Title:Absorption, Metabolism, Distribution, and Excretion of Letermovir
Volume: 22
Issue: 10
Author(s): Karsten Menzel*, Prajakti Kothare, Jacqueline B. McCrea, Xiaoyan Chu and Dirk Kropeit
Affiliation:
- Merck & Co., Inc., Kenilworth, New Jersey,United States
Keywords:
Drug metabolizing enzymes, drug-drug interactions, human ADME study, in vitro, in vivo, letermovir, OATP1B, transporters.
Abstract:
Background: Letermovir is approved for prophylaxis of cytomegalovirus infection and disease in
cytomegalovirus-seropositive hematopoietic stem-cell transplant (HSCT) recipients.
Objective: HSCT recipients are required to take many drugs concomitantly. The pharmacokinetics, absorption,
distribution, metabolism, and excretion of letermovir and its potential to inhibit metabolizing enzymes and transporters
in vitro were investigated to inform on the potential for drug-drug interactions (DDIs).
Methods: A combination of in vitro and in vivo studies described the absorption, distribution, metabolism, and
routes of elimination of letermovir, as well as the enzymes and transporters involved in these processes. The
effect of letermovir to inhibit and induce metabolizing enzymes and transporters was evaluated in vitro and its
victim and perpetrator DDI potentials were predicted by applying the regulatory guidance for DDI assessment.
Results: Letermovir was a substrate of CYP3A4/5 and UGT1A1/3 in vitro. Letermovir showed concentration-
dependent uptake into organic anionic transporting polypeptide (OATP)1B1/3-transfected cells and was a
substrate of P-glycoprotein (P-gp). In a human ADME study, letermovir was primarily recovered as unchanged
drug and minor amounts of a direct glucuronide in feces. Based on the metabolic pathway profiling of letermovir,
there were few oxidative metabolites in human matrix. Letermovir inhibited CYP2B6, CYP2C8,
CYP3A, and UGT1A1 in vitro, and induced CYP3A4 and CYP2B6 in hepatocytes. Letermovir also inhibited
OATP1B1/3, OATP2B1, OAT3, OCT2, BCRP, BSEP, and P-gp.
Conclusion: The body of work presented in this manuscript informed on the potential for DDIs when letermovir
is administered both intravenously and orally in HSCT recipients.
