Effect of letermovir on levonorgestrel and ethinyl estradiol pharmacokinetics
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ABSTRACT

OBJECTIVE: Letermovir is an inhibitor of the terminase complex of cytomegalovirus (CMV) used as prophylactic therapy in CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. As the combination oral contraceptive (COC) levonorgestrel/ethinyl estradiol (LNG/EE) may be coadministered in this target transplant population, the effects of letermovir on the pharmacokinetics (PK) of LNG and EE were investigated. MATERIALS AND METHODS: This was a phase I, open-label, fixed-sequence, two-period study conducted in healthy women (18 - 65 years old) of non-childbearing potential (protocol number MK-8228 035). On day 1 of period 1, participants received a single dose of COC (LNG 0.15 mg/EE 0.03 mg). Following a 7-day washout, oral letermovir 480 mg was administered once-daily on days 1 - 12 of period 2, with a single dose of COC coadministered on day 8. Blood samples were collected to determine LNG and EE PK, and safety was assessed. RESULTS: The AUC0-∞ geometric mean ratios (90% confidence intervals) for COC + letermovir/COC alone were 1.36 (1.30, 1.43) for LNG and 1.42 (1.32, 1.52) for EE, indicating that letermovir coadministration increased COC exposure. Coadministration had no clinically-meaningful effect on Cmax, tmax, or apparent terminal T1/2 for either LNG or EE. All treatments were generally well tolerated. CONCLUSION: Letermovir coadministration with COC resulted in an increase in LNG and EE exposure in healthy adult women; however, levels were within the established safety margins. There was no decrease in LNG or EE exposure with no apparent risk of contraceptive failure on coadministration of letermovir and COC.
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