In vitro studies for BCS classification of an antiviral agent, favipiravir

Timur, Selin Seda; karabulut, tutku ceren; Öner, Yalçın; Eroğlu, Hakan; Ataşoğlu, Meltem

doi:10.29228/jrp.91

In vitro studies for BCS classification of an antiviral agent, favipiravir

Selin Seda TİMUR, (Hacettepe Üniversitesi, Eczacılık Fakültesi, Eczacılık Teknolojisi Anabilim Dalı, Ankara, Türkiye)

Meltem ATAŞOĞLU, (Tobio Novelfarma İlaç Sanayi ve Ticaret Limited Şirketi, İstanbul, Türkiye)

Yalçın ÖNER, (Tobio Novelfarma İlaç Sanayi ve Ticaret Limited Şirketi, İstanbul, Türkiye)

Tutku Ceren KARABULUT, (Tobio Novelfarma İlaç Sanayi ve Ticaret Limited Şirketi, İstanbul, Türkiye)

Hakan EROGLU (Hacettepe Üniversitesi, Eczacılık Fakültesi, Eczacılık Teknolojisi Anabilim Dalı, Ankara, Türkiye)

Journal of research in pharmacy (online)

18 0

Yıl: 2021 Cilt: 25 Sayı: 6 Sayfa Aralığı: 944 - 952 Metin Dili: İngilizce DOI: 10.29228/jrp.91 İndeks Tarihi: 09-02-2022

In vitro studies for BCS classification of an antiviral agent, favipiravir

Öz:

Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is a purine nucleic acid analog, which is an antiviral agent used in the treatment of influenza. Since the recent outbreak caused by 2019-novel coronavirus (nCoV), there has been a seek for effective antiviral agents to be used in the treatment of coronavirus disease 2019 (COVID-19), and favipiravir has been one of the options which provides a broad-spectrum therapy. Herein, we studied the aqueous solubility and in vitro permeability characteristics of favipiravir in order to shed light on the BCS classification of this antiviral agent used in COVID-19 therapy. The in vitro solubility was assessed using saturated solution of favipiravir in four different aqueous media and the solubility values were evaluated during 72 h at 37 oC. The solubility of favipiravir was between 4.48 to 8.5 mg/ml, which is 5.85 to 10.63 times of calculated solubility limit. Caco-2 cell monolayers were utilized for the permeability assessment, and the drug solutions in three different concentrations including the highest dose required for bioequivalence exemption of the immediate release dosage form were applied. The effect of efflux transporters on the permeability of favipiravir was also determined using a P-gp inhibitor, Verapamil HCl. According to the data obtained from the in vitro studies, favipiravir can be considered as a representative of class I compound.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

[1] Du YX, Chen XP. Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019-nCoV Infection. Clin Pharmacol Ther. 2020; 108(2): 242-247.
[2] NIH U.S. National Library of Medicine, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=&term=favipiravir&cntry=&state=&city=&dist=. (accessed on 9 May 2021)
[3] NIH, National Library of Medicine, National Center for Biotechnology Information. PubChem Compound Summary for CID 492405, Favipiravir. https://pubchem.ncbi.nlm.nih.gov/compound/Favipiravir (accessed on 9 May 2021)
[4] Agrawal U, Raju R, Udwadia ZF. Favipiravir: A new and emerging antiviral option in COVID-19. Med J Armed Forces India. 2020; 76(4): 370-376.
[5] Joshi S, Parkar J, Ansari A, Vora A, Talwar D, Tiwaskar M, et al. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis. 2021; 102: 501-508.
[6] Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther. 2020; 209: 107512.
[7] Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017; 93(7): 449-463.
[8] Davit BM, Kanfer I, Tsang YC, Cardot JM. BCS Biowaivers: Similarities and Differences Among EMA, FDA, and WHO Requirements. AAPS J. 2016; 18(3): 612-618.
[9] EMA. ICH M9 on biopharmaceutics classification system-based biowaivers. EMA/CHMP/ICH/493213/2018 ICH M9 guideline on biopharmaceutics classification system-based biowaivers. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-m9-biopharmaceutics-classification-systembased-biowaivers-step-5_en.pdf (accessed on 9 May 2021)
[10] FDA. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. https://collections.nlm.nih.gov/catalog/nlm:nlmuid101720038-pdf (accessed on 9 May 2021)
[11] Berginc K, Sibinovska N, Zakelj S, Trontelj J, Legen I. Biopharmaceutical classification of desloratadine - not all drugs are classified the easy way. Acta Pharm. 2020; 70(2): 131-44.
[12] Lea T. Caco-2 Cell Line. In: Verhoeckx K et al., (Eds). The Impact of Food Bioactives on Health: in vitro and ex vivo models. Springer, Cham, 2015. pp. 103-111.
[13] Artursson P, Palm K, Luthman K. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev. 2001; 46(1-3): 27-43.
[14] Buckley ST, Fischer SM, Fricker G, Brandl M. In vitro models to evaluate the permeability of poorly soluble drug entities: challenges and perspectives. Eur J Pharm Sci. 2012; 45(3): 235-250.
[15] Gantzsch SP, Kann B, Ofer-Glaessgen M, Loos P, Berchtold H, Balbach S, et al. Characterization and evaluation of a modified PVPA barrier in comparison to Caco-2 cell monolayers for combined dissolution and permeation testing. J Control Release. 2014; 175: 79-86.
[16] Flaten GE, Dhanikula AB, Luthman K, Brandl M. Drug permeability across a phospholipid vesicle based barrier: a novel approach for studying passive diffusion. Eur J Pharm Sci. 2006; 27(1): 80-90.
[17] Flaten GE, Bunjes H, Luthman K, Brandl M. Drug permeability across a phospholipid vesicle-based barrier 2. Characterization of barrier structure, storage stability and stability towards pH changes. Eur J Pharm Sci. 2006; 28(4): 336-343.
[18] Sambuy Y, De Angelis I, Ranaldi G, Scarino ML, Stammati A, Zucco F. The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics. Cell Biol Toxicol. 2005; 21(1): 1-26.
[19] Behrens I, Kissel T. Do cell culture conditions influence the carrier-mediated transport of peptides in Caco-2 cell monolayers? Eur J Pharm Sci. 2003; 19(5): 433-442.
[20] EMA. Guideline on the investigation of drug interactions. https://www.ema.europa.eu/en/documents/scientificguideline/guideline-investigation-drug-interactions-revision-1_en.pdf (accessed on 9 May 2021)
[21] Incecayir T, Tsume Y, Amidon GL. Comparison of the permeability of metoprolol and labetalol in rat, mouse, and Caco-2 cells: use as a reference standard for BCS classification. Mol Pharm. 2013; 10(3): 958-966.
[22] Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun. 1991; 175(3): 880-885.
[23] Kim JS, Mitchell S, Kijek P, Tsume Y, Hilfinger J, Amidon GL. The suitability of an in situ perfusion model for permeability determinations: utility for BCS class I biowaiver requests. Mol Pharm. 2006; 3(6): 686-694.
[24] Da Silva LC, Da Silva TL, Antunes AH, Rezende KR. A Sensitive Medium-Throughput Method to Predict Intestinal Absorption in Humans Using Rat Intestinal Tissue Segments. J Pharm Sci. 2015; 104(9): 2807-2812.
[25] Gülsün T, Şahin S. Development and Validation of a RP-HPLC Method for Simultaneous Determination of Metformin Hydrochloride, Phenol Red and Metoprolol Tartrate for Intestinal Perfusion Studies. Lat. Am. J. Pharm. 2016; 35(1): 50-57.

