I am wondering what inferences we can reasonably draw from the existing literature about the biological plausibility of lopinavir/ritonavir (L/r) for SARS-CoV-2.
As I understand it, the reason it is being used is that it was used for the SARS virus and molecular docking studies suggested favorable binding energies. Based on a preprint (1), the binding energy (kJ/mol) of lopinavir for SARS-CoV-2 was -5.49, for SARS-CoV -2.12, for HIV-1 proteinase -5.78 (paper says "proteinase", I suspect this is a translation error or typo and "protease" was intended).
Looking at the Kaletra FDA labeling (2):
– Peak plasma concentration after taking L/r 400/100 mg BID for 3 weeks is 9.8 ug/mL
– At steady state lopinavir is 98-99% plasma-protein bound
– In the presence of 50% human serum, the mean EC50 of lopinavir against various HIV-1 strains ranged 65-289 nM. Without the human serum, EC50 was 10-27 nM.
For SARS, the cytopathic effect of the virus was inhibited by lopinavir 4 ug/ml, or 1 ug/ml combined in the presence of ribavirin (3).
These data raise the following thoughts and questions in my mind and I wonder how anyone with a more rigorous pharmacological or biochem background may see it:
– It seems like L/r is an effective HIV drug because its free serum concentration ends up on the same order of magnitude as the EC50 against HIV-1.
– It seems that the free lopinavir concentration achieved with standard dosing would be far below the concentrations shown to inhibit SARS in vitro.
– The binding energies of lopinavir and SARS-CoV-2 are comparable, with SARS-CoV being less negative. Is this reliably predictive of lower inhibitory concentrations in vitro or in vivo? What can we infer from this data – just “it’ll be better” or do comparable binding energies actually make comparable inhibitory concentrations likely?
– Chloroquine/hydroxychloroquine and L/r are drugs with very very favorable side effect profiles in most people. Ribavirin is less innocuous but if it decreases the L/r inhibitory concentrations for SARS-CoV-2 the same way that it does for SARS, should doctors using L/r for COVID-19 more strongly consider adding ribavirin? On the other hand, if the gap between serum lopinavir concentration and inhibitory concentration is so large that the use of these drugs is hopeless to begin with, piling on ribavirin would just expose patients to more risk for no reason.
– How were standard doses of lopinavir determined? What is the dose-limiting toxicity and is there room to escalate the dose to achieve effect against a virus which is not inhibited as readily as HIV-1?
To be clear, this is academic speculation, and I wouldn't advocate that anyone megadose a patient on off-label HIV drugs and throw ribavirin into the mix.
(2) https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021906s008,021251s019lbl.pdf
(3) https://thorax.bmj.com/content/thoraxjnl/59/3/252.full.pdf
Source: Original link
