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

Lee et al., npj Viruses, doi:10.1038/s44298-023-00013-1, Jan 2024
https://c19early.org/lee20.html
Animal study showing that paxlovid crosses biological barriers of the blood-placenta and blood-brain in rats. Authors developed a multisite microdialysis coupled with UHPLC-MS/MS to monitor nirmatrelvir levels in maternal blood, conceptus (fetus, placenta, and amniotic fluid), and brains of male and nonpregnant female rats after intravenous administration. Results demonstrated that nirmatrelvir rapidly penetrates the blood-placenta barrier to reach the conceptus and crosses the blood-brain barrier in male and nonpregnant female rats. Protein-unbound nirmatrelvir increased significantly during pregnancy but did not differ between nonpregnant female and male rats. Concentrations in blood, conceptus, and brain were higher than the effective concentration of 90% (EC90) after administration of nirmatrelvir plus ritonavir. Ritonavir provided a synergistic pharmacokinetic effect by inhibiting CYP3A enzymes, significantly enhancing nirmatrelvir levels in biological samples. The study highlights that pregnancy is an important factor affecting pharmacokinetics with increased protein-unbound nirmatrelvir in blood and tissues.
Lee et al., 24 Jan 2024, USA, peer-reviewed, 5 authors. Contact: thtsai@nycu.edu.tw.
The anti-COVID-19 drug Paxlovid crosses biological barriers of the placenta and brain in rats
Wan-Hsin Lee, Chung-Kai Sun, Chun-Hao Chang, Muh-Hwa Yang, Tung-Hu Tsai
npj Viruses, doi:10.1038/s44298-023-00013-1
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 90 = 292 ng/mL, unbound EC 90 = 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.
AUTHOR CONTRIBUTIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s44298-023-00013-1 . Correspondence and requests for materials should be addressed to Tung-Hu Tsai. Reprints and permission information is available at http://www.nature.com/ reprints Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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DOI record: { "DOI": "10.1038/s44298-023-00013-1", "ISSN": [ "2948-1767" ], "URL": "http://dx.doi.org/10.1038/s44298-023-00013-1", "abstract": "<jats:title>Abstract</jats:title><jats:p>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<jats:sub>90</jats:sub> = 292 ng/mL, unbound EC<jats:sub>90</jats:sub> = 90.5 ng/mL, 181 nM) after the administration of nirmatrelvir plus ritonavir. Ritonavir provides a synergistic pharmacokinetic effect. 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