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Assessment of Levothyroxine Sodium Bioavailability

Recommendations for an Improved Methodology Based on the Pooled Analysis of Eight Identically Designed Trials with 396 Drug Exposures

Clinical Pharmacokinetics volume 43, pages 1037–1053 (2004)Cite this article

Abstract

Background

Assessment of dosage form performance in delivering endogenous compounds, such as hormones, in vivo requires a specific approach.

Objectives

Assessment of relative bioavailability of levothyroxine sodium (L-T4) from eight solid preparations, compared with a liquid formulation, by using pharmacological doses, and critical evaluation of trial methodology based on the pooled analysis of individual data.

Design

Eight open-label, randomised, single-dose, crossover phase I studies using eight solid L-T4 dosage forms (25, 50, 75, 100, 125, 150, 175, 200μg per tablet; administered total doses 600, 625 or 700μg) and a liquid formulation; assessment of relative bioavailability by 90% confidence intervals for the relative area under the concentration-time curve (AUC) of total thyroxine (TT4), i.e. protein-bound plus free thyroxine, calculated by using the recommended log AUC four-way analysis of variance models for crossover designs. For the pooled analysis, general linear models were applied to assess the validity of model assumptions, to identify potential sources of effect modification, to discuss alternative modelling approaches with respect to endogenous hormone secretion and to give recommendations for future designs and sample sizes.

Participants

One hundred and sixty-nine healthy males; 29 of these individuals participating in two studies.

Interventions

Single oral doses of L-T4 tablets and the liquid formulation administered after fasting, separated by at least 6 weeks; a total of 396 drug exposures.

Main outcome measures

TT4 AUC from 0 to 48 hours and peak plasma concentration with and without baseline correction.

Results

Each study demonstrated equivalence of the tablets to the drinking solution, independent of the chosen analysis model. Sequence effects that could devalidate the chosen crossover approach were not found. Period effects with changing directions that could best be explained by seasonal variation were detected. While the pre-specified method of baseline correction of simply subtracting individual time-zero TT4 values was disadvantageous, the analysis of total AUC could be improved considerably by covariate adjustment for baseline TT4. With this approach, sample sizes could have been substantially reduced or, alternatively, the recommended equivalence ranges could be reduced to ±6%. Conclusion: Using a single pharmacological dose of L-T4 in two-period crossover designs is a safe and reliable procedure to assess L-T4 dosage form performance. With an adequate statistical modelling approach, the design is efficient and allows general conclusions with moderate sample sizes.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgments

The study series was funded by Henning Berlin GmbH, succeeded by Sanofi-Synthelabo, now part of the Aventis Group. The pooled analysis was investigator initiated. The sponsor had no influence on the study conduct or on the analysis and publication of the data.

Dr J. Pfeilschifter reports having received lecture fees from Henning Berlin GmbH, succeeded by Sanofi-Synthelabo, now part of the Aventis Group.

Drs C. Clanget, R. Ding, C. Goeggelmannm, V. Hinke, M. Lang, Y. Tayrouz, I. Walter-Sack and K. Wegscheider have no conflicts of interest directly relevant to the content of this study.

The authors thank Mrs Karin Arnold, Mrs Andrea Deschlmayr, Mrs Jutta Kocher, Mrs Magdalena Longo and Mrs Gisela Schwahn for their excellent technical assistance, and Walter E. Haefeli, Professor of Medicine and Clinical Pharmacology, for his helpful discussions and assistance in reviewing the manuscript.

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Affiliations

  1. Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University Medical Center, Heidelberg, Germany

    Ingeborg Walter-Sack, Reinhard Ding, Christoph Goeggelmann, Matthias Lang & Yorki Tayrouz

  2. Department of Internal Medicine I, Endocrinology and Metabolism, University Medical Center, Heidelberg, Germany

    Christof Clanget, Vera Hinke & Johannes Pfeilschifter

  3. Institute for Statistics and Econometry, University of Hamburg, Hamburg, Germany

    Karl Wegscheider

Authors
  1. Ingeborg Walter-Sack
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  2. Christof Clanget
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Correspondence to Ingeborg Walter-Sack.

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Walter-Sack, I., Clanget, C., Ding, R. et al. Assessment of Levothyroxine Sodium Bioavailability. Clin Pharmacokinet 43, 1037–1053 (2004). https://doi.org/10.2165/00003088-200443140-00006

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Keywords

  • Period Effect
  • Relative Bioavailability
  • Bioequivalence Study
  • Levothyroxine Sodium
  • Residual Standard Deviation