms or routes of administration:
    • F<em>rel=AUC</em>formulation1AUCformulation2F<em>{rel} = \frac{AUC</em>{formulation 1}}{AUC_{formulation 2}}
Absolute vs. Relative Bioavailability
  • Possible values:
    • Absolute bioavailability (F) ranges from 0 to 1.
    • Relative bioavailability can exceed 1.
  • High relative bioavailability does not equate to high systemic bioavailability.

Bioequivalence Studies

  • Purpose:
    • Compare bioavailability between a test product (new formulation) and a reference product (standard).
    • Establish if total AUC and maximum concentration (Cmax) of the test product are within 80%-125% of the reference product.
  • Importance in:
    • Generic drug approval post-patent expiration.
    • Changes in dosage forms, e.g., capsule to tablet during development.
  • The goal is therapeutic equivalence, minimizing the need for full clinical trials.
Definitions
  • Bioequivalence:
    • Defined by FDA as when two products are equivalent in the rate and extent of API availability at the action sites.
  • Reference Listed Drug (RLD):
    • Approved drug products used for comparison for generics.
Therapeutically Equivalent Products
  • Criteria for equivalence:
    • Pharmaceutical equivalents (same active ingredients, dosage form, route of administration, strength).
    • Assigned the same therapeutic equivalence codes by FDA (starting with "A").
  • Generic Substitution:
    • The process of replacing prescribed products with generic options.

Key Resources

  • Orange Book:
    • Lists therapeutic equivalence evaluations for approved drug products.
  • Purple Book:
    • Lists biological products, including biosimilars and interchangeable biological products.

Standard Bioequivalence Study Design

  • Design:
    • Randomized cross-over trial with each subject receiving both test and reference products over two periods with a washout phase (10 half-lives).
  • Subjects:
    • Typically 24 to 36 healthy adults.
  • Conditions:
    • Overnight fasting before and after administration.
  • Measurement:
    • AUC, Cmax, and tmax analyzed statistically.
Example of Crossover Design
  • Subjects receive both drugs in staggered periods:
    • E.g., Subject 1 receives Generic in Period 1 and RLD in Period 2.

Statistical Criteria for Bioequivalence

  • Employs two one-sided tests on log-transformed data to show:
    • 90% confidence interval (CI) for ratio of AUC, Cmax within 0.8 to 1.25 means bioequivalence achieved.
Example Interpretation

  • If 90% CI falls within 0.8-1.25, the products are bioequivalent.

  • If entirely outside this range, they are not bioequivalent.

  • No declaration of bioequivalence can be made in ambiguous results.