Formulation and Bioequivalence Testing of Fixed-Dose Combination Orally Disintegrating Tablets for the Treatment of Tuberculosis in the Paediatric Population

Abstract

Tuberculosis (TB) is believed to affect around 10 million people worldwide. Treatment for TB includes isoniazid and rifampicin, with fixed-dose combination (FDC) recommended for improved patient compliance. Similarly, orally disintegrating tablets (ODTs) are an increasingly popular dosage form that aid compliance since they do not require swallowing. In this study ODTs of isoniazid and rifampicin, either as discrete or FDC doses, were formulated and bioequivalence between single and combination doses compared using in vitro and in silico approaches. Dissolution profiles were compared using FDA advised difference (f 1) and similarity (f 2) testing in biorelevant media. Rifampicin release from FDCs decreased by approximately 15% in fed-state media (failed f 1 and f 2), which was attributed to enhanced rifampicin degradation in the presence of isoniazid at lower pH. Apparent permeability (P app) values derived from Caco-2 transport studies were included alongside dissolution results into a physiologically based pharmacokinetic (PBPK) model, to simulate in vivo bioavailability in healthy subjects. Models showed no difference in bioavailability between formulations or dosing (fasted or fed) state, despite the failures in dissolution-based bioequivalence testing, highlighting shortcomings in f 1 and f 2 assessment and the strength of PBPK models.

Publication DOI: https://doi.org/10.1016/j.xphs.2020.07.016
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
Additional Information: © 2020, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Uncontrolled Keywords: Analysis,Bioavailability,Biopharmaceutics classification system (BCS),Buccal delivery,Caco-2 cells,Computational ADME,Tablet(s),Pharmaceutical Science
Publication ISSN: 1520-6017
Last Modified: 11 Mar 2024 08:33
Date Deposited: 10 Aug 2020 14:13
Full Text Link:
Related URLs: https://www.sci ... 022354920303828 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2020-10
Published Online Date: 2020-07-22
Accepted Date: 2020-07-16
Authors: Dennison, Thomas J
Smith, Julian C
Badhan, Raj K S (ORCID Profile 0000-0002-0904-9324)
Mohammed, Afzal R (ORCID Profile 0000-0002-5212-3040)

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