Pharmacokinetics and Tolerability of Letermovir Coadministered With Azole Antifungals (Posaconazole or Voriconazole) in Healthy Subjects

Abstract

Letermovir is a human cytomegalovirus terminase inhibitor for cytomegalovirus infection prophylaxis in hematopoietic stem cell transplant recipients. Posaconazole (POS), a substrate of glucuronosyltransferase and P-glycoprotein, and voriconazole (VRC), a substrate of CYP2C9/19, are commonly administered to transplant recipients. Because coadministration of these azoles with letermovir is expected, the effect of letermovir on exposure to these antifungals was investigated. Two trials were conducted in healthy female subjects 18 to 55 years of age. In trial 1, single-dose POS 300 mg was administered alone, followed by a 7-day washout; then letermovir 480 mg once daily was given for 14 days with POS 300 mg coadministered on day 14. In trial 2, on day 1 VRC 400 mg was given every 12 hours; on days 2 and 3, VRC 200 mg was given every 12 hours, and on day 4 VRC 200 mg. On days 5 to 8, letermovir 480 mg was given once daily. Days 9 to 12 repeated days 1 to 4 coadministered with letermovir 480 mg once daily. In both trials, blood samples were collected for the assessment of the pharmacokinetic profiles of the antifungals, and safety was assessed. The geometric mean ratios (90%CIs) for POS+letermovir/POS area under the curve and peak concentration were 0.98 (0.83, 1.17) and 1.11 (0.95, 1.29), respectively. Voriconazole+letermovir/VRC area under the curve and peak concentration geometric mean ratios were 0.56 (0.51, 0.62) and 0.61 (0.53, 0.71), respectively. All treatments were generally well tolerated. Letermovir did not affect POS pharmacokinetics to a clinically meaningful extent but decreased VRC exposure. These results suggest that letermovir may be a perpetrator of CYP2C9/19-mediated drug-drug interactions.

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

“…It is unclear when CYP2C19 induction due to LMV reaches a maximum level. However, in a pharmacokinetic trace of LMV co-administered with VRCZ, the pharmacokinetics were assessed on day 8 after the 7-day administration of LMV [21]. Therefore, in the present study, the interaction was evaluated during the pre-LMV period, post-LMV 1 period, and post-LMV 2 period (each for 7 days).…”

“…This was because TAC is predominantly metabolized by CYP3A4 [13] and LMV is a moderate inhibitor of CYP3A4 [18]. In contrast, the effect of LMV on VRCZ was examined in 14 healthy subjects [21]. In that study, the area under the curve and peak concentration geometric mean ratios for VRCZ+LMV/VRCZ alone were 0.56 and 0.61, respectively.…”

“…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]. Therefore, when LMV is administered to patients receiving TAC and VRCZ, a reciprocal effect of LMV on TAC concentration is supposed to occur due to the following: (1) an increase in the TAC concentration due to the inhibition of CYP3A4 by LMV and (2) a decrease in the TAC concentration ascribed to the decrease in VRCZ concentration due to the induction of CYP2C19 by LMV.…”

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

“…Letermovir has important interactions with commonly used immunosuppressive drugs due to effects on cytochrome P4503A and organic anion transporters. 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].…”

Viral infections after allogeneic hematopoietic stem cell transplant

“…A significant advantage of letermovir is lack of myelosuppressive effect. However, caution should be exercised with its use due to its effect on the cytochrome enzyme system as it can increase the exposure of commonly used immunosuppressive medications, and decrease exposure to voriconazole (but not posaconazole) . It is also critical to realize that letermovir has NO activity against other herpes viruses (such as HSV and VZV), thus other antiviral therapy should be used (when indicated) during letermovir use.…”