Download PDF
Drug Res (Stuttg) 2023; 73(06): 349-354
DOI: 10.1055/a-2061-7074
Original Article

Does the Ethnic Difference Affect the Pharmacokinetics of Favipiravir? A Pharmacokinetic Study in Healthy Egyptian Volunteers and Development of Level C In-vitro In-vivo Correlation

Ehab R. Bendas 
1   Department of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt
,
Mamdouh R. Rezk
2   Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
,
Kamal A. Badr
3   Pharmaceutics Department, Faculty of Pharmacy, Deraya University, New Minya, Egypt
4   Advanced Research Center, Nasr City, Cairo, Egypt
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints

Abstract

Favipiravir is an antiviral drug used to treat influenza and is also being investigated for the treatment of SARS-CoV-2. Its pharmacokinetic profile varies depending on ethnic group. The present research examines the pharmacokinetic features of favipiravir in healthy male Egyptian volunteers. Another goal of this research is to determine the optimum dissolution testing conditions for immediate release tablets. In vitro dissolution testing was investigated for favipiravir tablets in three different pH media. The pharmacokinetic features of favipiravir were examined in 27 healthy male Egyptian volunteers. The parameter “AUC0-t” vs. percent dissolved was used to develop level C in vitro in vivo correlation (IVIVC) to set the optimum dissolution medium to achieve accurate dissolution profile for favipiravir (IR) tablets. The in vitro release results revealed significant difference among the three different dissolution media. The Pk parameters of twenty-seven human subjects showed mean value of Cpmax of 5966.45 ng/mL at median tmax of 0.75 h with AUC0-∞ equals 13325.54 ng.h/mL, showing half-life of 1.25 h. Level C IVIVC was developed successfully. It was concluded that Egyptian volunteers had comparable Pk values to American and Caucasian volunteers, however they were considerably different from Japanese subjects. AUC0-t vs. % dissolved was used to develop level C IVIVC to set the optimum dissolution medium. Phosphate buffer medium (pH 6.8) was found to be the optimum dissolution medium for in vitro dissolution testing for Favipiravir IR tablets.

Key words

favipiravir - pharmacokinetics - in vitro In vivo correlation (IVIVC) - ethnic effect.


