Sensitivity of empirical metrics of rate of absorption in bioequivalence studies

Arne Ring, L. Tóthfalusi, Laszlo Endrenyi, Michael Weiss

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Purpose. The sensitivity and effectiveness of indirect metrics proposed for the assessment of comparative absorption rates in bioequivalence studies [C(max), T(max), partial AUC (AUC(p)), feathered slope (SL(f)), intercept metric (I)] were originally tested by assuming first-order absorption. The present study re-evaluates their sensitivity performances using the more realistic inverse Gaussian (IG) model characterizing the input process for oral drug administration. Methods. Simulations were performed for both the first-order or exponential model (EX) which is determined by only one parameter, the mean absorption time (MAT = 1/k(a)), and the IG model, which additionally contains a shape parameter, the relative dispersion of absorption time distribution (CV2(A)). Kinetic sensitivities (KS) of the indirect metrics were evaluated from bioequivalence trials (error free data) generated with various ratios of the true parameters (MAT and CV2(A)) of the two formulations. Results. The behavior of the metrics was similar with respect to changes in MAT ratios with both models: KS was low with C(max), moderate with SL(f) and AUC(p), and high with I and T(max) following correction for apparent lag time (T(lag)). Changes of the shape parameter CV2(A), however; were not detectable by C(max), T(max), SL(f), and A UC(p). Changes in both MAT and CV2(A) were well reflected by I with CV2(A) ratio > 1. I exhibited approximately full KS also with CV2(A) -ratio <1 when a correction was first applied for the apparent lag time. Conclusions. The time profile of absorption rates is insufficiently characterized by only one parameter (MAT). Indirect metrics which are sensitive enough to detect changes in the scale and shape of the input profile could be useful for bioequivalence testing. Among the tested measures, I is particularly promising when a correction is applied for T(lag).

Original languageEnglish
Pages (from-to)583-588
Number of pages6
JournalPharmaceutical Research
Volume17
Issue number5
DOIs
Publication statusPublished - 2000

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Therapeutic Equivalency
Area Under Curve
Kinetics
Oral Administration
Testing
Pharmaceutical Preparations

Keywords

  • Absorption rate
  • Bioequivalence
  • Extended-release
  • Mean absorption time
  • Relative dispersion

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

Cite this

Sensitivity of empirical metrics of rate of absorption in bioequivalence studies. / Ring, Arne; Tóthfalusi, L.; Endrenyi, Laszlo; Weiss, Michael.

In: Pharmaceutical Research, Vol. 17, No. 5, 2000, p. 583-588.

