The PBPK LeiCNS-PK3.0 framework predicts Nirmatrelvir (but not Remdesivir or Molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells.

· No information exists on the pharmacokinetics of antiCOVID-19 drugs in human brain. · LeiCNS-PK3.0 framework predicts adequately the human brain pharmacokinetic profiles. · Nirmatrelvir is predicted to reach effective brain concentrations against COVID-19. · Ineffective brain concentrations are predicted for Molnupiravir and Remdesivir. · LeiCNS-PK3.0 is a promising tool to optimize and accelerate CNS drug development. SARS-CoV-2 was shown to infect and persist in the human brain cells for up to 230 days, highlighting the need to treat the brain viral load. The CNS disposition of the antiCOVID-19 drugs: Remdesivir, Molnupiravir, and Nirmatrelvir, remains, however, unexplored. Here, we assessed the human brain pharmacokinetic profile (PK) against the EC 90 values of the antiCOVID-19 drugs to predict drugs with favorable brain PK against the delta and the omicron variants. We also evaluated the intracellular PK of GS443902 and EIDD2061, the active metabolites of Remdesivir and Molnupiravir, respectively. Towards this, we applied LeiCNS-PK3.0, the physiologically based pharmacokinetic framework with demonstrated adequate predictions of human CNS PK. Under the recommended dosing regimens, the predicted brain extracellular fluid PK of only Nirmatrelvir was above the variants' EC 90. The intracellular levels of GS443902 and EIDD2061 were below the intracellular EC 90. Summarizing, our model recommends Nirmatrelvir as the promising candidate for (pre)clinical studies investigating the CNS efficacy of antiCOVID-19 drugs. [Display omitted] [ABSTRACT FROM AUTHOR]