Related Products: Remdesivir
It is reported that Remdesivir has begun a phase III clinical study against new coronavirus (2019-nCoV) at China-Japan Friendship Hospital. Gilead has done a lot of research on the dose and safety of Remdesivir. At the clinical dose, Remdesivir showed good overall safety in addition to the effect on liver function.
In large-scale clinical trials of anti-Ebola drugs, the mortality rate of patients in the experimental group treated with Remdesivir was 53% (175 patients, 82 survived after 28 days), and the efficacy was significantly lower than that of two monoclonal antibodies MAb114 (35% mortality) and REGN-EB3 (33% mortality). There is little difference between the 53% figure and the previously estimated average mortality rate of 50% of Ebola virus. In the experimental group of Remdesivir, one patient developed symptoms of hypotension and led to cardiac arrest, which was classified as a side effect of the drug. Of course, as Ebola worsens in a short period of time, it does not rule out the possibility that the rapid deterioration of the disease will lead to the death of the patient. In this clinical study, Remdesivir was administered intravenously 200mg on the first day in adults within 30 minutes, followed by 100mg daily within 30 minutes for 9 to 13 days according to viral load. This mode of administration is related to the drug metabolism of Remdesivir. After intravenous administration, Remdesivir will enter the cells and metabolize into active GS-443902. Studies in PBMC cells showed that the half-life of GS-443902 was more than 35h. In the case of daily administration, the active substance GS-443902 will form and accumulate in the body, so after the first dose of 200mg, the subsequent dose will be adjusted to 100mg to ensure the appropriate blood concentration in the body.
In the previous phase I clinical trial, a single dose of 3 to 225 mg intravenous climbing test was conducted, and no dose-related toxicity, hepatotoxicity and renal toxicity were observed. All adverse reactions were grade 1 or 2. In the study of repeated intravenous administration of 150 mg daily for 7 to 14 days, the subjects were tolerated. No grade 3 or 4 adverse reactions were observed. Reversible grade 1 to 2 adverse reactions were observed in several subjects, characterized by an increase in glutamic pyruvic transaminase or aspartate aminotransferase, and no abnormality in total bilirubin, alkaline phosphatase (ALP) or albumin. There were no abnormal or clinically significant changes in any of the subjects. In the multi-dose study, Remdesivir did not show any effect on renal function.
In the safety test in vitro, Remdesivir and GS-441524 have cytotoxicity and mitochondrial toxicity to many kinds of cells in vitro. In most in vitro toxicity tests, the marginal margin of Remdesivir and GS-441524 was more than 3.5 times. The in vitro data of hepatocyte culture system show that human hepatocytes are sensitive to Remdesivir-mediated toxicity, which may be due to the high cellular permeability and effective intracellular metabolism of drugs. In vivo tests, the systemic metabolites of Remdesivir detected in plasma did not show any pharmacological hepatotoxicity in vitro.
In the pharmacokinetic study of the human body, Remdesivir showed linear dose competition after intravenous infusion of Remdesivir solution at a single dose of 3 to 225mg for 2 hours. The 150mg Remdesivir solution repeated once a day (1h intravenous infusion) showed a 14-day linear competition. After intravenous administration of Remdesivir solution at a dose of 75mg and 150mg for 2 hours, Remdesivir showed a competition curve similar to that of freeze-dried preparation.
The maternal exposure level of 75 mg Remdesivir intravenously within 30 minutes was similar to that within 2 hours, but the PBMC exposure of GS-443902 was higher than that of remdesivir150 mg intravenously within 2 hours. This data supports administration within a short interval of 30 minutes, which is a more effective way of administration to maximize intracellular levels of the active metabolite GS-443902. GS-443902 in PBMC observed that the intracellular half-life was more than 35 hours, which supported the daily administration of Remdesivir.
In addition, the cumulative ratio of intracellular metabolites was 2.7 to 3.5 times. The first dose of 200mg Remdesivir, repeated the 100mg Remdesivir maintenance dose per day, ensuring the realization of the subsequent steady-state PBMC level of GS-443902. It is very important for the treatment of patients with acute infection.
Finally, briefly introduce the dosage form of the preparation. In addition to the active ingredients, the freeze-dried preparation also contains the following inactive ingredients: water for injection, sulfobutyl-β-cyclodextrin sodium (SBECD), adjusts the pH of the preparation to 3.0 to 4.0 with hydrochloric acid and/or sodium hydroxide, and then freeze-dried. According to the current stability data, the lyophilizer can be stored below 30 degrees for three years.
References
1. Mulangu, S., Dodd, L. E., Davey Jr, R. T., Tshiani Mbaya, O., Proschan, M., Mukadi, D., … & Ali, R. (2019). A randomized, controlled trial of Ebola virus disease therapeutics. New England Journal of Medicine, 381(24), 2293-2303.
2. Sheahan, T. P., Sims, A. C., Leist, S. R., Schäfer, A., Won, J., Brown, A. J., … & Spahn, J. E. (2020). Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nature Communications, 11(1), 1-14.
3. Tchesnokov, E. P., Feng, J. Y., Porter, D. P., & Götte, M. (2019). Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir. Viruses, 11(4), 326.
Related Products: Remdesivir