Dosing of convalescent plasma and hyperimmune anti-SARS-CoV-2 immunoglobulins: a phase I/II dose finding study

Abstract

AbstractBackgroundDuring the COVID-19 pandemic, trials on convalescent plasma (ConvP) were performed without preceding dose-finding studies. This study aimed to assess potential protective dosing regimens by constructing a population pharmacokinetic (popPK) model describing neutralizing antibody (Nab) titers following the administration of ConvP or hyperimmune globulins(COVIg).MethodsImmunocompromised patients, testing negative for anti-SARS-CoV-2 spike antibodies despite vaccination received a range of anti-SARS-CoV-2 antibodies in the form of COVIg or ConvP infusion. The popPK analysis was performed using NONMEM v7.4. Monte Carlo simulations were performed to assess potential COVIg and ConvP dosing regimens for prevention of COVID-19.Results44 patients were enrolled, and data from 42 were used for constructing the popPK model. A two-compartment elimination model with mixed residual error best described the Nab-titers after administration. Inter individual variation was associated to CL (44.3%), V1 (27.3%), and V2 (29.2%). Lean body weight and type of treatment (ConvP/COVIg) were associated with V1 and V2, respectively. Median elimination half-life was 20 days (interquartile-range: 17–25 days). Simulations demonstrated that even monthly infusions of 600ml of the ConvP or COVIg used in this trial would not achieve potentially protective serum antibody levels for >90% of the time. However, as a result of hybrid immunity and/or repeated vaccination plasma donors with extremely high Nab-titers are now readily available, and a >90% target attainment should be possible.ConclusionThe results of this study may inform future intervention studies on the prophylactic and therapeutic use of antiviral antibodies in the form of ConvP or COVIg.