Maternal-Fetal Letermovir Exposure In Vivo and Physiologically Based Pharmacokinetic Modeling: A Rationale for Congenital Cytomegalovirus Therapy.

BACKGROUND

Cytomegalovirus (CMV) affects 0.5%-2.0% of all live births and is the main nongenetic cause of congenital sensorineural hearing loss and neurological damage, yet no validated prenatal treatment exists for infected fetuses. Letermovir, a CMV-specific antiviral, is approved for prophylaxis in transplant recipients. This study aimed to quantify maternal-fetal exposure to letermovir following maternal administration, focusing on CMV-target fetal organs, particularly the brain.

METHODS

Seven pregnant women undergoing second-trimester termination of pregnancy for fetal anomalies received oral letermovir (240 or 480 mg once daily) for 3 days. On the day of termination, samples from maternal and fetal blood, placenta, and fetal organs were collected and analyzed. Plasma and tissue drug concentrations were compared to the letermovir half-maximal effective concentration to assess potential antiviral efficacy.

RESULTS

Letermovir achieved therapeutic levels in all compartments. Complementary physiologically based pharmacokinetic modeling confirmed adequate fetal exposure across pregnancy stages. No maternal adverse events were observed.

CONCLUSIONS

These unique in vivo data provide the first pharmacological rationale supporting letermovir use during pregnancy for congenital CMV therapy. Clinical Trials Registration. NCT04732260.