A paper which questions the trial of new formulation Merck Euthyrox (from lactose to mannitol).
Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?
Concordet D1,
Gandia P1,
Montastruc JL2,
Bousquet-Mélou A1,
Lees P3,
Ferran A1,
Toutain PL1
Clinical Pharmacokinetics, 01 Jul 2019, 58(7):827-833
DOI: 10.1007/s40262-019-00747-3 PMID: 30949873 PMCID: PMC6584220
Abstract
In France, more than 2.5 million patients are currently treated with levothyroxine, mainly as the marketed product Levothyrox®. In March 2017, at the request of French authorities, a new formulation of Levothyrox® was licensed, with the objective of avoiding stability deficiencies of the old formulation. Before launching this new formulation, an average bioequivalence trial, based on European Union recommended guidelines, was performed. The implicit rationale was the assumption that the two products, being bioequivalent, would also be switchable, allowing substitution of the new for the old formulation, thus avoiding the need for individual calibration of the dosage regimen of thyroxine, using the thyroid-stimulating hormone level as the endpoint, as required for a new patient on initiating treatment. Despite the fact that both formulations were shown to be bioequivalent, adverse drug reactions were reported in several thousands of patients after taking the new formulation. In this opinion paper, we report that more than 50% of healthy volunteers enrolled in a successful regulatory average bioequivalence trial were actually outside the a priori bioequivalence range. Therefore, we question the ability of an average bioequivalence trial to guarantee the switchability within patients of the new and old levothyroxine formulations. We further propose an analysis of this problem using the conceptual framework of individual bioequivalence. This involves investigating the bioavailability of the two formulations within a subject, by comparing not only the population means (as established by average bioequivalence) but also by assessing two variance terms, namely the within-subject variance and the variance estimating subject-by-formulation interaction. A higher within individual variability for the new formulation would lead to reconsideration of the appropriateness of the new formulation. Alternatively, a possible subject-by-formulation interaction would allow a judgement on the ability, or not, of doctors to manage patients effectively during transition from the old to the new formulation.
Concordet D, Gandia P, Montastruc JL, et al. Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients? Clinical Pharmacokinetics. 2019 Jul;58(7):827-833. DOI: 10.1007/s40262-019-00747-3. PMID: 30949873; PMCID: PMC6584220.
Freely accessible here:
europepmc.org/article/PMC/P...
There were several letters published concerning this paper. However, they are not all freely accessible. This is one from the original authors as a response!
Note that it is very even-handed and expressly dismisses bad faith from any party. More a case of the rules not properly covering the situation but being applied as if they did.
Authors’ Reply to Coste et al.: “Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?”
