Leukovir, an enteric-coated tablet, is the original drug product for
internal use. The well-known nucleosides cladribine and ribavirin are the
active ingredients of the drug product leukovir. Pharmacokinetic parameters of
the drug product for the internal use of leukovir active ingredients have been
established. The cladribine half-absorption period was t1/2a = 49.5 h, C0 = 276.4 μg/ml, Cmax = 6.0 μg/ml.
Distribution and accumulation parameters (Vd, Vss and AUC) have
indicated that the drug distribution between the blood cells and blood plasma
takes place in the same way, irrespective of the dosage form. Cladribine
half-life period is t1/2e = 0.62 hours. The molecule total
clearance and average lifetime in the body in the case of subcutaneous drug
administration are approximately the same. Ribavirin is characterized by a
half-absorption period of t1/2a = 0.71 h, C0 = 115.6 μg/ml and Cmax = 75.5 μg/ml. Ribavirin total volume of distribution (V
References
[1]
Compston, A. and Coles, A. (2008) Multiple Sclerosis. The Lancet, 372, 1502-1517.
https://doi.org/10.1016/S0140-6736(08)61620-7
[2]
Litvinenko, A.V. (2014) General Principles of Systemic Glucocorticoid Therapy. UkrainianPulmonologyJournal, 1, 60-64.
http://www.ifp.kiev.ua/doc/journals/upj/14/pdf14-1/ref/60_en.pdf
[3]
Giovannoni, G., Comi, G., Cook, S., Rammohan, K., Rieckmann, P., Soelberg-Sorensen, S.P., Vermersch, P., Chang, P., Hamlett, A., Musch, B., Greenberg, S.J. and Clarity Study Group (2010) A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis. The New England Journal of Medicine, 362, 416-426. https://doi.org/10.1056/NEJMoa0902533
[4]
Giovannoni, G., Soelberg-Sorensen, P., Cook S., Rammohan, K., Rieckmann, P., Comi, G., Dangond, F., Adeniji, A.K. and Vermersch, P. (2018) Safety and Efficacy of Cladribine Tablets in Patients with Relapsing-Remitting Multiple Sclerosis: Results from the Randomized Extension Trial of the CLARITY Study. Multiple Sclerosis 24, 1594-1604. https://pubmed.ncbi.nlm.nih.gov/28870107
https://doi.org/10.1177/1352458517727603
[5]
Leist, T.P., Comi, G., Cree, B.A., Coyle, P.K., Freedman, M.S., Hartung, H.P., Vermersch, P., Casset-Semanaz, F. and Scaramozza, M. (2014) Effect of Oral Cladribine on Time to Conversion to Clinically Definite Multiple Sclerosis in Patients with a First Demyelinating Event (ORACLE MS): A Phase 3 Randomized Trial. The Lancet Neurology, 13, 257-267. https://doi.org/10.1016/S1474-4422(14)70005-5
[6]
Mavenclad (2017) Assessment Report. Committee for Medicinal Products for Human Use (CHMP).
https://www.ema.europa.eu/en/documents/assessment-report/mavenclad-epar-public-assessment-report_en.pdf
[7]
Sipe, J.C., Romine, J.S., Koziol, J.A., McMillan, R., Zyroff, J. and Beutler, E. (1994) Cladribine in Treatment of Chronic Progressive Multiple Sclerosis. The Lancet, 344, 9-13. https://doi.org/10.1016/S0140-6736(94)91046-4
[8]
Kalinichenko, E., Ponteleeva, I. and Golubeva, M. (2020) Immunotropic Activity of a New Cladribine/Ribavirin-Based Composition. Annals of Pharmacology and Pharmaceutics, 5, 1196. https://www.researchgate.net/publication/346420067
Litchfield, J.T. and Wilcoxon, F. (1949) A Simplified Method of Evaluating Dose-Effect Experiments. Journal of Pharmacology and Experimental Therapeutics, 96, 99-113. https://pubmed.ncbi.nlm.nih.gov/18152921
[11]
Griffin, J.P. (2009) The Textbook of Pharmaceutical Medicine. John Wiley and Sons, Hoboken, 101-136. https://doi.org/10.1002/9781444317800
[12]
Hodge, A. and Sterner, B. (2005) Toxicity Classes. Canadian Center for Occupational Health and Safety.
[13]
Sanotsky, I.V. (1970) Methods of Determination of Toxicity and Hazardous Chemicals. Medicine, Moscow, 101-109.
[14]
Drug Product with a Prolonged Action for the Treatment of Multiple Sclerosis (Options). Patent of EurAsEC. 035792 В1. 2018/EA/0050 (BY) 2018.06.21.
http://www.eapatis.com/Data/EATXT/eapo2019/PDF/201800465.pdf
[15]
Albertioni, F., Juliusso, G. and Liliemark, J. (1993) On the Bioavailability of 2-chloro-2’-deoxyadenosine (CdA). The Influence of Food and Omeprazole. European Journal of Clinical Pharmacology, 44, 579-582.
