3.1 Lopinavir-ritonavir
Lopinavir-ritonavir is a fixed dose combination of drugs branded as Kaletra®. It was developed for the treatment of human immunodeficiency virus (HIV) disease. Lopinavir is a protease inhibitor that is co-administered with ritonavir to improve the pharmacokinetic (PK) properties of the drug (Chu et al., 2004). Lopinavir-ritonavir is a potential treatment for COVID-19 as it targets and deactivates the main protease (Mpro), which is involved in polyprotein processing and virus maturation (Dayer, Taleb-Gassabi, & Dayer, 2017). A standard dose of lopinavir-ritonavir is 400 mg/100 mg twice a day for HIV-1 treatment, and this has also been used for SARS-CoV-2 treatment (Cao et al., 2020).
The most frequent reported AEs for lopinavir-ritonavir treatment are gastrointestinal disturbances including diarrhoea, nausea and vomiting (Chandwani & Shuter, 2008). Dose-related diarrhoea have been reported in up to 25 % of patients and are thought to occur through a number of mechanisms including decreased proliferation of intestinal epithelial cells, disruption of intestinal barrier function, inducing endoplasmic reticulum stress and activating the unfolded protein response (X. Wu, Li, Peng, & Zhou, 2014). Diarrhoea is also a symptom in some COVID-19 patients and so lopinavir-ritonavir has the potential to exacerbate this. Pancreatitis has been reported in a small number of patients following lopinavir-ritonavir treatment although this was more frequent in those with a pre-existing history of pancreatitis (Chandwani & Shuter, 2008; Oldfield & Plosker, 2006). Additionally, patients with underlying liver diseases should have regular monitoring of hepatic function (Palacios et al., 2006). Caution should be exerted for those patients taking concomitant medication as lopinavir-ritonavir inhibits P-glycoprotein (P-gp) and cytochrome P450 (CYP) -3A4, which therefore may alter the PK of other compounds (L. Zhang, Zhang, & Huang, 2009). A COVID-19 drug interaction website has been developed by The Liverpool Drug Interaction Group which details DDIs with lopinavir-ritonavir and a number of drugs, which in some cases can lead to potentially serious and/or life-threatening reactions (Group, 2020; AbbVie Inc., 2016).
Since the SARS-CoV-2 outbreak, 73 clinical trials have been registered (up to 6th June 2020) to test lopinavir-ritonavir as a potential treatment for SARS-CoV-2 with variable outcomes in terms of efficacy. In one trial of 199 patients with confirmed SARS-CoV-2, 13 patients on the lopinavir-ritonavir arm were withdrawn due to AEs (Cao et al., 2020). In a different trial, patients who were administered lopinavir-ritonavir (200 mg/ 50 mg) also experienced gastrointestinal AEs (Li et al., 2020).