Plasma Concentrations and Safety of Lopinavir/Ritonavir in COVID-19 Patients

Abstract

Background: Although the efficacy of lopinavir/ritonavir has not been proven, it has been proposed as an off-label treatment for COVID-19. Previously, it has been reported that the plasma concentrations of lopinavir significantly increase in inflammatory settings. As COVID-19 may be associated with major inflammation, assessing the plasma concentrations and safety of lopinavir in COVID-19 patients is essential.

Methods: Real-world COVID-19 data based on a retrospective study.

Results: Among the 31 COVID-19 patients treated with lopinavir/ritonavir between March 18, 2020 and April 1, 2020, higher lopinavir plasma concentrations were observed, which increased by 4.6-fold (interquartile range: 3.6-6.2), compared with the average plasma concentrations in HIV. Lopinavir concentrations in all except one patient were above the upper limit of the concentration range of HIV treatment. Approximately one to 5 patients prematurely stopped treatment mainly because of an ADR related to hepatic or gastrointestinal disorders.

Conclusions: Lopinavir plasma concentrations in patients with moderate-to-severe COVID-19 were higher than expected, and they were associated with the occurrence of hepatic or gastrointestinal adverse drug reactions. However, a high plasma concentration may be required for in vivo antiviral activity against SARS-CoV-2, as suggested by previous studies. Therefore, in the absence of adverse drug reaction, lopinavir dosage should not be reduced. Caution is essential because off-label use can be associated with a new drug safety profile.

FIGURE 1.

Lopinavir/ritonavir plasma concentrations and magnitude of increase in lopinavir plasma concentrations of COVID-19 patients as compared to those of HIV patients. A, Plasma concentrations analyzed at peak and trough in 6 and 18 patients with COVID-19, respectively. Boxes represent interquartile range and median, whiskers represent min and max values. Horizontal red lines represent the peak and trough concentrations observed in HIV patients after 400 mg/100 mg lopinavir/ritonavir twice daily (ie, for lopinavir at peak 7000–11,000 ng/mL and at trough 1000–8000 ng/mL; for ritonavir at peak 300–500 ng/mL and at trough 100–250 ng/mL).^, B, Magnitude of increase in lopinavir plasma concentrations compared with the average plasma concentrations observed in HIV patients (ie, 9000 ng/mL at peak and 4000 ng/mL at trough). C and D, C-reactive protein (r² = 0.03) and interleukin-6 plasma levels (r² = 0.02) according to the magnitude of increase in lopinavir plasma concentrations.