The Effect of Oral Letermovir Administration on the Pharmacokinetics of a Single Oral Dose of P‐Glycoprotein Substrate Digoxin in Healthy Volunteers

Abstract

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor approved in the United States, Canada, Japan, and the European Union for prophylaxis of CMV infection and disease in CMV-seropositive, allogeneic, hematopoietic stem-cell transplant recipients. In vitro, letermovir is a substrate and potential modulator of P-glycoprotein. The potential of letermovir to alter the pharmacokinetics of digoxin (a P-glycoprotein substrate) upon coadministration in healthy subjects was therefore investigated in a phase 1 trial (EudraCT: 2011-004516-39). Oral letermovir 240 mg was administered twice daily for 12 days with a single oral digoxin 0.5-mg dose on day 7; after a washout period, oral digoxin 0.5 mg was administered on day 35 (sequence 1). The period order was reversed after a 28-day washout for sequence 2. Pharmacokinetics and safety were evaluated. The presence of steady-state letermovir reduced digoxin area under the plasma concentration-time curve from administration until last quantifiable measurement by 12% and maximum plasma concentration by 22% compared with digoxin alone; digoxin half-life and elimination rate remained similar in both conditions. The between-subject variability of digoxin maximum plasma concentration was higher with letermovir than without (42% vs 31%) and similar for digoxin area under the plasma concentration-time curve in both periods. No specific safety or tolerability concerns were identified. Overall, letermovir had no clinically relevant effect on concomitant administration with digoxin.

Pharmacokinetics, Safety, and Tolerability of Letermovir Following Single‐ and Multiple‐Dose Administration in Healthy Japanese Subjects

“…23 No clinically significant interactions were observed in clinical DDI studies of letermovir and mycophenolate mofetil, fluconazole, posaconazole, ethinyl estradiol, levonorgestrel, or digoxin. 15,22,[24][25][26] Letermovir AUC was ≈1.6and 3.8-fold higher in subjects with moderate and severe hepatic impairment, respectively, than in healthy subjects. 27 The observed changes in letermovir exposure in subjects with moderate hepatic impairment are not considered to be clinically relevant.…”

“…Based on the physiologically based pharmacokinetic (PBPK) analyses, letermovir has the potential to increase the plasma concentrations of CYP2C8 substrates 23 . No clinically significant interactions were observed in clinical DDI studies of letermovir and mycophenolate mofetil, fluconazole, posaconazole, ethinyl estradiol, levonorgestrel, or digoxin 15,22,24–26 …”