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).