040: An Interactive Approach for Evaluation of Monoclonal Antibody Dosing in Light of Rapidly Evolving SARS-CoV-2 Variants

Statement of Purpose: The COVID-19 pandemic continues to pose a significant threat to global public health, with the emergence of fast-changing variants that can potentially undermine current treatment and prophylaxis efforts. Several recombinant human monoclonal antibodies (mAb) have been authorized to treat mild to moderate COVID-19 infections. However, due to the emergence of new variants of SARS-CoV-2, the evaluation of probability of target attainment for early treatment with mAbs in the context of the changing variant prevalence may require continuous reassessment.

Description of Methods & Materials: We developed an interactive tool (R Shiny, R v4.2.2) that can be used to conduct and visualize PKPD analyses in light of new variants. Specifically, the tool enables evaluation of probability of target attainment for early treatment; as well as the predicted maximum duration of protection for prophylaxis under different scenarios of dosing and variant in vitro EC50 shifts relative to wildtype. Typical two-compartmental PK parameters for half-life extended mAbs were used to simulate PK profiles after intravenous or intramuscular injection. Simulation was conducted in R using mrgsolve package (v1.0.6). Information including 1) route of administration (IV or IM) and dose; 2) mAb lung distribution assumption; 3) variants EC90 and prevalence; were included and can be defined as numeric input by the user. The simulation outputs include probability of target attainment (defined as percentage of patient population covered by mAb) and duration of protection (defined as the duration when mAb concentration was above tissue-adjusted (ta) EC90) based on user input. All simulations were based on targets using in vitro neutralization data and did not account for potential additional effects (e.g. effector function) with some mAbs.

Data & Results: Representative screen shots from the interactive tool are shown (Figure 1). In “single variant” interface, the tool provides both a visualization of PK profile over a certain taEC90 and the corresponding table of target containment for a specific variant of interest. In the “two variants” interface, the tool enables visualization of target attainment assuming a specific prevalence ratio between two given variants. This tool gives user flexibility to simulate mAb dosing regimens against a single variant of interest or a number of variants mimicking realistic variant prevalence scenarios.

Interpretation, Conclusion or Significance: In summary, the PKPD simulation tool can enable cross-functional teams to evaluate probability of target engagement for a mAb dosing regimen in light of the changing COVID-19 variant landscape.

Disclosures: This research was funded by GSK and Vir Biotech. Ahmed Nader and Qianwen Wang are employees of GSK, Maribel Reyes is an employee of Vir Biotech.