Research output: Contribution to journalArticle

Ring, Arne ; Tóthfalusi, L. ; Endrenyi, Laszlo ; Weiss, Michael. / Sensitivity of empirical metrics of rate of absorption in bioequivalence studies. In: Pharmaceutical Research. 2000 ; Vol. 17, No. 5. pp. 583-588.
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abstract = "Purpose. The sensitivity and effectiveness of indirect metrics proposed for the assessment of comparative absorption rates in bioequivalence studies [C(max), T(max), partial AUC (AUC(p)), feathered slope (SL(f)), intercept metric (I)] were originally tested by assuming first-order absorption. The present study re-evaluates their sensitivity performances using the more realistic inverse Gaussian (IG) model characterizing the input process for oral drug administration. Methods. Simulations were performed for both the first-order or exponential model (EX) which is determined by only one parameter, the mean absorption time (MAT = 1/k(a)), and the IG model, which additionally contains a shape parameter, the relative dispersion of absorption time distribution (CV2(A)). Kinetic sensitivities (KS) of the indirect metrics were evaluated from bioequivalence trials (error free data) generated with various ratios of the true parameters (MAT and CV2(A)) of the two formulations. Results. The behavior of the metrics was similar with respect to changes in MAT ratios with both models: KS was low with C(max), moderate with SL(f) and AUC(p), and high with I and T(max) following correction for apparent lag time (T(lag)). Changes of the shape parameter CV2(A), however; were not detectable by C(max), T(max), SL(f), and A UC(p). Changes in both MAT and CV2(A) were well reflected by I with CV2(A) ratio > 1. I exhibited approximately full KS also with CV2(A) -ratio <1 when a correction was first applied for the apparent lag time. Conclusions. The time profile of absorption rates is insufficiently characterized by only one parameter (MAT). Indirect metrics which are sensitive enough to detect changes in the scale and shape of the input profile could be useful for bioequivalence testing. Among the tested measures, I is particularly promising when a correction is applied for T(lag).",
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N2 - Purpose. The sensitivity and effectiveness of indirect metrics proposed for the assessment of comparative absorption rates in bioequivalence studies [C(max), T(max), partial AUC (AUC(p)), feathered slope (SL(f)), intercept metric (I)] were originally tested by assuming first-order absorption. The present study re-evaluates their sensitivity performances using the more realistic inverse Gaussian (IG) model characterizing the input process for oral drug administration. Methods. Simulations were performed for both the first-order or exponential model (EX) which is determined by only one parameter, the mean absorption time (MAT = 1/k(a)), and the IG model, which additionally contains a shape parameter, the relative dispersion of absorption time distribution (CV2(A)). Kinetic sensitivities (KS) of the indirect metrics were evaluated from bioequivalence trials (error free data) generated with various ratios of the true parameters (MAT and CV2(A)) of the two formulations. Results. The behavior of the metrics was similar with respect to changes in MAT ratios with both models: KS was low with C(max), moderate with SL(f) and AUC(p), and high with I and T(max) following correction for apparent lag time (T(lag)). Changes of the shape parameter CV2(A), however; were not detectable by C(max), T(max), SL(f), and A UC(p). Changes in both MAT and CV2(A) were well reflected by I with CV2(A) ratio > 1. I exhibited approximately full KS also with CV2(A) -ratio <1 when a correction was first applied for the apparent lag time. Conclusions. The time profile of absorption rates is insufficiently characterized by only one parameter (MAT). Indirect metrics which are sensitive enough to detect changes in the scale and shape of the input profile could be useful for bioequivalence testing. Among the tested measures, I is particularly promising when a correction is applied for T(lag).

AB - Purpose. The sensitivity and effectiveness of indirect metrics proposed for the assessment of comparative absorption rates in bioequivalence studies [C(max), T(max), partial AUC (AUC(p)), feathered slope (SL(f)), intercept metric (I)] were originally tested by assuming first-order absorption. The present study re-evaluates their sensitivity performances using the more realistic inverse Gaussian (IG) model characterizing the input process for oral drug administration. Methods. Simulations were performed for both the first-order or exponential model (EX) which is determined by only one parameter, the mean absorption time (MAT = 1/k(a)), and the IG model, which additionally contains a shape parameter, the relative dispersion of absorption time distribution (CV2(A)). Kinetic sensitivities (KS) of the indirect metrics were evaluated from bioequivalence trials (error free data) generated with various ratios of the true parameters (MAT and CV2(A)) of the two formulations. Results. The behavior of the metrics was similar with respect to changes in MAT ratios with both models: KS was low with C(max), moderate with SL(f) and AUC(p), and high with I and T(max) following correction for apparent lag time (T(lag)). Changes of the shape parameter CV2(A), however; were not detectable by C(max), T(max), SL(f), and A UC(p). Changes in both MAT and CV2(A) were well reflected by I with CV2(A) ratio > 1. I exhibited approximately full KS also with CV2(A) -ratio <1 when a correction was first applied for the apparent lag time. Conclusions. The time profile of absorption rates is insufficiently characterized by only one parameter (MAT). Indirect metrics which are sensitive enough to detect changes in the scale and shape of the input profile could be useful for bioequivalence testing. Among the tested measures, I is particularly promising when a correction is applied for T(lag).

KW - Absorption rate

KW - Bioequivalence

KW - Extended-release

KW - Mean absorption time

KW - Relative dispersion

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