"Authors'Reply to Coste et al"International audienc

Alain Bousquet-Mélou

Aude A. Ferran

Didier Concordet

J Coste

Jean-Louis Montastruc

ML Chen

Peggy Gandia

Peter Lees

Pierre-Louis Toutain

RB Shah

U Gottwald-Hostalek

V Blakesley

VA Blakesley

English

Concordet, D

Gandia, P

Montastruc, J L

Bousquet-Mélou, A

Lees, P

Ferran, A

Toutain, P L

RVC Research Online

Vol.:(0123456789)Clinical Pharmacokinetics https://doi.org/10.1007/s40262-019-00780-2LETTER TO THE EDITORAuthors’ Reply to Coste et al.: “Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?”Didier Concordet1 · Peggy Gandia1 · Jean‑Louis Montastruc2 · Alain Bousquet‑Mélou1 · Peter Lees3 · Aude A. Ferran1 · Pierre‑Louis Toutain1,3  © The Author(s) 2019We are pleased to respond to the letter of Coste at al. [1] as follows. Nowhere in our article is any claim made to analyse the problem of symptoms reported with the new formulation of  Levothyrox®. Our sole aim was to challenge scientifi-cally the principle of using an average bioequivalence (ABE) approach to document a switchability issue. This is a par-ticular concern, given that substitution of a new formulation was imposed on several million patients.First, we address the question of correcting (or not) the raw data for basal values of thyroxine (T4). Our article is neither misplaced nor misleading in this regard, and, for the avoidance of doubt, we direct readers to the 2010 Euro-pean Union (EU) guideline [2]. It is a requirement of this guideline that a baseline correction should be applied to the variable area under the curve for products containing endogenous compounds as active constituents. The guideline states explicitly “If the substance being studied is endoge-nous, the calculation of pharmacokinetic parameters should be performed using baseline correction so that the calcu-lated pharmacokinetic parameters refer to the additional concentrations provided by the treatment”. Moreover, the guideline further qualifies this requirement in stating: “The exact method for baseline correction should be pre-specified and justified in the study protocol. In general, the stand-ard subtractive baseline correction method, meaning either subtraction of the mean of individual endogenous pre-dose concentrations or subtraction of the individual endogenous predose AUC, is preferred”. We have followed the guideline to the letter and note that the US Food and Drug Administra-tion guideline [3] gives a similar direction.Furthermore, we draw attention to the fact that the French Regulatory Authorities’ evaluation dossier for  Levothyrox® explicitly endorsed this baseline correction [4]. Neverthe-less, it is the case that the actual methods used to correct baseline concentrations of endogenous compounds have been debated in the literature. In a review on the methodol-ogy adopted to assess the bioequivalence of levothyroxine [5], it was concluded that the so-called correction Method 1, comprising subtraction from each T4 concentration of the mean of control concentrations, is the most appropriate and was, indeed, cited in the US Food and Drug Administration guideline [3]. This method we followed precisely.Second, in their letter to the Editor, Coste et al. stated “Furthermore, the authors use results obtained from adjusted IER, rather than from unadjusted IER, to affirm the “fact that more than 50% of individuals were outside the a priori bioequivalence range (0.90–1.11)”. In response, we confirm the soundness of this approach, as the EU guide-line indicates that it is only “In rare cases where substantial increases over baseline endogenous levels are seen, base-line correction may not be needed”. Even when consider-ing only the unadjusted baseline area under the curve, the number of subjects outside the a priori acceptance interval of 0.90–1.11 is still sufficiently high (17%) to constitute a red warning signal of possible non-individual bioequiva-lence. This might be suspected when the percentage exceeds 10% [6]. In addition, it has been alleged that the applica-tion of criteria for determination of bioequivalence, without This reply refers to the article available at https ://doi.org/10.1007/s4026 2-019-00779 -9.A comment refers to the article available at https ://doi.org/10.1007/s4026 2-019-00747 -3. * Pierre-Louis Toutain  pltoutain@wanadoo.fr1 INTHERES, Université de Toulouse, INRA, ENVT, Toulouse, France2 Service de Pharmacologie Médicale et Clinique, INSERM, UMR 1027, CIC INSERM 1436, Faculté de Médecine, Centre Hospitalier Universitaire de Toulouse, Université de Toulouse, Toulouse, France3 The Royal Veterinary College, University of London, London, UK D. Concordet et al.accounting for endogenous T4 levels, resulted in a failure to identify products that differed by as much as 25–33% [7].We question this technical polemical argument, which fails to address the main messages conveyed by our article. The article did not challenge the data analysis, as conducted by the company; in fact, we endorsed this when stating, “it is acknowledged that the trial and analyses were conducted professionally according to current EU guidelines” [8].To be clear, what we are challenging is the validity of an ABE investigation to impose, administratively, substitution of an older by a newly formulated product for almost 3 mil-lion patients. We make this challenge because an ABE study is not