The placental transfer of nirmatrelvir using the ex vivo human placental perfusion model

AIMS: Nirmatrelvir is an effective therapeutic option for COVID-19 infection and is often administered after symptom onset in pregnant individuals, but few data are available on the associated fetal exposure. The placental perfusion model evaluates maternal-fetal drug transfer across the human placenta and thus can determine fetal drug exposure. The objective of our study was to quantify the amount of nirmatrelvir transfer across the human placenta using the ex vivo placental perfusion model. METHODS: In a dual closed-closed perfusion of a single human placenta lobule, nirmatrelvir was added to the maternal circulation at its clinical concentration (2.21 μg/mL) or at 10 times this level (22.1 μg/mL). For each placenta studied, there was a 1-h perfusion control period followed by a 3-h exposure period. Samples of the perfusate were collected throughout the experiment to measure nirmatrelvir concentrations and placental viability markers. RESULTS: Perfusions conducted with nirmatrelvir at 2.21 μg/mL (n = 4) and 22.1 μg/mL (n = 5) concentrations showed a fetal-maternal concentration ratio (F:M) of 0.34 and 0.42, respectively, at 180 min. F:M was adjusted for nonplacental physiological factors, including binding of albumin and α-1-acid glycoprotein, and ionization. The adjusted F:M ranged from 0.26 to 0.35 for placentas perfused with 2.21 μg/mL and from 0.33 to 0.47 for placentas perfused with 22.1 μg/mL of nirmatrelvir. CONCLUSIONS: Nirmatrelvir readily crosses the term human placenta in a concentration-dependent manner. These transfer kinetics provide a foundation for future physiologically based pharmacokinetic modelling, supporting the development of personalized nirmatrelvir dosing strategies in pregnancy.