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

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.

[Pharmacokinetic changes related to acute infection. Examples from the SARS-CoV-2 pandemic]. / Modifications pharmacocinétiques liées à une infection aiguë. Exemples issus de la pandémie de SARS-CoV-2.

The knowledge of factors of pharmacokinetic variability is important in order to personalize pharmacological treatment, particularly for drugs with a narrow therapeutic range for which pharmacological therapeutic monitoring is recommended. Inflammation is a protective response against acute infections and injuries that contributes to intra- and inter-individual variability in drug exposure by modulating the activity of enzymes involved in drug metabolism, and by altering the binding of drugs to plasma proteins. The understanding of the impact of inflammation on drug metabolism and the related clinical consequences allow to better take into consideration the effect of inflammation on the variability of drug exposure. We first summarized the molecular mechanisms by which inflammation contributes to the inhibition of drug metabolism enzymes. We then presented an updated overview of the consequences of the outcome of acute infectious event on pharmacokinetic exposure of drugs with a narrow therapeutic range and that are substrates of cytochrome P450, and the related clinical consequences. Finally, in the context of the COVID-19 pandemic, we reported examples of drug overexposures in COVID- 19 infected patients.