Absorption, Metabolism, Distribution, and Excretion of Letermovir

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 were 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.

Pharmacokinetics and Safety of Letermovir and Midazolam Coadministration in Healthy Subjects

“…25 The small amount of metabolites together with negligible amounts of drug-related material recovered in urine in a human absorption, distribution, metabolism, and excretion study supported that metabolism and renal excretion play a minor role in the elimination of letermovir. 25 In vitro studies have shown that letermovir is an inhibitor of cytochrome P450 (CYP) 3A4, CYP2C8, and uridine 5 -diphosphoglucuronosyltransferase 1A1/3 and of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein, as well as the hepatic uptake transporters OATP1B1/OATP1B3. 25 In particular, letermovir inactivated CYP3A4/5 (as measured by midazolam 1 -hydroxylation) with a K i value of 35 μM, a K inact value of 0.0473 min -1 and an efficiency (K inact /K i ) of 1.3 min -1 mM -1 .…”

“…25 In particular, letermovir inactivated CYP3A4/5 (as measured by midazolam 1 -hydroxylation) with a K i value of 35 μM, a K inact value of 0.0473 min -1 and an efficiency (K inact /K i ) of 1.3 min -1 mM -1 . 25 As letermovir is a dual inhibitor and inducer of CYP3A4 in vitro, the net effect of letermovir on CYP3A needed to be studied in a clinical DDI study with a CYP3A probe substrate such as midazolam. Clinical DDI studies with other CYP3A substrates, including cyclosporine A, tacrolimus, and sirolimus, have also been conducted, and these are addressed further in the Discussion section.…”

“…Therefore, it is reasonable to evaluate the potential for letermovir to cause drug-drug interactions (DDIs), and the clinical development program included a number of studies evaluating potential DDIs. 19,20,[22][23][24][25] The clearance of letermovir in humans is predominantly governed via organic anion transporting polypeptide 1B (OATP1B)-mediated uptake into the liver, the major organ of its elimination. 25 The small amount of metabolites together with negligible amounts of drug-related material recovered in urine in a human absorption, distribution, metabolism, and excretion study supported that metabolism and renal excretion play a minor role in the elimination of letermovir.…”

“…19,20,[22][23][24][25] The clearance of letermovir in humans is predominantly governed via organic anion transporting polypeptide 1B (OATP1B)-mediated uptake into the liver, the major organ of its elimination. 25 The small amount of metabolites together with negligible amounts of drug-related material recovered in urine in a human absorption, distribution, metabolism, and excretion study supported that metabolism and renal excretion play a minor role in the elimination of letermovir. 25 In vitro studies have shown that letermovir is an inhibitor of cytochrome P450 (CYP) 3A4, CYP2C8, and uridine 5 -diphosphoglucuronosyltransferase 1A1/3 and of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein, as well as the hepatic uptake transporters OATP1B1/OATP1B3.…”

“…25 In vitro studies have shown that letermovir is an inhibitor of cytochrome P450 (CYP) 3A4, CYP2C8, and uridine 5 -diphosphoglucuronosyltransferase 1A1/3 and of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein, as well as the hepatic uptake transporters OATP1B1/OATP1B3. 25 In particular, letermovir inactivated CYP3A4/5 (as measured by midazolam 1 -hydroxylation) with a K i value of 35 μM, a K inact value of 0.0473 min -1 and an efficiency (K inact /K i ) of 1.3 min -1 mM -1 . 25 As letermovir is a dual inhibitor and inducer of CYP3A4 in vitro, the net effect of letermovir on CYP3A needed to be studied in a clinical DDI study with a CYP3A probe substrate such as midazolam.…”