ORAL BIOEQUIVALENCE STUDY OF TEDIZOLID TABLETS 200 MG IN HEALTHY INDIAN SUBJECTS UNDER FASTING CONDITIONS.
Main Article Content
Keywords
.
Abstract
Objective: To compare the rate and extent of absorption and also to monitor the safety and tolerability of a single dose of Tedizolid Tablets 200 mg of Test drug with Reference Product SIVEXTRO® (tedizolid phosphate) tablets 200mg
Design: Open label, balanced, randomized single-dose, two-treatment, two-sequence, two-period two-way Crossover design.
Setting: Clinical, Bioanalytical and Quality Assurance Services, Bion Clinicals Pvt. Ltd.
Participants: 24 Healthy, Adult, Human Subjects Under Fasting Conditions.
Method: Twenty-four subjects were dosed with the investigational product [test (T) or reference (R) (as per the randomization schedule)] with approximately 240 ± 02 mL of water at ambient temperature were dosed. Plasma concentrations of Tedizolid were determined using a LC-MS/MS method developed at Bion Clinicals Pvt. Ltd.,Pune,India. Intra-subject variability of the pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of Tedizolid was estimated using the root mean square error obtained after carrying out an analysis of variance for bioequivalence assessment. Also, the relative bioavailability was evaluated by calculating least squares mean ratios for Cmax, AUC0-t , and AUC0–∞ for tedizolid to tedizolid (reference). The 90% confidence intervals for the ratios of least squares means between drug formulations were calculated for the Ln-transformed data of both Cmax, AUC0-t and AUC0-∞ of Tedizolid. Additionally, the power of the test to detect a 20% difference between the test product (T) and reference product (R) was computed and reported for Tedizolid.
Results: The mean age, height, weight and BMI (Body Mass Index) of the subjects who were dosed in the study were 28.3 years, 167.5 cms, 68.17 Kgs and 24.28Kg/m2 respectively. The ratios of geometric least squares means of the test product (T) and reference product (R) for the Ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of Tedizolid were found to be 92.92%, 96.36% and 96.36% respectively.
The 90% confidence intervals for the ratios of geometric least squares means for the Ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of Tedizolid were found to be 88.49% - 97.57%, 93.96% - 98.82% and 94.06% - 98.71% respectively. No adverse event was observed and the changes in lab parameters were clinically non-significant.
Conclusion: The 90% confidence intervals of the differences of least squares means for the Ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of Tedizolid were within the bioequivalence acceptance limits of 80.00 - 125.00% and thus the test product (T) Tedizolid Tablets 200 mg and reference product (R) SIVEXTRO® (tedizolid phosphate) tablets 200mg were found bioequivalent with respect to rate and extent of absorption. The 200 mg oral dose of Tedizolid was well tolerated and was found safe.
References
2. Flanagan SD, Bien PA, Muñoz KA, Minassian SL, Prokocimer PG. Pharmacokinetics of tedizolid following oral administration: single and multiple dose, effect of food, and comparison of two solid forms of the prodrug. Pharmacotherapy. 2014 Mar;34(3):240–50.
3. Zhanel GG, Love R, Adam H, Golden A, Zelenitsky S, Schweizer F, et al. Tedizolid: a novel oxazolidinone with potent activity against multidrug-resistant gram-positive pathogens. Drugs. 2015 Feb;75(3):253–70.
4. Flanagan S, Fang E, Muñoz KA, Minassian SL, Prokocimer PG. Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid. Pharmacotherapy. 2014 Sep;34(9):891–900.
5. Prokocimer P, Bien P, Surber J, Mehra P, DeAnda C, Bulitta JB, et al. Phase 2, randomized, double-blind, dose-ranging study evaluating the safety, tolerability, population pharmacokinetics, and efficacy of oral torezolid phosphate in patients with complicated skin and skin structure infections. Antimicrob Agents Chemother. 2011 Feb;55(2):583–92.
6. Bien P, Prokocimer P, Munoz KA, Bethune C. Absolute bioavailability of TR-701 FA and pharmacokinetics after single and multiple dose intravenous administration in healthy adult subjects. In: Poster presented at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy. 2010. p. 12–5.
7. Flanagan S, Minassian SL, Morris D, Ponnuraj R, Marbury TC, Alcorn HW, et al. Pharmacokinetics of tedizolid in subjects with renal or hepatic impairment. Antimicrob Agents Chemother [Internet]. 2014;58(11):6471–6. Available from: http://europepmc.org/ abstract/ MED/25136024
8. Prokocimer P, De Anda C, Fang E, Mehra P, Das A. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial. JAMA. 2013 Feb;309(6):559–69.
9. Moran GJ, Fang E, Corey GR, Das AF, De Anda C, Prokocimer P. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2014 Aug;14(8):696–705.
10. McKee EE, Ferguson M, Bentley AT, Marks TA. Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones. Antimicrob Agents Chemother. 2006 Jun;50(6):2042–9.
11. Hall RG 2nd, Smith WJ, Putnam WC, Pass SE. An evaluation of tedizolid for the treatment of MRSA infections. Expert Opin Pharmacother. 2018 Sep;19(13):1489–94.
12. The U.S. Department of Health and Human Services-FDA/CDER, 2012. . Office of generic drugs Orange book: Approved drug products with therapeutic equivalence evaluations. Available from: http://www.fda.gov/downloads/Drugs/Development ApprovalProcess/ UCM071436.pdf. [Last accessed on Aug 2023]
13. The US Food and Drug Administration (FDA); 2009. . FDA center for drug evaluation and research Office of generic drugs. What are generic drugs?. Available from: http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingGenericDrugs/ucm144456.html. [Last accessed on Aug 2023 ]
14. Sahre M, Sabarinath S, Grant M, et al. Skin and soft tissue concentrations of tedizolid (formerly torezolid), a novel oxazolidinone, following a single oral dose in healthy volunteers. Int J Antimicrob Agents. 2012;40:51–4.
15. Prokocimer P, Bien P, Surber J, et al. Phase 2, randomized, double-blind, dose-ranging study evaluating the safety, tolerability, population pharmacokinetics, and efficacy of oral torezolid phosphate in patients with complicated skin and skin structure infections. Antimicrob Agents Chemother. 2011;55:583–92
16. Note for Guidance on the Investigation of Bioavailability and Bioequivalence Committee for Proprietary Medicinal Products. CPMP/EWP/QWP/1401/ 98. London; 26 July 2001
Article Sidebar
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.
Mahesh Walave
Head - Medical Writing and Regulatory Affairs Department, Bion Clinicals Pvt
Deepak Bagde
Deepak Bagde, Head - CRO, Bion Clinicals Pvt Ltd.
Atul Aparadh
Head – Clinical Research Department, Bion Clinicals Pvt Ltd
Vinayak Bhosale
Head - Bioanalytical Research Department, Bion Clinicals Pvt Ltd
Vishwas Pukale
Head – Quality Assurance Department, Bion Clinicals Pvt Ltd
Prashant Kumthekar
Deputy Manager – Clinical Research Department, Exemed Pharmaceuticals