MICA: Pharmacokinetic/Pharmacodynamic (PKPD) Model Development to Inform SARS-CoV-2 Antiviral Development

Antivirals generally need to reduce viral load to positively influence clinical endpoints such as hospitalisation or mortality. To prioritise antivirals for Phase III trials, Phase II trials seeking significant viral load decrease versus placebo are required. Interpreting viral load is challenging since it changes with time since infection (rises then falls) and by sampling site. This proposal seeks to develop a pharmacometric nonlinear mixed effects model of SARS-CoV-2 viral dynamics. The model will be used to design and analyse efficient antiviral Phase II trials, and prioritise antivirals and antiviral combinations for Phase III. The target cell limited model, along with its common extensions (eclipse phase and innate and adaptive immune components) and simplifications (quasi-steady-state assumption between infected cell and free virus numbers), will be compared using graphical and numerical model diagnostics. A preferred model will be chosen and applied to viral load data in ongoing trials and to simulate outcomes to optimally design future trials. The model will be applied to real-world clinical data to seek subgroups of hospitalised patients who may benefit from antivirals. It will also be used to perform a model-based appraisal of whole genome sequence-derived biomarkers such as subgenomic RNA, to be assessed as a possible Phase II endpoint. This work will be carried out by a collaboration of academic, clinical and pharmaceutical industry investigators who will develop and share SARS-CoV-2 antiviral modelling best practice.