Letermovir (MK-8228) is a potent inhibitor of the cytomegalovirus (CMV) terminase complex that is being developed for the prophylaxis of CMV infection in transplant patients, who often also receive antifungal prophylaxis. The pharmacokinetics of the azole antifungals voriconazole or posaconazole were evaluated along with their tolerability when coadministered with letermovir.
An open-label, fixed sequence trial was designed to evaluate the potential effect of letermovir on the pharmacokinetics (PK) of voriconazole in 14 healthy female subjects. Voriconazole was administered for 4 days to achieve steady state followed by 24 hours of PK sampling after the last dose. The next day letermovir was dosed alone for 4 days at 480 mg daily, followed by coadministration of letermovir with voriconazole for 4 additional days. PK sampling was carried out after the last dose of voriconazole/letermovir.
In a second open-label, fixed sequence, two-period, drug-drug interaction study between letermovir and posaconazole, a single oral dose of 300 mg of posaconazole was given in Period 1 to 16 healthy female subjects. In Period 2, 480 mg of letermovir was given once daily for 14 days, and 300 mg of posaconazole was coadministered on Day 14. Each period was followed by PK sampling for posaconazole. Safety was monitored throughout both studies by repeated clinical and laboratory tests.
The geometric mean ratios (GMRs) of voriconazole+letermovir/voriconazole for AUC0-12hr and Cmax were 0.56 and 0.61, respectively, with corresponding 90% CI of [0.51, 0.62], and [0.53, 0.71]. The GMRs (90%CI) for AUC0-inf and Cmax of posaconazole when co-administered with multiple doses of letermovir were similar to that after administration of posaconazole alone with 0.98 (0.82, 1.16), and 1.11 (0.95, 1.29), respectively. When given with either voriconazole or posaconazole, letermovir was well tolerated with no serious AEs or discontinuations due to AEs.
The decrease in voriconazole exposure when coadministered with letermovir may be clinically meaningful, whereas the exposure of posaconazole is unaffected by letermovir coadministration. Letermovir was well tolerated when coadministered with either posaconazole or voriconazole.
A. Van Schanke, Merck: Employee , Salary
J. Udo De Haes, Merck: Employee , Salary
A. Hussaini, Parexel: Employee , Salary
H. Jordan, PMRI: Employee , Salary
M. Drexel, Merck: Employee , Salary
B. Kantesaria, Merck: Employee , Salary
C. Smith, Merck: Employee , Salary
C. Tsai, Merck: Employee , Salary
C. Cho, Merck: Employee , Salary
R. Pop, PMRI: Employee , Salary
K. Menzel, Merck: Employee , Salary
E. Hulskotte, Merck: Employee , Salary
J. Butterton, Merck: Employee , Salary
E. Marcantonio, Merck: Employee , Salary
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