Bioavailability BA and Bioequivalence BE of Endogenous Substance Drug Products - PowerPoint PPT Presentation

1 / 18
About This Presentation
Title:

Bioavailability BA and Bioequivalence BE of Endogenous Substance Drug Products

Description:

Potassium Chloride Modified-Release Tablets and Capsules: In Vivo Bioequivalence ... Case Study II: Potassium Chloride. Summary. Summary ... – PowerPoint PPT presentation

Number of Views:643
Avg rating:3.0/5.0
Slides: 19
Provided by: dalepc
Category:

less

Transcript and Presenter's Notes

Title: Bioavailability BA and Bioequivalence BE of Endogenous Substance Drug Products


1
Bioavailability (BA) and Bioequivalence (BE) of
Endogenous Substance Drug Products
  • Dale P. Conner, Pharm.D.
  • Division of Bioequivalence
  • OGD, CDER, FDA

2
Objective
  • Awareness topic discussion
  • Provide information to ACPS on the challenges for
    BA/BE assessment of endogenous drugs
  • More detailed discussion is planned for the
    future
  • Biopharmaceutics Subcommittee meeting
  • ACPS meeting
  • At this meeting FDA seeks ACPS recommendations on
    how to develop the information needed to enhance
    the science in this area.

3
Introduction
  • BA and BE of endogenous substance drug products
    need special considerations
  • Not addressed in the general BA/BE guidance,
    Bioavailability and Bioequivalence Studies for
    Orally Administered Drug Products - General
    Considerations

4
Introduction
  • Specific recommendations
  • Potassium Chloride Modified-Release Tablets and
    Capsules In Vivo Bioequivalence and In Vitro
    Dissolution Testing (Draft - Issued 8/2002,
    Posted 8/6/2002)
  • Levothyroxine Sodium Tablets - In Vivo
    Pharmacokinetic and Bioavailability Studies and
    In Vitro Dissolution Testing (Issued 2/2001,
    Posted 3/8/2001)

5
Introduction
  • Other Drugs with no specific BA/BE guidance
  • Estrogens
  • Testosterone
  • Progesterone
  • Calcitriol
  • Ursidiol
  • Insulin
  • Human growth hormone

6
Definition of Bioequivalence
  • Pharmaceutical equivalents whose rate and extent
    of absorption are not statistically different
    when administered to patients or subjects at the
    same molar dose under similar experimental
    conditions

7
Purpose of BE
  • Therapeutic equivalence (TE)
  • Bioequivalent products can be substituted for
    each other without any adjustment in dose or
    other additional therapeutic monitoring.
  • The most efficient method of assuring TE is to
    assure that the formulations perform in an
    equivalent manner.

8
Model of Oral Dosage Form Performance
Pharmacokinetic Measurement
Clinical/PD Measurement
Dosage Form Performance
Therapeutic Effect
Gut Wall
Drug in Solution
Blood
Site of Activity
Dosage Form
ln Dose
Dose
9
Model of Oral Dosage Form Endogenous Drug
Performance
Pharmacokinetic Measurement
Clinical/PD Measurement
Body Production
Dosage Form Performance
Feedback
Therapeutic Effect
Gut Wall
Drug in Solution
Blood
Site of Activity
Dosage Form
ln Dose
Dose
10
Model of Oral Dosage Form Endogenous (KCl) Drug
Performance
Pharmacokinetic Measurement
Clinical/PD Measurement
Body Stores
Dosage Form Performance
Urine
Therapeutic Effect
Gut Wall
Drug in Solution
Blood
Site of Activity
Dosage Form
ln Dose
Dose
11
Statistical Analysis (Two One-sided Tests
Procedure)
  • AUC and Cmax
  • Log-transformed data
  • ANOVA
  • Model Period, Sequence, Subject(Seq), Treatment
  • 90 Confidence Intervals (CI) must fit between
    80-125

12
Issues with Endogenous Substance
Bioavailability/Bioequivalence
  • Assay sensitivity
  • Endogenous baseline
  • Feedback inhibition of endogenous production
  • Circadian rhythm
  • Linear/non-linear pharmacokinetics

13
Agenda
  • Case Study I Levothyroxine - Background
  • Results of a Study by Abbott Labs
  • Levothyroxine BA
  • Case Study II Potassium Chloride
  • Summary

14
(No Transcript)
15
Summary
  • BE is a test of the comparative performance of
    formulations
  • Release of the drug substance from the drug
    product
  • Rate
  • Extent

16
Summary
  • Baseline correction of data may be necessary to
    ensure a sensitive method for the demonstration
    of BE
  • Characteristics of baseline
  • Methods for correction
  • Magnitude of baseline in relationship to the
    values after treatment

17
Summary
  • Endogenous baselines that change due to the
    administration of exogenous drug substance
    present a technical challenge to the
    demonstration of BA and BE
  • Circadian patterns
  • Feedback
  • Pharmacokinetics

18
Summary
  • Can a decision tree be developed that will guide
    sponsors in the correct BA and BE studies to be
    done for other endogenous drug products?
Write a Comment
User Comments (0)
About PowerShow.com