Pharmacokinetics of Pentanedioic Acid Imidazolyl Ethanamide in Healthy Volunteers

Relevance. Pentanedioic acid imidazolyl ethanamide (PAIE) has been used clinically as an antiviral agent for a long time, however, there is no information in the available literature concerning the dependence of PAIE pharmacokinetics on isoenzymes polymorphism of the cytochrome P450 system (CYP), as well as on the variability of pharmacokinetic parameters in humans. The aim of the study is to determine the main pharmacokinetic parameters of PAIE in healthy volunteers and to assess the contribution of polymorphism of CYP P450 isoenzymes to the variability of pharmacokinetic parameters.

Material and methods. The study included 12 healthy volunteers (5 men and 7 women) of the Caucasian race, who took In[1]gavirin® at a dose of 180 mg (2 capsules of 90 mg) on an empty stomach during two dosing periods, separated by a 7-day washout period. Determination of PAIE concentration in blood plasma and urine samples was carried out by high-performance liquid chromatography–mass spectrometry. Polymorphism of CYP genes was analyzed using the polymerase chain re[1]action method in order to analyze the pharmacogenetic features of PAIE metabolism in volunteers during the study.

Results. After oral administration, PAIE quickly reached the systemic circulation: the maximum concentration of 578.88±145.21 ng/ml was observed after about 2 hours. Pharmacokinetic parameters of PAIE did not show high intraindividual variability and did not depend on polymorphism of isoenzymes CYP1A1, CYP2C9, and CYP2D6. Within 48 hours after the administration of the studied drug, about half of the taken dose of PAIE was excreted in the urine unchanged, which indicates a significant contribution of the kidneys to the elimination of PAIE. The only adverse event registered in 1 volunteer was a clinically insignificant decrease in the level of leukocytes, which did not require medical intervention and was resolved without consequences.

Conclusion. PAIE is characterized by predictable pharmacokinetics, low intraindividual variability of pharmacokinetic parameters, and a favorable safety profile.

1. Electronic resource]. 2017. URL: http://cr.rosminzdrav.ru/#!/ recomend/909 (accessed: 10.02.2021).

2. Zarubaev V.V., Kalinina N. A., Shtro A. A., Belyaevskaya S. V., Slita A. V., Nebolsin V. E, Kiselev O. I. Activity of Ingavirin (6-[2-(1H-Imidazol-4- yl)ethylamino]-5-oxo-hexanoic acid) against human respiratory viruses in in vivo experiments. Pharmaceuticals (Basel). 2011; 4 (12): 1518–1534. doi: 10.3390/ph4121518

3. Malík I., Kovac G., Padrtova T., Hudecova L. Ingavirin might be a promising agent to combat Severe Acute Respiratory Coronavirus 2 (SARS CoV-2). Ceska Slov Farm. 2020; 69 (3): 107–111.

4. Gripp i drugie os trye respiratornye virusnye infektsii: printsipy vybora preparatov dlya lecheniya (dokazatel'naya meditsina) i skhemy naznacheniya, algoritmy okazaniya meditsinskoj pomoshchi bol'nym. Spetsificheskaya profilaktika grippa. Metodicheskie rekomendatsii № 64. Moskva, 2019. [Electronic resource] // https://mosgorzdrav.ru/. URL: https://mosgorzdrav.ru/ ru-RU/science/default/download/507.html. (accessed: 10.02.2021). (in Russian)

5. Kolobukhina L.V. Malyshev N.A., Merkulova L.N., Burtseva E.I., Shchelkanov M.Jyu. Izuchenie effektivnosti i bezopasnosti novogo protivovirusnogo preparata Ingavirin® pri lechenii bol'nykh grippom. RMZh. 2008; 16 (22): 1502. (in Russian)

6. Kolobukhina L.V., Merkulova L.N., Shchel kanov M.Jyu., Burtseva E.I., Isaeva E.I., Malyshev N.A., L'vov D.K. Efficacy of Ingavirinin in adults with influenza. 2013; 4 (07): 45–512. (in Russian).

7. Kolobukhina L.V., Merkulova L.N., Grigoryan S.S. i dr. Effektivnost' i bezopasnost' preparata Ingavirin® v lechenii grippa i drugikh ORVI u vzros lykh. Cpravochnik Poliklinicheskogo Vracha. 2010; 9: 22–27. (in Russian)

8. Heppe N.A., Kondyurina E.G., Kolosova N.G., Jablokova E.A. Clinical Efficacy and Safety of Pentanedioic Acid Imidazolyl Ethanamide in Patients aged 3 to 6 years with influenza and other acute respiratory viral infections based on the results of double-blind randomized placebo-controlled multicenter study. Ros Vestn Perinatol i Pediatr 2020; 65:(6): 166–174 doi: 10.21508/1027–4065–2020–65–6–166–174 (in Russian)

9. Geppe N.A., Malakhov A.B., Kondyurina E.G. Ra tionale for the choice of ARVI antiviral therapy in pediatrics (meta-analysis of pentanedioic acid imidazolyl ethanamide clinical studies for ARVI treatment in children of different age groups). Vopr Prakt Pediatr. (Clinical Practice in Pediatrics). 2020; 15 (3): 106–114. doi: 10.20953/1817-7646- 2020-3-106-114 (In Russian)]

10. Pratt V.M., Del Tredici A. L., Hachad H., Ji Y., Kalman L. V., Scott S. A., Weck K. E. Recommendations for clinical CYP2C19 genotyping allele se lection: a report of the association for molecular pathology. J Mol Diagn. 2018; 20 (3): 269–276. doi: 10.1016/j.jmoldx.2018.01.011