A Fully Replicate, Cross-over, Bioequivalence Study to Compare Two Prolonged Release, Multi-matrix Tablet Formulations of Budesonide in Healthy Indian Adults

Abstract

Introduction: Budesonide is a synthetic, non halogenated corticosteroid, structurally related to 16α-hydroxyprednisolone, which is approved as first-line therapy for various gastrointestinal disorders. Budesonide prolonged-release tablets incorporating multi-matrix technology {Cortiment® 9 mg: Reference product (R)} were approved in India for induction of remission in adult patients with mild-to-moderate active ulcerative colitis. Aim: To assess the bioavailability, safety and tolerability of a single dose of generic budesonide prolonged-release tablets 9 mg {CortirowaTM OD; Test product (T)} and demonstrate their bioequivalence to Reference product (R) in healthy Indian adults under fasting conditions. Materials and Methods: In this randomised, open-label, single-dose, balanced, 2-treatment, 2-sequence, 4-period, fully replicate, cross-over bioequivalence study conducted from 12 July 2021 to 08 August 2021 at Ecron Acunova Limited, Manipal, India, 56 participants were randomly allocated (1:1) to treatment sequences Test-Reference-Test-Reference (TRTR) or Reference-Test-Reference-Test (RTRT). After a 10-hour overnight fast, participants were administered a single oral dose of T or R along with 240 mL of water. After each dose, a total of 26 venous blood samples (each 4 mL) were collected from each participant, at hourly intervals until 20 hours, and at 24, 30, 36, 48, and 72 hours. Plasma budesonide concentrations were analysed using a validated Liquid ChromatographyTandem-Mass Spectrometry (LC-MS/MS) method. Based on the randomisation sequences, the treatment periods were defined as test product treatment Period-1 (T1), test product treatment Period-2 (T2), reference product treatment Period-1 (R1), and reference product treatment Period-2 (R2). The primary pharmacokinetic parameters were peak plasma concentration (Cmax) and area under the concentration-time curve from time zero to the last sample with quantifiable concentration (AUC0-t). Results: Test and reference products were comparable in terms of mean (standard deviation) Cmax {pg/mL: T1=2163.0 (1423.9) and T2=2456.25 (1346.035) vs R1=2301.59 (1582.995) and R2=2437.62 (1437.665)} and AUC0-t {hr.pg/mL: T1=27938.0 (16431.23) and T2=33629.58 (18407.253) vs R1=25882.41 (17250.267) and R2=33146.25 (19350.222)}. As the within-subject Standard Deviation (SD) of R (SWR) for Cmax and AUC0-t was ≥0.294, the reference-Scaled Average Bioequivalence (SABE) approach was used. The bioequivalence criteria prespecified using the Scaled Average Bioequivalence (SABE) approach were met as the 95% upper confidence bound for (μT-μR)2 - θs2 WR of Cmax (-0.255371831) and AUC0-t (-0.445865013) were both ≤0, and the point estimate (T/R) geometric mean ratio of Cmax (0.97) and AUC0-t (1.06) were both within 0.80 and 1.25. While 10 Adverse Events (AEs) were reported in the study, all were of mild intensity. Conclusion: CortirowaTM OD was bioequivalent to Cortiment® 9 mg in healthy Indian adults under fasting conditions. Both the products were found to be well tolerated.