intended for and therefore should not be used to guar-antee the switchability within patients of two formulations.In summary, what must be questioned is that a new for-mulation, possibly highly variable in its pharmacokinetic profile (implicitly indicated by the 216 subjects planned and used to demonstrate the ABE [9]), should be marketed on the basis of an ABE, for a drug like levothyroxine, with a narrow therapeutic index [10–12], without any further evaluation or precautions.In a future publication, we shall challenge this use of an atypically large number of subjects (204 for the present ABE trial). Further, we will propose that this effectively nullifies the necessarily precautionary intention of the EU guideline, when recommending shortening the a priori acceptance interval from 0.80–1.25 to 0.90–1.11.Finally, we accept that there is neither conspiracy nor malice on either side of this debate, but rather a difference of judgement on data derived and conclusions drawn. It is scientific argument that must fuel this crucial debate, with its welfare considerations, and not media opinions, when these are not based on sound science.Compliance with Ethical Standards Funding No sources of funding were used in the preparation of this reply.Conflict of interest Didier Concordet, Peggy Gandia, Jean-Louis Montastruc, Alain Bousquet-Mélou, Peter Lees, Aude A. Ferran, and Pierre-Louis Toutain have no conflicts of interest that are directly rel-evant to the content of this reply.Open Access This article is distributed under the terms of the Crea-tive Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.References 1. Coste J, Bertagna X, Zureik M. Comment on: “Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?”. Clin Pharmacokinet. 2019. https ://doi.org/10.1007/s4026 2-019-00779 -9. 2. Anonymous. “Guideline on the investigation of bioequivalence” (EMA, London, 2010). http://www.ema.europ a.eu/docs/en_GB/docum ent_libra ry/Scien tific _guide line/2010/01/WC500 07003 9.pdf. Accessed 28 Apr 2019. 3. Anonymous. Guidance for industry: bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA. Draft guidance. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2013 Biopharmaceutics. Available from: https ://www.fda.gov/downl oads/Drugs /Guida nceCo mplia nceRe gulat oryIn forma tion/Guida nces/UCM37 7465.pdf. Accessed 28 Apr 2019. 4. Anonymous. Levothyrox; preliminary assessment report. Phar-macokinetic comment on a generic application. Rapport interne ANSM sur les études de bioéquivalence (15/09/2017). ANSM. https ://www.ansm.sante .fr/conte nt/downl oad/11011 5/13954 69/versi on/1/file/Rappo rt+d%C3%A9val uatio n+bioeq uival ence+_+Levot hyrox .pdf. Accessed 28 Apr 2019. 5. Blakesley VA. Current methodology to assess bioequivalence of levothyroxine sodium products is inadequate. AAPS J. 2005;7:E42–6. 6. Chen ML, Patnaik R, Hauck WW, Schuirmann DJ, Hyslop T, Williams R. An individual bioequivalence criterion: regulatory considerations. Stat Med. 2000;19:2821–42. 7. Blakesley V, Awni W, Locke C, Ludden T, Granneman GR, Braverman LE. Are bioequivalence studies of levothyroxine sodium formulations in euthyroid volunteers reliable? Thyroid. 2004;14:191–200. 8. Concordet D, Gandia P, Montastruc J-L, Bousquet-Mélou A, Lees P, Ferran A, et al.  Levothyrox® new and old formulations: are they switchable for millions of patients? Clin Pharmacokinet. 2019. https ://doi.org/10.1007/s4026 2-019-00747 -3. (Epub ahead of print). 9. Gottwald-Hostalek U, Uhl W, Wolna P, Kahaly GJ. New levothy-roxine formulation meeting 95-105% specification over the whole shelf-life: results from two pharmacokinetic trials. Curr Med Res Opin. 2017;33:169–74. 10. Shah RB, Collier JS, Sayeed VA, Bryant A, Habib MJ, Khan MA. Tablet splitting of a narrow therapeutic index drug: a case with levothyroxine sodium. AAPS PharmSciTech. 2010;11:1359–67. 11. Anonymous. Recommandations sur la substitution des spéciali-tés à base de lévothyroxine sodique . Lettres aux professionnels de santé. 2010. https ://www.ansm.sante .fr/S-infor mer/Infor matio ns-de-secur ite-Lettr es-aux-profe ssion nels-de-sante /Recom manda tions -sur-la-subst ituti on-des-speci alite s-a-base-de-levot hyrox ine-sodiq ue-Lettr e-aux-profe ssion nels-de-sante . Accessed 28 Apr 2019. 12. Anonymous. Levothyroxine sodium. Food and Drug Adminis-tration; 2014 p. 2. https ://www.fda.gov/downl oads/Drugs /Guida nceCo mplia nceRe gulat oryIn forma tion/Guida nces/UCM42 8208.pdf. Accessed 28 Apr 2019.

Authors' Reply to Coste et al.: "Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?"

Concordet, Didier

Gandia, Peggy

Montastruc, Jean-Louis

Bousquet‐mélou, Alain

Lees, Peter

Ferran, Aude

Toutain, Pierre-Louis

HAL: Hyper Article en Ligne

Authors' Reply to Coste et al.:"Levothyrox New and Old Formulations: Are they Switchable for Millions of Patients?"

HAL-Inserm

Crossref

Authors’ Reply to Coste et al.: “Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?”

Hal-Diderot

HAL ENVT (Ecole Nationale Vétérinaire de Toulouse)

GANDIA, Peggy

Bousquet-Mélou, Alain

ProdInra

Authors' Reply to Coste et al.:"Levothyrox  New and Old Formulations: Are they Switchable for Millions of Patients?"

https://hal.inrae.fr/hal-02623560v1/document

Authors' Reply to Coste et al.: "Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?"

Abstract

Similar works

Full text

Available Versions