APA	Timur S, Ataşoğlu M, Öner Y, karabulut t, Eroğlu H (2021). In vitro studies for BCS classification of an antiviral agent, favipiravir. , 944 - 952. 10.29228/jrp.91
Chicago	Timur Selin Seda,Ataşoğlu Meltem,Öner Yalçın,karabulut tutku ceren,Eroğlu Hakan In vitro studies for BCS classification of an antiviral agent, favipiravir. (2021): 944 - 952. 10.29228/jrp.91
MLA	Timur Selin Seda,Ataşoğlu Meltem,Öner Yalçın,karabulut tutku ceren,Eroğlu Hakan In vitro studies for BCS classification of an antiviral agent, favipiravir. , 2021, ss.944 - 952. 10.29228/jrp.91
AMA	Timur S,Ataşoğlu M,Öner Y,karabulut t,Eroğlu H In vitro studies for BCS classification of an antiviral agent, favipiravir. . 2021; 944 - 952. 10.29228/jrp.91
Vancouver	Timur S,Ataşoğlu M,Öner Y,karabulut t,Eroğlu H In vitro studies for BCS classification of an antiviral agent, favipiravir. . 2021; 944 - 952. 10.29228/jrp.91
IEEE	Timur S,Ataşoğlu M,Öner Y,karabulut t,Eroğlu H "In vitro studies for BCS classification of an antiviral agent, favipiravir." , ss.944 - 952, 2021. 10.29228/jrp.91
ISNAD	Timur, Selin Seda vd. "In vitro studies for BCS classification of an antiviral agent, favipiravir". (2021), 944-952. https://doi.org/10.29228/jrp.91

APA	Timur S, Ataşoğlu M, Öner Y, karabulut t, Eroğlu H (2021). In vitro studies for BCS classification of an antiviral agent, favipiravir. Journal of research in pharmacy (online), 25(6), 944 - 952. 10.29228/jrp.91
Chicago	Timur Selin Seda,Ataşoğlu Meltem,Öner Yalçın,karabulut tutku ceren,Eroğlu Hakan In vitro studies for BCS classification of an antiviral agent, favipiravir. Journal of research in pharmacy (online) 25, no.6 (2021): 944 - 952. 10.29228/jrp.91
MLA	Timur Selin Seda,Ataşoğlu Meltem,Öner Yalçın,karabulut tutku ceren,Eroğlu Hakan In vitro studies for BCS classification of an antiviral agent, favipiravir. Journal of research in pharmacy (online), vol.25, no.6, 2021, ss.944 - 952. 10.29228/jrp.91
AMA	Timur S,Ataşoğlu M,Öner Y,karabulut t,Eroğlu H In vitro studies for BCS classification of an antiviral agent, favipiravir. Journal of research in pharmacy (online). 2021; 25(6): 944 - 952. 10.29228/jrp.91
Vancouver	Timur S,Ataşoğlu M,Öner Y,karabulut t,Eroğlu H In vitro studies for BCS classification of an antiviral agent, favipiravir. Journal of research in pharmacy (online). 2021; 25(6): 944 - 952. 10.29228/jrp.91
IEEE	Timur S,Ataşoğlu M,Öner Y,karabulut t,Eroğlu H "In vitro studies for BCS classification of an antiviral agent, favipiravir." Journal of research in pharmacy (online), 25, ss.944 - 952, 2021. 10.29228/jrp.91
ISNAD	Timur, Selin Seda vd. "In vitro studies for BCS classification of an antiviral agent, favipiravir". Journal of research in pharmacy (online) 25/6 (2021), 944-952. https://doi.org/10.29228/jrp.91