A unifying model to explain high nirmatrelvir therapeutic efficacy, low post-exposure prophylaxis efficacy, and frequent viral rebound.

In a pivotal trial, a 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic infection, decreased hospitalization and death by 89.1% and reduced nasal viral load by 0.87 log relative to placebo in high-risk individuals. Yet, ritonavir-boosted nirmatrelvir failed as post-exposure prophylaxis in a follow-up trial, and frequent viral rebound has been observed in the community. We developed a mathematical model capturing viral-immune dynamics and nirmatrelvir pharmacokinetics that recapitulated viral loads from this and another clinical trial. Our results suggest that nirmatrelvir's in vivo potency is significantly lower than in vitro assays predict. A maximally potent agent would reduce the viral load by approximately 3.5 logs relative to placebo at 5 days. The model identifies that earlier initiation and shorter treatment duration are key predictors of post-treatment rebound. Extension of early symptomatic treatment to 10 days and post-exposure prophylaxis to 15 days, rather than increasing dose or dosing frequency, is predicted to significantly lower the incidence of viral rebound.