Drug Interactions between D-Penamine and remdesivir

GENERALLY AVOID: Coadministration of remdesivir with nephrotoxic agents may increase the plasma concentrations of its main metabolite, GS-441524, and the excipient, sulfobutylether-beta-cyclodextrin sodium (SBECD). Both GS-441524 and SBECD are primarily eliminated by the kidneys, thus renal impairment secondary to the use of nephrotoxic agents may reduce their clearance and increase the risk of accumulation. In addition, there may be a potential for additive renal adverse effects, as exposures to both remdesivir and SBECD have been individually associated with nephrotoxicity in animal studies. In male rhesus monkeys given remdesivir 5, 10 or 20 mg/kg/day for 7 days, increases in mean urea nitrogen and creatinine, renal tubular atrophy, and basophilia and casts were observed at all dosage levels, while one death occurred at the highest dosage. In rats, dosage levels at or above 3 mg/kg/day for up to 4 weeks resulted in findings indicative of kidney injury and/or dysfunction. Systemic exposures (AUC) of GS-441524 were 0.1 times (monkeys at 5 mg/kg/day) and 0.3 times (rat at 3 mg/kg/day) the exposure in humans given the recommended therapeutic dose, but exposures of other metabolites found in human plasma, including an unidentified major metabolite (M27), were not reported. Given the differences in metabolite profiles and the unknown mechanism via which these toxicities may occur, the clinical relevance to humans is unclear. With respect to SBECD, exposure in rats at doses approximately 50-fold greater (3,000 mg/kg) than that typically administered in humans has been associated with liver necrosis and obstruction of the renal tubules due to vacuolation. However, these effects have not been reported in humans.

MANAGEMENT: Some authorities recommend avoiding the concomitant use of remdesivir with drugs that can reduce renal function. Caution is advised if remdesivir is used in patients who have recently received potentially nephrotoxic agents (e.g., aminoglycosides; polypeptide, glycopeptide, and polymyxin antibiotics; amphotericin B; adefovir; cidofovir; tenofovir; foscarnet; cisplatin; deferasirox; gallium nitrate; lithium; mesalamine; certain immunosuppressants; intravenous bisphosphonates; intravenous pentamidine; high intravenous dosages of methotrexate; high dosages and/or chronic use of nonsteroidal anti-inflammatory agents). Renal function (estimated glomerular filtration rate, or eGFR, for adult and pediatric patients older than 28 days; serum creatinine for full-term neonates at least 7 days up to 28 days old) should be evaluated prior to starting remdesivir and monitored daily during treatment or as clinically appropriate. Remdesivir should not be initiated in patients with an eGFR below 30 mL/min (or serum creatinine >=1 mg/dL in full-term neonates), and should be discontinued immediately if eGFR falls to less than 30 mL/min during treatment (or renal function substantially declines in full-term neonates).

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