Dataset Information

Pharmacokinetics of Ambroxol Sustained Release (Mucosolvan^® Retard) Compared with Other Formulations in Healthy Volunteers.

ABSTRACT:

Introduction

Ambroxol is used in the treatment of acute and chronic respiratory conditions characterized by abnormal mucus secretion and impaired mucus transport and is available in a variety of formulations. This study aimed to compare the steady-state (SS) pharmacokinetic characteristics of extended-release (ER) 75-mg retard capsules with two immediate-release (IR) formulations (60-mg effervescent tablets and 30-mg tablets) over a 24-h period.

Methods

An open-label, randomized, three-period, six-sequence crossover study was conducted in healthy volunteers aged 18-45 years who had a normal body mass index. The test (ER 75-mg retard capsule once daily) and reference treatments (half of IR 60-mg effervescent tablet twice daily or 30-mg IR tablet twice daily) were administered on days 1-5 of each treatment period. Meals were standardized and concomitant therapy was prohibited. Blood samples for pharmacokinetic assessment were collected on day 5 (SS) of each treatment period. The co-primary endpoints were exposure (AUC_{SS 0-24}) and maximum plasma level (C_{max SS}).

Results

Twenty-four participants received ambroxol (male n = 13, 54.2%; mean ± standard deviation [SD] age 25.0 ± 6.4 years) and 23 completed the study. ER retard capsules provided similar AUC_SS 0-24 compared to IR tablets (geometric means ratio [GMR] 110.7%; 90% confidence interval [CI] 99.8%, 122.7%) and effervescent tablets (GMR 106.9%; 90% CI 100.3%, 114.0%). ER retard capsules provided similar C_max SS compared to IR tablets (GMR 84.7%, 90% CI 77.0%, 93.3%), and lower C_max SS compared to effervescent tablets (GMR 80.9%, 90% CI 73.9%, 88.6%). Time to C_max SS (t_max SS) was longer with ER retard capsules (6.0 h) than with IR tablets (2.0 h) or effervescent tablets (1.0 h).

Conclusions

ER ambroxol 75-mg retard capsules given once daily showed a similar pharmacokinetic profile to IR ambroxol formulations and therefore can be used instead of these in the treatment of respiratory conditions. CLINICALTRIALS.

Gov identifier

NCT02036775.

SUBMITTER: Ollier C

PROVIDER: S-EPMC7229136 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Dataset Information

Pharmacokinetics of Ambroxol Sustained Release (Mucosolvan^® Retard) Compared with Other Formulations in Healthy Volunteers.

Introduction

Methods

Results

Conclusions

Gov identifier

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Dataset Information

Pharmacokinetics of Ambroxol Sustained Release (Mucosolvan® Retard) Compared with Other Formulations in Healthy Volunteers.

Introduction

Methods

Results

Conclusions

Gov identifier

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Pharmacokinetics of Ambroxol Sustained Release (Mucosolvan^® Retard) Compared with Other Formulations in Healthy Volunteers.