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

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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.

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