Boffito et al. recalled the critical importance to correctly interpret protein binding. Changes of
lopinavir pharmacokinetics in
coronavirus disease 2019 (COVID-19) are a perfect illustration. Indeed, several studies described that total
lopinavir plasma concentrations were considerably higher in patients with severe
COVID-19 than those reported in patients with HIV. These findings have led to a reduction of the dose of
lopinavir in some patients, hypothesizing an inhibitory effect of
inflammation on
lopinavir metabolism. Unfortunately, changes in
plasma protein binding were never investigated. We performed a retrospective cohort study. Data were collected from the medical records of patients hospitalized for
COVID-19 treated with
lopinavir/
ritonavir in intensive care units or
infectious disease departments of Toulouse University Hospital (France). Total and unbound concentrations of
lopinavir,
C reactive protein,
albumin, and alpha-1-acid
glycoprotein (AAG) levels were measured during routine care on the same samples. In patients with
COVID-19, increased total
lopinavir concentration is the result of an increased AAG-bound
lopinavir concentration, whereas the unbound concentration remains constant, and insufficient to reduce the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral load. Although international guidelines have recently recommended against using
lopinavir/
ritonavir to treat severe
COVID-19, the description of
lopinavir pharmacokinetics changes in
COVID-19 is a textbook case of the high risk of misinterpretation of a total
drug exposure when changes in protein binding are not taken into consideration.