Pharmacometric Evaluation of Bioequivalence Approaches for Orally Inhaled Drug Products

MISSING IMAGE

Material Information

Title:
Pharmacometric Evaluation of Bioequivalence Approaches for Orally Inhaled Drug Products
Physical Description:
1 online resource (101 p.)
Language:
english
Creator:
Kandala, Bhargava
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Pharmaceutical Sciences, Pharmaceutics
Committee Chair:
HOCHHAUS,GUENTHER
Committee Co-Chair:
PALMIERI,ANTHONY,III
Committee Members:
DERENDORF,HARTMUT C
WINNER,LAWRENCE HERMAN

Subjects

Subjects / Keywords:
bioequivalence -- inhalation -- pharmacodynamics -- pharmacokinetics
Pharmaceutics -- Dissertations, Academic -- UF
Genre:
Pharmaceutical Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Background: To establish bioequivalence (BE) of orally inhaled drug products (OIDPs), the US Food and Drug Administration (FDA) recommends pharmacodynamic (PD)/clinical studies to establish equivalence in clinical efficacy. The feasibility of such studies is debated in the scientific community. Objectives: a) To develop a clinical trial simulation model suitable to evaluate the feasibility of PD BE studies of generic OIDPs by (1) incorporating variability of the biomarker (exhaled nitric oxide, methacholine challenge) in defined patient populations and to predict their response to OIDPs, (2) applying a bootstrap based non-parametric approach to construct distributions of relative bioavailability for test vs. reference formulations, (3) performing power calculations for the simulated studies considering non-linear dose response relationships. b) Analysis of a PD crossover study to evaluate equivalence in clinical efficacy of two dry powder inhalers, Formoterol Aerolizer (FA) and Formoterol Novolizer (FN) in patients with stable asthma using PC20 as the primary end-point. Results: For FeNO crossover studies, highest power was achieved when the test dose is close to ED50. 90% power was obtained for 32 high responders as opposed to 128 intermediate responders. For the scenario wherein the test dose is on the top of the dose response curve 90% power is obtained with 128 high responders in the study whereas with the same number of intermediate responders 20% power was obtained. The 90% CI interval of relative bioavailability for the 12 mcg dose of FN relative to FA was 0.94-1.45. The 90% Fieller CI for relative potency of the Novolizer compared to the Aerolizer was estimated to be 0.97-1.34. Discussion: PD approach for establishing BE of OIDPs seems feasible in terms of the sample sizes only when 1) Study population consists of high responders and are less variable, 2) Test dose is close to the estimated ED50 value of the drug and biomarker combination, 3) BE criteria are relaxed. Most of the generic formulations have doses much larger than the relevant ED50 values warranting large sample sizes to demonstrate bioequivalence. FN was shown to be BE to FA. Modeling and simulation suggest that it will be a challenge performing bioequivalence studies for corticosteroids using FeNO, while the methacholine challenge is a viable pulmonary bioassay for beta-2 agonists.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Bhargava Kandala.
Thesis:
Thesis (Ph.D.)--University of Florida, 2014.
Local:
Adviser: HOCHHAUS,GUENTHER.
Local:
Co-adviser: PALMIERI,ANTHONY,III.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2014-11-30

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2014
System ID:
UFE0046683:00001