Dosing of convalescent plasma and hyperimmune anti-SARS-CoV-2 immunoglobulins: a phase I/II dose finding study
Sammy Huygens (1), Tim Preijers (2,6), Francis H. Swaneveld (3), Ilona Kleine Budde (4), Corine H. Geurts van Kessel (5), Birgit C.P. Koch (2,6), Bart J.A. Rijnders (1)
1 Department of Internal Medicine, Section of Infectious Diseases and Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; 2 Department of Hospital Pharmacy, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands; 3 Unit of Transfusion Medicine, Sanquin Blood Supply Foundation, 1066 CX Amsterdam, The Netherlands; 4 Clinical Operations, Prothya Biosolutions, 1066 CX Amsterdam, The Netherlands; 5 Department of Viroscience, Erasmus MC, WHO Collaborating Centre for Arbovirus and Viral Hemorrhagic Fever Reference and Research, Rotterdam, Netherlands; 6 Rotterdam Clinical Pharmacometrics group, Rotterdam, The Netherlands.
Introduction: During the COVID-19 pandemic, trials on convalescent plasma (ConvP) and hyperimmune globulins (COVIg) were performed without preceding dose-finding studies.[1,2] ConvP and COVIg consist of polyclonal antibodies (pAbs) and may be less susceptible to changes in the spike protein in comparison with monoclonal virus neutralizing antibodies (mAbs).[3,4] MAbs as well as pAbs may be used to prevent SARS-CoV-2-virus infections in immunocompromised patients who lack an endogenous antibody response after vaccination. However, dosing regimens of ConvP or COVIg that result in a potentially protective neutralizing antibody (Nab) titer are unknown because proper dose-finding studies with ConvP and COVIg remain unavailable.
Objectives: 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 COVIg.
Methods: Immunocompromised 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. ConvP was provided by the Dutch bloodbank (Sanquin Blood Supply) and COVIg was manufactured by Prothya Biosolutions. Both products were produced while the ancestral variant (Wuhan-1) type was dominant in the Netherlands and, therefore, the Nab-titer against this strain was measured. Because IgG titers correlated well with neutralization assays of the ancestral virus, titers of IgG antibodies against the spike protein measured with the LIAISON® SARS-CoV-2 TrimericS IgG assay (DiaSorin) were used.[5] Results of the CLIA are reported in binding affinity units (BAU) per mL, which is the preferred unit for binding capacity by the World Health Organization (WHO).[6] The popPK analysis was performed using non-linear mixed effect modeling with NONMEM v7.4 (ICON Development Solutions, Ellicott City, MD, USA). Monte Carlo simulations were performed to assess potential COVIg and ConvP dosing regimens for the prevention of COVID-19.
Results:
44 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. Population PK parameter estimates (IIV) were 9.1 mLh-1 for CL (44.3%), 3790 mL for V1 (27.3%), 27.0 mLh-1 for Q, and 1640 mL V2 (29.2%). Lean body weight and type of treatment (ConvP/COVIg) allowed explaining the IIV from V1 and V2, respectively. Median terminal elimination half-life was 20 days (interquartile range: 17–25 days).
Simulations demonstrated that even monthly infusions of 600 mL of the ConvP or COVIg used in this trial would not achieve potentially protective serum antibody levels for >90% of the time. Moreover, the 90% probability target attainment (PTA) for the 300 BAUmL-1 titer threshold could not be achieved using 600 mL ConvP every 8 weeks. For a target of 100 BAUmL-1, the 90% PTA was achieved with longer dosing intervals as long as ConvP or COVIg with high concentrations can be administrated (e.g. every 8 weeks with 32,000 BAUmL-1 or higher). 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.
Conclusions: Administered dosing regimens did not allow to achieve the predetermined 90% PTA titer thresholds. However, dosing regimens with higher antibody concentrations are possible. The 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.
References:
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