A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19.

Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., Ruan, L., Song, B., Cai, Y., Wei, M., Li, X., Xia, J., Chen, N., Xiang, J., Yu, T., Bai, T., Xie, X., Zhang, L., Li, C., Yuan, Y., … Wang, C. (2020). A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. The New England journal of medicine, NEJMoa2001282. Advance online publication. https://doi.org/10.1056/NEJMoa2001282

Excerpt:

Nearly 14% of lopinavir–ritonavir recipients were unable to complete the full 14-day course of administration. This was due primarily to gastrointestinal adverse events, including anorexia, nausea, abdominal discomfort, or diarrhea, as well as two serious adverse events, both acute gastritis. Two recipients had self-limited skin eruptions. Such side effects, including the risks of hepatic injury, pancreatitis, more severe cutaneous eruptions, and QT prolongation, and the potential for multiple drug interactions due to CYP3A inhibition, are well documented with this drug combination. The side-effect profile observed in the current trial arouses concern about the use of higher or more prolonged lopinavir–ritonavir dose regimens in efforts to improve outcomes.

Blockage of hERG channels by HIV protease inhibitors

Anson, Blake D et al. The Lancet, Volume 365, Issue 9460, 682 - 686

We identified 24 patients with QT prolongation or torsade de pointes, or both, associated with protease inhibitors, using the Food and Drug Administration's voluntary adverse event reporting system. Attending physicians thought that protease inhibitors were the most probable cause of these symptoms in 14 of the patients. Drug-induced QT prolongation is usually caused by block of human ether-a-go-go-related gene (HERG) potassium channels, and we showed that lopinavir, nelfinavir, ritonavir, and saquinavir caused dose-dependent block of HERG channels heterologously expressed in HEK293 cells in vitro. We also recorded block by lopinavir of repolarising potassium current (I Kr) channels in neonatal mouse cardiac myocytes. Our data show that four protease inhibitors block HERG channels, suggesting that protease inhibitors could predispose individuals to QT prolongation and torsade de pointes.

European Medicines Agency:
Summary on Compassionate Use of Remdesivir

Excerpt:

Additional remdesivir did show only a weak inhibition in vitro of the hERG channel, IC20 and IC50 values for the inhibitory effect were 7.5 μM and 28.9 μM, respectively; at least 6-fold and 26-fold, respectively, above the estimated free drug concentration (1.1 μM) at Cmax of the currently proposed 200-mg maximum clinical dose.