Metrics comparing simulated early concentration profiles for the determination of bioequivalence

Laszlo Endrenyi, Ferenc Csizmadia, Laszlo Tothfalusi, Mei Ling Chen

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Purpose. To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles. Methods. Two-period crossover trials were simulated with increasing assumed ratios of the true absorption rate constants of the two formulations, and with various kinetic models. Kinetic sensitivities (KS) and standard errors (SE) of the various metrics were recorded and the percentage of trials accepting bioequivalence (the statistical power) was evaluated. The principal metrics included the partial AUC (AUC(p)), the intercept obtained by linear extrapolation of the ratios of the lower over higher concentrations (C) measured for the two formulations (I(L/H)), and the ratios of intercepts extrapolated from logarithmic C/time values of the two products (M(log)). For comparison, also properties of C(max) and an ideally evaluated measure (ld) were determined. Results. M(log) showed generally the highest statistical power and KS, and also the largest SE, closely followed by I(L/H). Partial AUC exhibited lower power and KS, but also smaller SE than the intercept procedures. The three methods had much higher power, KS and SE than C(max). These comparisons were maintained over various kinetic conditions and experimental designs. The effective evaluation of bioequivalence in the early phase of studies is assured with 3 (or more) measurements until the population average peak of the reference formulation. Conclusions. The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. M(log) had the highest statistical power, closely followed by I(L/H) and then by partial AUC.

Original languageEnglish
Pages (from-to)1292-1299
Number of pages8
JournalPharmaceutical Research
Volume15
Issue number8
DOIs
Publication statusPublished - 1998

Fingerprint

Therapeutic Equivalency
Kinetics
Area Under Curve
Extrapolation
Design of experiments
Cross-Over Studies
Rate constants
Research Design
Population

Keywords

  • Absorption rate
  • Bioequivalence
  • Early exposure
  • Experimental design
  • Intercept metric
  • Partial AUC

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

Cite this

Metrics comparing simulated early concentration profiles for the determination of bioequivalence. / Endrenyi, Laszlo; Csizmadia, Ferenc; Tothfalusi, Laszlo; Chen, Mei Ling.

In: Pharmaceutical Research, Vol. 15, No. 8, 1998, p. 1292-1299.

Research output: Contribution to journalArticle

Endrenyi, Laszlo ; Csizmadia, Ferenc ; Tothfalusi, Laszlo ; Chen, Mei Ling. / Metrics comparing simulated early concentration profiles for the determination of bioequivalence. In: Pharmaceutical Research. 1998 ; Vol. 15, No. 8. pp. 1292-1299.
@article{d301efb6c810457bbd78862bbe3aaa60,
title = "Metrics comparing simulated early concentration profiles for the determination of bioequivalence",
abstract = "Purpose. To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles. Methods. Two-period crossover trials were simulated with increasing assumed ratios of the true absorption rate constants of the two formulations, and with various kinetic models. Kinetic sensitivities (KS) and standard errors (SE) of the various metrics were recorded and the percentage of trials accepting bioequivalence (the statistical power) was evaluated. The principal metrics included the partial AUC (AUC(p)), the intercept obtained by linear extrapolation of the ratios of the lower over higher concentrations (C) measured for the two formulations (I(L/H)), and the ratios of intercepts extrapolated from logarithmic C/time values of the two products (M(log)). For comparison, also properties of C(max) and an ideally evaluated measure (ld) were determined. Results. M(log) showed generally the highest statistical power and KS, and also the largest SE, closely followed by I(L/H). Partial AUC exhibited lower power and KS, but also smaller SE than the intercept procedures. The three methods had much higher power, KS and SE than C(max). These comparisons were maintained over various kinetic conditions and experimental designs. The effective evaluation of bioequivalence in the early phase of studies is assured with 3 (or more) measurements until the population average peak of the reference formulation. Conclusions. The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. M(log) had the highest statistical power, closely followed by I(L/H) and then by partial AUC.",
keywords = "Absorption rate, Bioequivalence, Early exposure, Experimental design, Intercept metric, Partial AUC",
author = "Laszlo Endrenyi and Ferenc Csizmadia and Laszlo Tothfalusi and Chen, {Mei Ling}",
year = "1998",
doi = "10.1023/A:1011912512966",
language = "English",
volume = "15",
pages = "1292--1299",
journal = "Pharmaceutical Research",
issn = "0724-8741",
publisher = "Springer New York",
number = "8",

}

TY - JOUR

T1 - Metrics comparing simulated early concentration profiles for the determination of bioequivalence

AU - Endrenyi, Laszlo

AU - Csizmadia, Ferenc

AU - Tothfalusi, Laszlo

AU - Chen, Mei Ling

PY - 1998

Y1 - 1998

N2 - Purpose. To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles. Methods. Two-period crossover trials were simulated with increasing assumed ratios of the true absorption rate constants of the two formulations, and with various kinetic models. Kinetic sensitivities (KS) and standard errors (SE) of the various metrics were recorded and the percentage of trials accepting bioequivalence (the statistical power) was evaluated. The principal metrics included the partial AUC (AUC(p)), the intercept obtained by linear extrapolation of the ratios of the lower over higher concentrations (C) measured for the two formulations (I(L/H)), and the ratios of intercepts extrapolated from logarithmic C/time values of the two products (M(log)). For comparison, also properties of C(max) and an ideally evaluated measure (ld) were determined. Results. M(log) showed generally the highest statistical power and KS, and also the largest SE, closely followed by I(L/H). Partial AUC exhibited lower power and KS, but also smaller SE than the intercept procedures. The three methods had much higher power, KS and SE than C(max). These comparisons were maintained over various kinetic conditions and experimental designs. The effective evaluation of bioequivalence in the early phase of studies is assured with 3 (or more) measurements until the population average peak of the reference formulation. Conclusions. The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. M(log) had the highest statistical power, closely followed by I(L/H) and then by partial AUC.

AB - Purpose. To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles. Methods. Two-period crossover trials were simulated with increasing assumed ratios of the true absorption rate constants of the two formulations, and with various kinetic models. Kinetic sensitivities (KS) and standard errors (SE) of the various metrics were recorded and the percentage of trials accepting bioequivalence (the statistical power) was evaluated. The principal metrics included the partial AUC (AUC(p)), the intercept obtained by linear extrapolation of the ratios of the lower over higher concentrations (C) measured for the two formulations (I(L/H)), and the ratios of intercepts extrapolated from logarithmic C/time values of the two products (M(log)). For comparison, also properties of C(max) and an ideally evaluated measure (ld) were determined. Results. M(log) showed generally the highest statistical power and KS, and also the largest SE, closely followed by I(L/H). Partial AUC exhibited lower power and KS, but also smaller SE than the intercept procedures. The three methods had much higher power, KS and SE than C(max). These comparisons were maintained over various kinetic conditions and experimental designs. The effective evaluation of bioequivalence in the early phase of studies is assured with 3 (or more) measurements until the population average peak of the reference formulation. Conclusions. The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. M(log) had the highest statistical power, closely followed by I(L/H) and then by partial AUC.

KW - Absorption rate

KW - Bioequivalence

KW - Early exposure

KW - Experimental design

KW - Intercept metric

KW - Partial AUC

UR - http://www.scopus.com/inward/record.url?scp=0031689198&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031689198&partnerID=8YFLogxK

U2 - 10.1023/A:1011912512966

DO - 10.1023/A:1011912512966

M3 - Article

VL - 15

SP - 1292

EP - 1299

JO - Pharmaceutical Research

JF - Pharmaceutical Research

SN - 0724-8741

IS - 8

ER -