https://pubmed.ncbi.nlm.nih.gov/8104793
https://doi.org/10.1007/BF02440863
[16]
Juliusson, G., Heldal, D. and Hippe. E. (1995) Subcutaneous Injections of 2-Chlorodeoxyadenosine for Symptomatic Hairy Cell Leukemia. Journal of Clinical Oncology, 13, 989-995. https://doi.org/10.1200/JCO.1995.13.4.989
[17]
Liliemark, J., Albertioni, F. and Hassan, M. (1992) On the Bioavailability of Oral and Subcutaneous 2-chloro-2’-deoxyadenosine in Humans; Alternative Routes of Administration. Journal of Clinical Oncology, 10, 1514-1518.
https://pubmed.ncbi.nlm.nih.gov/1357107
https://doi.org/10.1200/JCO.1992.10.10.1514
[18]
Liliemark, J. (1997) The Clinical Pharmacokinetics of Cladribine. Clinical Pharmacokinetics, 32, 120-131. https://doi.org/10.2165/00003088-199732020-00003
https://link.springer.com/article/10.2165%2F00003088-199732020-00003
[19]
Tarasiuk, A., Skierski, J. and Kazimierczuk, Z. (1994) Stability of 2-Chloro-2’-Deoxya-denosine at Various pH and Temperature. Archivum Immunologiae et Therapiae Experimentalis (Warsz), 42, 13-15. https://pubmed.ncbi.nlm.nih.gov/7503627
[20]
Voronina, Т.А. (2005) Guidelines for the Study of Immunotropic Activity of Pharmacological Substances. In: Khaitov, R.M., Gushchin, I.S., Pinegin, B.V. and Zebrov, A.I., Eds., Guide to Experimental (Preclinical) Study of New Pharmacological Substances, R.U. Khabriev, Part 4, Moscow, 501-514.
[21]
El-Kattan, A. and Varma, M. Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability. In: Paxton, J., Ed., Topics on Drug Metabolism, InTech, Rijeka, Croatia, 294 p. https://doi.org/10.5772/31087
[22]
Linghui, L. (2009) Effect of Dietary Purines on the Pharmacokinetics of Orally Administered Ribavirin. The Journal of Clinical Pharmacology, 49, 661-667.
https://pubmed.ncbi.nlm.nih.gov/19369574
https://doi.org/10.1177/0091270009335002
[23]
Hermann, R., Karlsson, M.O., Novakovic, A.M., Terranova, N., Fluck, M. and Munafo A. (2019) The Clinical Pharmacology of Cladribine Tablets for the Treatment of Relapsing Multiple Sclerosis. Clinical Pharmacokinetics, 58, 283-297.
https://doi.org/10.1007/s40262-018-0695-9
[24]
Chtioui, H., Millius, C., Lammle, B. and Lauterburg, B.H. (2009) Concomitant Treatment with Lamivudine Renders Cladribine Inactive by Inhibition of Its Phosphorylation. British Journal of Haematology, 144, 136-137.
https://doi.org/10.1111/j.1365-2141.2008.07432.x
[25]
Laugel, B., Borlat, F., Galibert, L., Vicari, A., Weissert, R., Chvatchko, Y., et al. (2011) Cladribine Inhibits Cytokine Secretion by T Cells Independently of Deoxycytidine Kinase Activity. Journal of Neuroimmunology, 240-241, 52-57.
https://www.jni-journal.com/article/S0165-5728(11)00263-3/fulltext
https://doi.org/10.1016/j.jneuroim.2011.09.010
[26]
Kraus, S.H.P., Luessi, F., Trinschek, B., Lerch, S., Hubo, M., Poisa-Beiro, L., et al. (2014) Cladribine Exerts an Immunomodulatory Effect on Human and Murine Dendritic Cells. International Immunopharmacology, 18, 347-357.
https://www.sciencedirect.com/science/article/pii/S1567576913004785?via%3Dihub
https://doi.org/10.1016/j.intimp.2013.11.027
[27]
Fissolo, N., Calvo-Barreiro, L., Eixarch, H., Boschert, U., Espejo, C., Montalban, X. and Comabella, M. (2021) Immunomodulatory Effects Associated with Cladribine Treatment. Cells, 10, 3488. https://doi.org/10.3390/cells10123488
[28]
Jensen, K., Johnson, L.A., Jacobson, P.A., Kachler, S., Kirstein, M.N., Lamba, J., et al. (2012) Cytotoxic Purine Nucleoside Analogs Bind to A1, A2A, and A3 Adenosine Receptors. Naunyn-Schmiedeberg’s Archives of Pharmacology, 385, 519-525.
https://link.springer.com/article/10.1007%2Fs00210-011-0719-6
https://doi.org/10.1007/s00210-011-0719-6
[29]
Novitskiy, S.V., Ryzhov, S, Zaynagetdinov, R, Goldstein, A.E., Huang, Y., Tikhomirov, O.Y., et al. (2008) Adenosine Receptors in Regulation of Dendritic Cell Differentiation and Function. Blood, 112, 1822-1831.
https://www.researchgate.net/publication/5296697
https://doi.org/10.1182/blood-2008-02-136325
[30]
Likchachev, S.A., Kalinichenko, E.N., Nedzved, G.K., Buniak, A.G. (2014) Evaluate the Efficacy and Safety of Leykovir in the Treatment of Patients with Multiple Sclerosis. Actual Problems of Neurology and Neurosurgery. Peer-Reviewed Collection of Scientific Papers, Minsk, Issue 17, 5-15.
https://www.researchgate.net/publication/357082154