Publication History

Received: 24 January 2023

Accepted: 21 March 2023

Article published online:
24 April 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Oldstone MBA. History of Virology. Encyclopedia of Microbiology 2014; 608-612
    PubMedGoogle Scholar
  • 2 Lucas W. Viral Capsids and Envelopes: Structure and Function. in ELS. John Wiley & Sons, Ltd; 2010. DOI: 10.1002/9780470015902.a0001091.pub2
    CrossrefGoogle Scholar
  • 3 Herrington CS, Coates PJ, Duprex WP. Viruses and disease: emerging concepts for prevention, diagnosis and treatment. J Pathol 2015; 235: 149-152
    CrossrefPubMedGoogle Scholar
  • 4 Hu B, Guo H, Zhou P. et al. Characteristics of SARS-CoV-2 and COVID-19. Nature Reviews Microbiology 2021; 19: 141-154
    CrossrefPubMedGoogle Scholar
  • 5 Bezbaruah R, Borah P, Kakoti BB. et al. Developmental Landscape of Potential Vaccine Candidates Based on Viral Vector for Prophylaxis of COVID-19. Front Mol Biosci 2021; 8: 635337
    CrossrefPubMedGoogle Scholar
  • 6 Francis AI, Ghany S, Gilkes T. et al. Review of COVID-19 vaccine subtypes, efficacy and geographical distributions. Postgrad Med J. 2021
    PubMedGoogle Scholar
  • 7 Frediansyah A, Tiwari R, Sharun K. et al. Antivirals for COVID-19: A critical review. Clinical epidemiology and global health 2021; 9: 90-98
    CrossrefPubMedGoogle Scholar
  • 8 Richardson P, Griffin I, Tucker C. et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. The Lancet 2020; 395: e30-e31
    CrossrefPubMedGoogle Scholar
  • 9 Kadam RU, Wilson IA. Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proceedings of the National Academy of Sciences 2017; 114: 206-214
    CrossrefPubMedGoogle Scholar
  • 10 Liu X, Wang X-J. Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines. Journal of Genetics and Genomics 2020; 47: 119-121
    CrossrefPubMedGoogle Scholar
  • 11 Eastman RT, Roth JS, Brimacombe KR. et al. Correction to Remdesivir: A Review of Its Discovery and Development Leading to Human Clinical Trials for Treatment of COVID-19. ACS central science 2020; 6: 1009
    CrossrefPubMedGoogle Scholar
  • 12 Joshi S, Parkar J, Ansari A. et al. Role of favipiravir in the treatment of COVID-19. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 2021; 102: 501-508
    CrossrefPubMedGoogle Scholar
  • 13 Udwadia ZF, Singh P, Barkate H. et al. Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial. International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 2021; 103: 62-71
    CrossrefPubMedGoogle Scholar
  • 14 Chen R, Wang T, Song J. et al. Antiviral Drug Delivery System for Enhanced Bioactivity, Better Metabolism and Pharmacokinetic Characteristics. International journal of nanomedicine 2021; 16: 4959-4984
    CrossrefPubMedGoogle Scholar
  • 15 Zaborenko N, Shi Z, Corredor CC. et al. First-Principles and Empirical Approaches to Predicting In Vitro Dissolution for Pharmaceutical Formulation and Process Development and for Product Release Testing. AAPS J 2019; 21: 32
    CrossrefPubMedGoogle Scholar
  • 16 Marzouk HM, Rezk MR, Gouda AS. et al. A novel stability-indicating HPLC-DAD method for determination of favipiravir, a potential antiviral drug for COVID-19 treatment; application to degradation kinetic studies and in-vitro dissolution profiling. Microchem J 2022; 172: 106917
    CrossrefPubMedGoogle Scholar
  • 17 Morsy MI, Nouman EG, Abdallah YM. et al. A novel LC-MS/MS method for determination of the potential antiviral candidate favipiravir for the emergency treatment of SARS-CoV-2 virus in human plasma: Application to a bioequivalence study in Egyptian human volunteers. J Pharm Biomed Anal 2021; 199: 114057
    CrossrefPubMedGoogle Scholar
  • 18 Rezk MR, Badr KA, Abdel-Naby NS. et al. A novel, rapid and simple UPLC-MS/MS method for quantification of favipiravir in human plasma: Application to a bioequivalence study. Biomed Chromatogr 2021; 35: e5098
    CrossrefPubMedGoogle Scholar
  • 19 Du YX, Chen XP. Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019-nCoV Infection. Clin Pharmacol Ther 2020; 108: 242-247
    CrossrefPubMedGoogle Scholar
  • 20 Madelain V, Nguyen TH, Olivo A. et al. Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials. Clinical pharmacokinetics 2016; 55: 907-923
    CrossrefPubMedGoogle Scholar
  • 21 Ison MG, Scheetz MH. Understanding the pharmacokinetics of Favipiravir: Implications for treatment of influenza and COVID-19. EBioMedicine 2021; 63: 103204
    CrossrefPubMedGoogle Scholar
