Study: Too Little Lopinavir in Lungs to Treat COVID-19

Plasma levels of lopinavir (LPV) were found to be over three-fold greater in patients with coronavirus 2019 (COVID-19) than with HIV/AIDS due to inflammatory processes inhibiting metabolism of the drug, but the unbound LPV concentrations in the lungs were calculated to be sub-therapeutic against the novel corona virus.

Given the body of evidence that systemic inflammation can reduce hepatic cytochrome P450 (CYP450) metabolic enzymes, and recognizing the prominent inflammatory diathesis in COVID-19, Catia Marzolini, PharmD, PhD, Division of Infectious Diseases and Hospital Hygiene, University Hospital Basel and University of Basel, and colleagues sought to determine whether the inflammation affected the metabolism and pharmacodynamics of LPV, which had been trialed, along with hydroxychloroquine, to treat COVID-19.

"The release of inflammatory cytokines such as interleukin-6 (IL-6) activates intracellular signaling cascades, leading to the downregulation of cytochrome P450 enzymes," Marzolini and colleagues explained.

"Treatment rationales for COVID-19 have focused on both antiviral activity and control of the infection induced cytokine storm," the investigators wrote. "Direct interaction between the 2 modalities must be evaluated, however, because infections and inflammatory diseases have an impact on drug metabolism."

Marzolini and colleagues identified 92 patients who were hospitalized for confirmed COVID-19 infection between February 25 and April 30, 2020 in Basel, and for whom plasma concentrations of LPV, as well as for hydroxychloroquine were available. Lopinavir is a substrate for CYP450 3A4 and so could be affected by the inflammatory process in COVID-19, the investigators note, while hydroxychloroquine has a different metabolic route and served as a comparator in this study.

LPV was administered in fixed combination with ritononavir (LPV/r). C-reactive protein (CRP) values were utilized as a marker of inflammation severity.

The investigators reported that LPV concentrations were significantly higher in patients with CRP ≥75mg/L than those with <75mg/ml (median levels: 30.7 vs 20.9 μg/ml, P <.001). They also pointed out that these levels in patients with COVID-19 were 3.5-fold higher than those historically reported with HIV-AIDS (ie, 7.1 μg/ml). Hydroxycholoroquine levels appeared independent of CRP values, and the posited effect of inflammation on CYP450 enzymatic metabolism.

The use of the anti-IL6 agent, tocilizumab, in some patients provided an additional indication of the influence of inflammation on LVP plasma levels, which were reduced as inflammation was reduced with the treatment.

"Our data show a significant decrease in LPV levels (18.7 vs 28.8 μg/ml), but we can see that LPV levels are not back to normal 2 days after administering tocilizumab," Marzolini told ContagionLive®.

Marzolini and colleagues also calculated the approximate unbound concentration of LPV in the lungs that corresponded to the determined plasma trough concentrations. They point out that sufficient LPV levels would be needed in the lungs to inhibit the enzyme, 3-chymotrypsin-like protease (3CL^pro) that is used by SARS-CoV-2 to cleave to the host cell.

"The extrapolated trough concentration for unbound LPV in the lung is 0.41 μg/ml." Marzolini said. "Considering that the inhibitory concentration of LPV for SARS-CoV-2 is 16.4 μg/ml, you would need at least 40 fold higher unbound concentrations in the lung.

"Higher concentrations cannot be reached with the current drug formulation," she observed. "As far as I know, there are no formulation platforms for pulmonary delivery of LPV/r."

Marzolini also noted that ritonavir, in the existing fixed combination formulation with LPV, adds to the inhibitory effect on CYP450 3A4.

"Higher ritonavir levels will cause, in turn, more inhibition and therefore will further increase lopinavir levels," she said. "Thus, the effect of inflammation is probably more pronounced for lopinavir compared to a non-boosted CYP 3A4 substrate, as its exposure depends on ritonavir which is also impacted by inflammation."