Pharmacokinetic Drug‐Drug Interactions Between Letermovir and the Immunosuppressants Cyclosporine, Tacrolimus, Sirolimus, and Mycophenolate Mofetil

Abstract

Letermovir (AIC246, MK‐8228) is a human cytomegalovirus terminase inhibitor indicated for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients that is also being investigated for use in other transplant settings. Many transplant patients receive immunosuppressant drugs, of which several have narrow therapeutic ranges. There is a potential for the coadministration of letermovir with these agents, and any potential effect on their pharmacokinetics (PK) must be understood. Five phase 1 trials were conducted in 73 healthy female participants to evaluate the effect of letermovir on the PK of cyclosporine, tacrolimus, sirolimus, and mycophenolic acid (active metabolite of mycophenolate mofetil [MMF]), as well as the effect of cyclosporine and MMF on letermovir PK. Safety and tolerability were also assessed. Coadministration of letermovir with cyclosporine, tacrolimus, and sirolimus resulted in 1.7‐, 2.4‐, and 3.4‐fold increases in area under the plasma concentration–time curve and 1.1‐, 1.6‐, and 2.8‐fold increases in maximum plasma concentration, respectively, of the immunosuppressants. Coadministration of letermovir and MMF had no meaningful effect on the PK of mycophenolic acid. Coadministration with cyclosporine increased letermovir area under the plasma concentration–time curve by 2.1‐fold and maximum plasma concentration by 1.5‐fold, while coadministration with MMF did not meaningfully affect the PK of letermovir. Given the increased exposures of cyclosporine, tacrolimus, and sirolimus, frequent monitoring of concentrations should be performed during administration and at discontinuation of letermovir, with dose adjustment as needed. These data support the reduction in clinical dosage of letermovir (to 240 mg) upon coadministration with cyclosporine.

Letermovir and its role in the prevention of cytomegalovirus infection in seropositive patients receiving an allogeneic hematopoietic cell transplant

“…33 This observed effect is likely due to cyclosporine inhibiting the liver uptake transporters OATP1B1/3, which are responsible for letermovir elimination, and supports the dose adjustment to 240 mg of letermovir when given concomitantly. 33 Lastly, the co-administration of letermovir with mycophenolate mofetil had no meaningful effect on the pharmacokinetics of mycophenolate mofetil, and vice versa. 33 Posaconazole and voriconazole are commonly used in HCT patients to prevent opportunistic fungal infections.…”

“…33 Lastly, the co-administration of letermovir with mycophenolate mofetil had no meaningful effect on the pharmacokinetics of mycophenolate mofetil, and vice versa. 33 Posaconazole and voriconazole are commonly used in HCT patients to prevent opportunistic fungal infections. Two pharmacokinetic trials conducted in healthy female subjects evaluated the interactions between these azole antifungals and 480 mg of letermovir.…”

Tacrolimus Concentration after Letermovir Initiation in Hematopoietic Stem Cell Transplantation Recipients Receiving Voriconazole: A Retrospective, Observational Study

“…Data are expressed as Data are expressed as mean ± SD for normally distributed continuous variables, median (25, 75% interquartile range) for abnormal distributed continuous variables or number (percentage). In a previous study, the co-administration of LMV at clinical doses with TAC resulted in a 2.4-fold increase in the area under the plasma TAC concentration-time curve and a 1.6-fold increase in the maximum plasma TAC concentration in 14 healthy female participants [20]. This was because TAC is predominantly metabolized by CYP3A4 [13] and LMV is a moderate inhibitor of CYP3A4 [18].…”

“…It is a weak-to-moderate inhibitor of CYP3A4 and a weak-to-moderate inducer of CYP2C9 and CYP2C19 [18]. The interaction between LMV and TAC has been assessed in healthy participants, and LMV was found to increase TAC exposure [19,20]. The interaction between LMV and VRCZ has also been assessed in healthy participants, and it was found that LMV decreases VRCZ exposure [21].…”

Make Sure You Have a Safety Net: Updates in the Prevention and Management of Infectious Complications in Stem Cell Transplant Recipients

“…Letermovir decreases voriconazole levels by inducing CYP2C9/19, but does not alter posaconazole levels [8]. Coadministration of letermovir with cyclosporine, tacrolimus and sirolimus leads to increased exposure to these immunosuppressive drugs; therefore, a dose of 240 mg daily is suggested if cyclosporine is co-administered [9]. In contrast, letermovir does not alter exposure to mycophenolate.…”