Boffito et al. recalled the critical importance to correctly interpret protein binding. Changes of lopinavir pharmacokinetics in COVID-19 are a perfect illustration. Indeed, several studies described that total lopinavir plasma concentrations were considerably higher in severe COVID-19 patients than those reported in HIV patients. These findings have led to a reduction of the dose of lopinavir in some patients, hypothetizing 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 COVID-19 patients, 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 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.< Leer menos