The anti-COVID-19 drug Paxlovid crosses biological barriers of the placenta and brain in rats.

Paxlovid (nirmatrelvir plus ritonavir) is an orally available drug for the treatment of COVID-19 disease. However, limited information remains on the biological barrier transfer of nirmatrelvir. In the present study, we investigated whether nirmatrelvir crosses the blood-placenta barrier to reach the conceptus (the collective term for the fetus, placenta, and amniotic fluid) during pregnancy and the blood-brain barrier (BBB) in male rats. Additionally, in this study, gender and pregnancy issues were investigated. Multisite microdialysis coupled with validated UHPLC-MS/MS was developed to monitor nirmatrelvir levels in maternal blood and the conceptus in pregnant rats and of the blood and brain in male and nonpregnant female rats after administration of nirmatrelvir (15 mg/kg, i.v.) alone and nirmatrelvir (15 mg/kg, i.v.) combined with ritonavir (7 mg/kg, i.v.). Pharmacokinetic results showed that nirmatrelvir rapidly penetrates the blood-placenta barrier to reach the conceptus after administration of nirmatrelvir (15 mg/kg, i.v.) alone and nirmatrelvir (15 mg/kg, i.v.) combined with ritonavir (7 mg/kg, i.v.) in pregnant rats. Nirmatrelvir also crosses the BBB in male and nonpregnant female rats in the same dose regimen. Compared to sex and pregnancy factors, the results show that protein-unbound nirmatrelvir increased significantly during pregnancy and did not differ between nonpregnant female and male rats. The results indicated that the concentrations of nirmatrelvir in the blood, conceptus, and brain were higher than the effective concentration of 90% (total EC = 292 ng/mL, unbound EC = 90.5 ng/mL, 181 nM) after the administration of nirmatrelvir plus ritonavir. Ritonavir provides a synergistic pharmacokinetic effect. Pregnancy is an important issue with increased protein-unbound nirmatrelvir in the blood and tissues.