No Evidence of a Drug-Drug Interaction Between Letermovir (MK-8228) and Mycophenolate Mofetil

Introduction

Letermovir (MK-8228) is a potent, once-daily inhibitor of the cytomegalovirus (CMV) terminase complex that is being developed for the prophylaxis of CMV infection in transplant patients. This study evaluated the pharmacokinetic interactions, safety and tolerability of letermovir when coadministered in healthy subjects with mycophenolate mofetil (MMF), which is the morpholinoethyl ester prodrug of mycophenolic acid (MPA).

Materials & Methods

This was an open label trial in 14 healthy female subjects that explored the pharmacokinetic parameters of a single 1 mg oral dose of MMF administered alone on day 1 and administered on day 12 with letermovir given orally as 480 mg once daily from day 8 and continued through day 16. Letermovir pharmacokinetics were assessed at single dose (day 5) and at steady state on day 12 (with MMF) and on day 16 (alone following MMF washout).

 Results

Coadministration of a single dose of 1 mg of MMF with 480 mg daily letermovir at steady state had no effect on the pharmacokinetics of MPA. The MPA AUC_0-inf and C_max geometric mean ratios (GMRs) [90% confidence interval] for the comparison (MMF with letermovir/MMF alone) were 1.08 [0.96, 1.21] and 0.96 [0.81, 1.13], respectively. Coadministration of 480 mg daily letermovir at steady state with a single dose of 1 mg MMF has no clinically meaningful effect on the pharmacokinetics of letermovir with AUC_0-24 and Cmax GMR of 1.18 [1.04, 1.33] and 1.11 [0.92, 1.35], respectively. The letermovir geometric mean accumulation ratio (Day 16/Day 5) and 95% CI were 1.13 [0.90, 1.42] for AUC_0-24 and 1.01 [0.79, 1.28] for C_max, indicating that accumulation of letermovir when administered as daily doses is minimal. All related AEs were reported as mild in severity and resolved. Following coadministration of letermovir and MMF, no clinically meaningful changes were observed in clinical laboratory values, vital signs, ECG or physical exam results.

Conclusions

Multiple dose administration of 480 mg letermovir daily with a single dose of 1 mg MMF was generally well tolerated by the healthy subjects in this study. Co-administration of letermovir with MMF had no clinically meaningful effect on the PK of letermovir or MMF. Letermovir and MMF may be coadministered without dose adjustment.