Evaluation of the bioequivalence of highly-variable drugs and drug products

L. Tóthfalusi, Laszlo Endrenyi, Kamal K. Midha, Maureen J. Rawson, John W. Hubbard

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Purpose. To establish procedures for the effective evaluation of bioequivalence (BE) for highly-variable drugs and drug products (HVD/P). Methods. 2- and 4-period crossover BE studies with 24 subjects were simulated which generally assumed within-subject coefficients of variation of 40%. The relationship between the fraction of studies in which BE was accepted (the statistical power) and the ratio of geometric means (GMR) of the two formulations was evaluated for various methods of analysis. These included, primarily, scaled average BE (ABE), the corresponding approach of expanding BE limits (BEL), and, for comparison, unscaled ABE and scaled individual BE (IBE). Results. Scaled ABE and expanding BEL showed very similar properties in both 2- and 4-period studies. They had steeper power curves than scaled IBE. Unscaled ABE had very low statistical power. The acceptance of BE by unscaled and scaled ABE and expanding BEL was almost independent of subject-by-formulation interaction and the ratio of within-subject variations of the two formulations. By contrast, the conclusions reached by scaled IBE were strongly affected by these parameters. Conclusions. Scaled ABE and expanding BEL evaluate BE effectively for HVD/P in both 2- and 4-period investigations. However, additional, useful information can be obtained from 4-period studies.

Original languageEnglish
Pages (from-to)728-733
Number of pages6
JournalPharmaceutical Research
Volume18
Issue number6
DOIs
Publication statusPublished - 2001

Fingerprint

Therapeutic Equivalency
Drug products
Pharmaceutical Preparations
Cross-Over Studies

Keywords

  • 2- and 4-period crossover design
  • Bioequivalence
  • Highly-variable drugs
  • Regulatory limits
  • Scaled regulatory criterion
  • Simulated clinical trials

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

Cite this

Evaluation of the bioequivalence of highly-variable drugs and drug products. / Tóthfalusi, L.; Endrenyi, Laszlo; Midha, Kamal K.; Rawson, Maureen J.; Hubbard, John W.

In: Pharmaceutical Research, Vol. 18, No. 6, 2001, p. 728-733.

Research output: Contribution to journalArticle

Tóthfalusi, L. ; Endrenyi, Laszlo ; Midha, Kamal K. ; Rawson, Maureen J. ; Hubbard, John W. / Evaluation of the bioequivalence of highly-variable drugs and drug products. In: Pharmaceutical Research. 2001 ; Vol. 18, No. 6. pp. 728-733.
@article{abca52437e4a4cc79df878376e692bd2,
title = "Evaluation of the bioequivalence of highly-variable drugs and drug products",
abstract = "Purpose. To establish procedures for the effective evaluation of bioequivalence (BE) for highly-variable drugs and drug products (HVD/P). Methods. 2- and 4-period crossover BE studies with 24 subjects were simulated which generally assumed within-subject coefficients of variation of 40{\%}. The relationship between the fraction of studies in which BE was accepted (the statistical power) and the ratio of geometric means (GMR) of the two formulations was evaluated for various methods of analysis. These included, primarily, scaled average BE (ABE), the corresponding approach of expanding BE limits (BEL), and, for comparison, unscaled ABE and scaled individual BE (IBE). Results. Scaled ABE and expanding BEL showed very similar properties in both 2- and 4-period studies. They had steeper power curves than scaled IBE. Unscaled ABE had very low statistical power. The acceptance of BE by unscaled and scaled ABE and expanding BEL was almost independent of subject-by-formulation interaction and the ratio of within-subject variations of the two formulations. By contrast, the conclusions reached by scaled IBE were strongly affected by these parameters. Conclusions. Scaled ABE and expanding BEL evaluate BE effectively for HVD/P in both 2- and 4-period investigations. However, additional, useful information can be obtained from 4-period studies.",
keywords = "2- and 4-period crossover design, Bioequivalence, Highly-variable drugs, Regulatory limits, Scaled regulatory criterion, Simulated clinical trials",
author = "L. T{\'o}thfalusi and Laszlo Endrenyi and Midha, {Kamal K.} and Rawson, {Maureen J.} and Hubbard, {John W.}",
year = "2001",
doi = "10.1023/A:1011015924429",
language = "English",
volume = "18",
pages = "728--733",
journal = "Pharmaceutical Research",
issn = "0724-8741",
publisher = "Springer New York",
number = "6",

}

TY - JOUR

T1 - Evaluation of the bioequivalence of highly-variable drugs and drug products

AU - Tóthfalusi, L.

AU - Endrenyi, Laszlo

AU - Midha, Kamal K.

AU - Rawson, Maureen J.

AU - Hubbard, John W.

PY - 2001

Y1 - 2001

N2 - Purpose. To establish procedures for the effective evaluation of bioequivalence (BE) for highly-variable drugs and drug products (HVD/P). Methods. 2- and 4-period crossover BE studies with 24 subjects were simulated which generally assumed within-subject coefficients of variation of 40%. The relationship between the fraction of studies in which BE was accepted (the statistical power) and the ratio of geometric means (GMR) of the two formulations was evaluated for various methods of analysis. These included, primarily, scaled average BE (ABE), the corresponding approach of expanding BE limits (BEL), and, for comparison, unscaled ABE and scaled individual BE (IBE). Results. Scaled ABE and expanding BEL showed very similar properties in both 2- and 4-period studies. They had steeper power curves than scaled IBE. Unscaled ABE had very low statistical power. The acceptance of BE by unscaled and scaled ABE and expanding BEL was almost independent of subject-by-formulation interaction and the ratio of within-subject variations of the two formulations. By contrast, the conclusions reached by scaled IBE were strongly affected by these parameters. Conclusions. Scaled ABE and expanding BEL evaluate BE effectively for HVD/P in both 2- and 4-period investigations. However, additional, useful information can be obtained from 4-period studies.

AB - Purpose. To establish procedures for the effective evaluation of bioequivalence (BE) for highly-variable drugs and drug products (HVD/P). Methods. 2- and 4-period crossover BE studies with 24 subjects were simulated which generally assumed within-subject coefficients of variation of 40%. The relationship between the fraction of studies in which BE was accepted (the statistical power) and the ratio of geometric means (GMR) of the two formulations was evaluated for various methods of analysis. These included, primarily, scaled average BE (ABE), the corresponding approach of expanding BE limits (BEL), and, for comparison, unscaled ABE and scaled individual BE (IBE). Results. Scaled ABE and expanding BEL showed very similar properties in both 2- and 4-period studies. They had steeper power curves than scaled IBE. Unscaled ABE had very low statistical power. The acceptance of BE by unscaled and scaled ABE and expanding BEL was almost independent of subject-by-formulation interaction and the ratio of within-subject variations of the two formulations. By contrast, the conclusions reached by scaled IBE were strongly affected by these parameters. Conclusions. Scaled ABE and expanding BEL evaluate BE effectively for HVD/P in both 2- and 4-period investigations. However, additional, useful information can be obtained from 4-period studies.

KW - 2- and 4-period crossover design

KW - Bioequivalence

KW - Highly-variable drugs

KW - Regulatory limits

KW - Scaled regulatory criterion

KW - Simulated clinical trials

UR - http://www.scopus.com/inward/record.url?scp=0034865996&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034865996&partnerID=8YFLogxK

U2 - 10.1023/A:1011015924429

DO - 10.1023/A:1011015924429

M3 - Article

VL - 18

SP - 728

EP - 733

JO - Pharmaceutical Research

JF - Pharmaceutical Research

SN - 0724-8741

IS - 6

ER -