Pharmacokinetic analysis of placental transfer of ritonavir as a component of paxlovid using microdialysis in pregnant rats

Background: Ritonavir is one of the most potent CYP3A4 inhibitor currently on the market, and is often used together with other antiviral drugs to increase their bioavailability and efficacy. Paxlovid, consisting of nirmatrelvir and ritonavir, was approved for the treatment of COVID-19. As previous studies regarding the use of ritonavir during pregnancy were limited to ex-vivo experiments and systemic safety data, to fully explore the detailed pharmacokinetics of ritonavir in pregnant rats' blood and conceptus, an analytical method consisted of multi-microdialysis coupled with UHPLC-MS/MS were developed to analyze the pharmacokinetics of ritonavir, both as a component of Paxlovid and by itself. 17 days pregnant female Sprague-Dawley rats were randomly split into three experimental group: normal dosage of ritonavir alone (7 mg kg(-1)), normal dosage of Paxlovid (ritonavir 7 mg kg(-1) + nirmatrelvir 15 mg kg(-1)), and 3x dosage of ritonavir (21 mg kg(-1)). Results: 3x dosage of ritonavir produced a more than 3x increase in rats' blood and placenta. Transfer rate of ritonavir to the placenta, amniotic fluid, and fetus were determined to be 20.7%, 13.8%, and 4.7% respectively. Concentration of ritonavir in the placenta, amniotic fluid, and fetus did not significantly go down after 8 h. Significance: Overall, ritonavir's metabolism was not influenced by the presence of nirmatrelvir in pregnant rats. A 3x increase in dosage produced a concentration of roughly 4x, most likely a result of ritonavir's auto-inhibition effect on cytochrome P450 proteins. Accumulation of ritonavir is possible in placenta, amniotic fluid, and fetus.