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.