Randomized Clinical Trial
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Pharmacol. Feb 17, 2023; 12(1): 1-11
Published online Feb 17, 2023. doi: 10.5497/wjp.v12.i1.1
Pharmacokinetics/Pharmacodynamics study of Fixtral SB as compared to supra bioavailable itraconazole and conventional itraconazole
Syed Mujtaba Hussain Naqvi, Monil Yogesh Neena Gala, Snehal Muchhala, Anand Arumugam, Dhananjay Panigrahi, Dipak Patil, Rahul Rathod, Amey Mane
Syed Mujtaba Hussain Naqvi, Monil Yogesh Neena Gala, Snehal Muchhala, Rahul Rathod, Amey Mane, Medical Affairs, Dr Reddy’s Laboratories, Hyderabad 500016, India
Anand Arumugam, Dipak Patil, Global Clinical Management, Dr Reddy’s Laboratories, Hyderabad 500016, India
Dhananjay Panigrahi, Formulation Development, Dr Reddy’s Laboratories, Hyderabad 500016, India
Author contributions: Syed N, Monil G, Snehal M, Anand A, Dhananjay P, Dipak P, Rahul R, Amey M equally contributed to this work; designed research; performed research; analyzed data and drafted the paper; all authors provided critical feedback and helped shape the research, analysis, and manuscript.
Institutional review board statement: The study protocol, informed consent forms and other relevant documents (subjects’ accrual) were reviewed and approved by ‘Ethicare Ethics committee’. Pre-screening and general safety instructions in view of COVID-19 pandemic were reviewed and approved by ‘Human Care Independent Ethics Committee’. The study was performed in compliance with the principles of the Declaration of Helsinki for Medical Research involving human subjects, the Guideline for Good Clinical Practice and Drug Control General of India regulatory guidelines.
Clinical trial registration statement: This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki [Ethical Principles for Medical Research Involving Human Subjects, Revised by 71th WMA General Assembly at Cordoba, Spain (virtual), in 2020] and that were consistent with Good Clinical Practices and Drug Control General of India regulatory guidelines.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All the authors report that they are employees of Dr Reddy’s Laboratories Ltd. The authors report no other conflicts of interest in this work.
Data sharing statement: The datasets are available only on request due to privacy/ethical restrictions.
CONSORT 2010 statement: The authors have read and filled out the CONSORT Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Monil Yogesh Neena Gala, MBBS, MD, Doctor, Medical Affairs, Dr Reddy’s Laboratories, Dr Reddy's Laboratories Ltd, Global Generics, 7-1-27, Ameerpet, Hyderabad 500016, Telangana, India. monil.yogesh@drreddys.com
Received: September 16, 2022
Peer-review started: September 16, 2022
First decision: October 31, 2022
Revised: November 11, 2022
Accepted: February 7, 2023
Article in press: February 7, 2023
Published online: February 17, 2023
Processing time: 153 Days and 18.3 Hours
Abstract
BACKGROUND

Itraconazole is a broad-spectrum triazole antifungal inhibiting fungal growth by inhibiting ergosterol synthesis and exhibits a nonlinear pharmacokinetic profile. Erratic absorption pattern with wide fluctuations in blood levels causes inconsistent and unpredictable clinical behaviour of this drug despite its low minimum inhibitory concentration (MIC) as compared to other antifungal agents.

AIM

To compare the oral bioavailability and bioequivalence of Fixtral SB (supra bioavailable itraconazole) with reference product R2 (supra bioavailable 2 × 50 mg itraconazole).

METHODS

The study population consisted of 54 healthy volunteers, aged between 18-45 years and randomized to receive a single oral dose of either test [T; Fixtral SB (supra bioavailable itraconazole) 100 mg] or reference product (R1; Sporanox 100 mg × 2 capsules and R2; Lozanoc capsules 50 mg × 2 capsules). Blood samples were taken pre-dose and post-dose up to 96 h. The study evaluated bioequivalence by comparing the oral bioavailability of the test product with reference product R2. The pharmacodynamic characteristics of the drug were evaluated by comparing the test product with reference product R1. Pharmacokinetics (PK)-PD comparative analysis [area under the concentration-time curve (AUC)/ minimum inhibitory concentration (MIC) > 25] was performed for conventional itraconazole 100 mg and supra bioavailable itraconazole 50 mg. Adverse events (AEs) assessments were performed in each study period and post-study evaluation.

RESULTS

Statistical analysis of primary PK variables revealed bioequivalence, with confidence intervals being completely inside the acceptance criteria of 80%-125%. The peak concentration levels of itraconazole were achieved at 10 h (T) and 8.5 h (R2), respectively. Pharmacodynamic parameter assessment showed that AUC/MIC for R1 are comparable to Fixtral SB 100mg for MIC levels up to 16mcg/mL (P > 0.05 and observed P = 0.3196). Six AEs were observed that were mild to moderate in severity and resolved. No severe AE was reported.

CONCLUSION

Test product itraconazole Capsule 100 mg is bioequivalent with the reference product (R2) at 100 mg dose (2 capsules of Lozanoc® 50 mg) under fed conditions. Pharmacodynamics activity in terms of AUC/MIC is comparable between the test product at 100 mg dose and marketed itraconazole 200 mg. Fixtral SB is expected to have therapeutically similar efficacy at half the equivalent dose. Tested formulations were found to be safe and well tolerated.

Keywords: Supra-Bioavailable itraconazole; Conventional itraconazole; Oral bioavailability; Pharmacodynamics; Efficacy; Adverse events

Core Tip: Itraconazole, a triazole antifungal with a broad spectrum, has a nonlinear pharmacokinetic profile due to its variable oral bioavailability. Based on these criteria, a comparison of Fixtral SB (supra bioavailable itraconazole) 100 mg with Lozanoc capsules 50mg administered as two capsules was performed, revealing that Fixtral SB is expected to have therapeutically comparable efficacy at half the equivalent dose. In terms of area under the concentration-time curve/minimum inhibitory concentration, the pharmacodynamic activity of the test product at 100 mg dose and the marketed itraconazole 200 mg is comparable. All of the formulations tested were found to be safe and well tolerated, with manageable side effects.