Mumbai : The Mumbai headquartered pharma giant Cipla has sought approval from the subject expert committee (SEC) at the Central Drugs Standard Control Organisation (CDSCO) to modify Covid-19 drug remdesivir’s composition to minimise its adverse effects on the kidneys.
The drug firm has submitted a proposal to SEC seeking to replace sulfobutylether-ß-cyclodextrin (SBECD), the excipient in remdesivir with Polysorbate 80 and PEG 300 with the intention to reduce the renal toxicity.
SBECD is applied in the formulation process as a solubilizing agent because remdesivir has limited aqueous solubility feature. Since SBECD has a renal excretion root, patients with moderate or severe renal impairment have exposure to SBECD. Hence eGFR (estimated glomerular filtration rate) needs to be monitored in the time of administration of remdesivir, especially in patients with renal impairment. The discontinuation of remdesivir is required if eGFR levels drop to half level from baseline.
Polysorbate 80 is a thickening agent that is used in personal care products and also as a food additive while PEG 300 is used as an inactive ingredient in the pharmaceutical industry as a solvent.
The SEC deliberated the proposal at its meeting on December 17-18, 2020 and recommended that the firm should conduct bioequivalence study and also clinical trial to assess the renal toxicity of the new formulation.
Accordingly, the committee asked the drug maker to submit bioequivalence study protocol and clinical trial protocol to CDCSO for further review by it.
Although there is no evidence of remdesivir-related nephrotoxicity but an assessment of renal function in COVID-19 patients is recommended before and during treatment with remdesivir.
Available data from a single randomized, controlled trial in COVID-19 did not demonstrate an increased risk of renal adverse events in patients randomized to receive remdesivir. In addition, significant renal adverse events were not reported when remdesivir was used in a clinical trial for Ebola, according to a study published in Journal of the American Society of Nephrology (JASN).
The study further said “Because remdesivir has limited water solubility, the intravenous preparation contains the vehicle SBECD. Animal studies have associated SBECD accumulation with liver necrosis and renal tubule obstruction, which occurred in animals at doses 50- to 100-fold higher than expected for a 5- to 10-day remdesivir course.”
Each 100 mg of lyophilized powder and solution of remdesivir contain 3 and 6 g of SBECD, respectively, well below the maximum recommended safety threshold dose of 250 mg/kg per day of SBECD, the study added.
A couple of months back, the European Medicines Agency announced that it will determine whether there was a causal relationship between acute kidney injury and remdesivir.
Considering the emergency and unmet medical need for COVID-19 disease, CDSCO has approved restricted emergency use of remdesivir injectable formulations for treatment of patients with severe COVID-19 infection. The injectable drug was approved for administration as part of a maximum five-day regimen.
Cipla in July launched its generic version of remdesivir at Rs. 4,000 per 100 mg vial under the brand name ‘Cipremi’.
Besides Cipla, Hetero, Jubilant Life Sciences, Zydus Cadila, Dr Reddy’s Laboratories and Mylan India entered into non-exclusive licensing agreements with drug major Gilead Sciences Inc for manufacturing and distribution of remdesivir.