Neglecting Plasma Protein Binding in COVID-19 Patients Leads to a Wrong Interpretation of Lopinavir Overexposure

Clin Pharmacol Ther. 2021 Apr;109(4):1030-1033. doi: 10.1002/cpt.2196. Epub 2021 Mar 9.


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.

MeSH terms

  • Aged
  • Albumins / metabolism
  • Antiviral Agents / pharmacokinetics*
  • Antiviral Agents / therapeutic use
  • C-Reactive Protein / metabolism
  • COVID-19 Drug Treatment*
  • Female
  • Glycoproteins / metabolism
  • Humans
  • Lopinavir / pharmacokinetics*
  • Lopinavir / therapeutic use
  • Male
  • Middle Aged
  • Plasma / physiology*
  • Protein Binding / physiology*
  • Retrospective Studies
  • SARS-CoV-2
  • Viral Load


  • Albumins
  • Antiviral Agents
  • Glycoproteins
  • Lopinavir
  • C-Reactive Protein