A Phase 1 Multiple‐Dose, Open‐Label, Pharmacokinetic Study of Nirmatrelvir/Ritonavir in Healthy Lactating Women

In accordance with the Centers for Disease Control and Prevention recommendations, pregnant women and those with a recent pregnancy (i.e., lactating) are considered at high risk of developing severe COVID-19 and qualify for treatment with nirmatrelvir/ritonavir. However, clinical data are lacking in this population because breastfeeding women were excluded from the nirmatrelvir/ritonavir clinical development program and pivotal Phase 2/3 studies. We report findings from a prospective Phase 1 trial (NCT05441215) designed and conducted in accordance with the US Food and Drug Administration guidance on clinical lactation studies that evaluated the pharmacokinetics and safety of multiple oral doses of nirmatrelvir/ritonavir in healthy lactating women using paired breast milk and maternal plasma data. Eight participants were enrolled and completed the study. After administration of nirmatrelvir/ritonavir 300 mg/100 mg to steady-state, the concentrations of both nirmatrelvir and ritonavir in breast milk were consistently lower than maternal plasma. Based on standard infant breast milk consumption (150 mL/kg/day), the mean absolute daily doses of nirmatrelvir and ritonavir that an infant would receive were 0.1595 and 0.0057 mg/kg/day, respectively, representing 1.8% and 0.19% of the bodyweight-normalized maternal dose. All treatment-emergent adverse events were mild to moderate in severity. No deaths, serious or severe adverse events, dose reductions, interruptions, or discontinuations were reported. In conclusion, nirmatrelvir/ritonavir 300 mg/100 mg was safe and well tolerated in healthy lactating women, with infant exposure considered to be low and well within the acceptability criteria of < 10% of the body weight-normalized maternal dose.