  • 22 Dixon JR. The International Conference on Harmonization Good Clinical Practice guideline. Qual Assur 1998; 6: 65-74
    CrossrefPubMedGoogle Scholar
  • 23 Emanuel EJ. Reconsidering the Declaration of Helsinki. Lancet. 2013; 381: 1532-1533
    CrossrefPubMedGoogle Scholar
  • 24 Manti S, Licari A. How to obtain informed consent for research. Breathe (Sheff) 2018; 14: 145-52.
    CrossrefPubMedGoogle Scholar
  • 25 Volpato NM, Silva RL, Brito AP. et al. Multiple level C in vitro/in vivo correlation of dissolution profiles of two L-thyroxine tablets with pharmacokinetics data obtained from patients treated for hypothyroidism. Eur J Pharm Sci 2004; 21: 655-660
    CrossrefPubMedGoogle Scholar
  • 26 Andrade C. Z Scores, Standard Scores, and Composite Test Scores Explained. Indian J Psychol Med 2021; 43: 555-557
    CrossrefPubMedGoogle Scholar
  • 27 Website. Report on the Deliberation Results. Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare Last accessed on July 2, 2022. 2014.
    PubMed
  • 28 Rastogi V, Yadav P, Lal N. et al. Mathematical prediction of pharmacokinetic parameters-an in-vitro approach for investigating pharmaceutical products for IVIVC. Future Journal of Pharmaceutical Sciences 2018; 4: 175-184
    CrossrefPubMedGoogle Scholar
  • 29 Mutair AA, Shamou J, Alhumaid S. et al. Overview of clinical outcome and therapeutic effectiveness of Favipiravir in patients with COVID-19 admitted to intensive care unit, Riyadh, Saudi Arabia. J Infect Public Health 2022; 15: 389-394
    CrossrefPubMedGoogle Scholar
  • 30 Gülhan R, Eryüksel E, Gülçebi İdriz Oğlu M. et al. Pharmacokinetic characterization of favipiravir in patients with COVID-19 2022; 88: 3516-3522
    PubMed
  • 31 Bosaeed M, Alharbi A, Mahmoud E. et al. Efficacy of favipiravir in adults with mild COVID-19: a randomized, double-blind, multicentre, placebo-controlled clinical trial. Clin Microbiol Infect 2022; 28: 602-608
    CrossrefPubMedGoogle Scholar
  • 32 Ross A, Willson VL. One-sample T-test. Basic and advanced statistical tests. Springer; 2017: 9-12
    CrossrefGoogle Scholar
  • 33 Chubb H, Simpson JM. The use of Z-scores in paediatric cardiology. Ann Pediatr Cardiol 2012; 5: 179-184
    CrossrefPubMedGoogle Scholar
  • 34 Sağlam O, Güney B, Saraner N. et al. Bioequivalence study of two favipiravir tablet formulations in healthy male subjects. International journal of clinical pharmacology and therapeutics 2021; 59: 409-416
    CrossrefPubMedGoogle Scholar
  • 35 Bechert U, Christensen JM, Nguyen C. et al. Pharmacokinetics of orally administered phenylbutazone in African and Asian elephants (Loxodonta africana and Elephas maximus). J Zoo Wildl Med 2008; 39: 188-200
    CrossrefPubMedGoogle Scholar
  • 36 Nakagawa S, Johnson PCD, Schielzeth H. The coefficient of determination R(2) and intra-class correlation coefficient from generalized linear mixed-effects models revisited and expanded. J R Soc Interface 2017; 14 (134): 20170213
    CrossrefPubMedGoogle Scholar
  • 37 Göktuğ Ö, Altaş E, Kayar G. et al. The Development and the Validation of a Novel Dissolution Method of Favipiravir Film-Coated Tablets. Scientia Pharmaceutica 2022; 90: 3
    CrossrefPubMedGoogle Scholar
  • 38 Zhou D, Qiu Y. editors. Understanding Biopharmaceutics Properties for Pharmaceutical Product Development and Manufacturing II – Dissolution and In Vitro- In Vivo Correlation. 2010
    Google Scholar
  • 39 Kesisoglou F, Hermans A, Neu C. et al. Development of In Vitro-In Vivo Correlation for Amorphous Solid Dispersion Immediate-Release Suvorexant Tablets and Application to Clinically Relevant Dissolution Specifications and In-Process Controls. J Pharm Sci 2015; 104: 2913-2922
    CrossrefPubMedGoogle Scholar
  • 40 Balan G, Timmins P, Greene DS. et al. In vitro-in vivo correlation (IVIVC) models for metformin after administration of modified-release (MR) oral dosage forms to healthy human volunteers. J Pharm Sci 2001; 90: 1176-1185
    CrossrefPubMedGoogle Scholar
  • 41 Lake OA, Olling M, Barends DM. In vitro/in vivo correlations of dissolution data of carbamazepine immediate release tablets with pharmacokinetic data obtained in healthy volunteers. Eur J Pharm Biopharm 1999; 48: 13-19
    CrossrefPubMedGoogle Scholar
  • 42 González-García I, Mangas-Sanjuan V, Merino-Sanjuán M. et al. IVIVC approach based on carbamazepine bioequivalence studies combination. Pharmazie 2017; 72: 449-455
    PubMedGoogle Scholar