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

Abstract

Letermovir is a human cytomegalovirus terminase inhibitor for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients. The pharmacokinetics, safety, and tolerability of letermovir were assessed in healthy Japanese subjects in 2 phase 1 trials: trial 1—single ascending oral doses (240, 480, and 720 mg) and intravenous (IV) doses (240, 480, and 960 mg), and trial 2—multiple oral doses (240 and 480 mg once daily for 7 days). Following administration of oral single and multiple doses, letermovir was absorbed with a median time to maximum plasma concentration of 2 to 4 hours, and concentrations declined in a biphasic manner with a terminal half‐life of ≈10 to 13 hours. The post absorption plasma concentration–time profile of letermovir following oral administration was similar to the profile observed with IV dosing. There was minimal accumulation with multiple‐dose administration. Letermovir exposure in healthy Japanese subjects was ≈1.5‐ to 2.5‐fold higher than that observed in non‐Japanese subjects. Based on the population pharmacokinetic analysis, weight differences primarily accounted for the higher exposures observed in Asians. Letermovir was generally well tolerated following oral and IV administration to healthy Japanese subjects.

Developing a mechanistic understanding of the nonlinear pharmacokinetics of letermovir and prospective drug interaction with everolimus using physiological‐based pharmacokinetic modeling

“…The predictive performance of the letermovir PBPK model was assessed as follows: A visual predictive check (VPC) was performed assessing the ability of the PBPK model to describe the central tendency and variability in observed concentration‐time profiles of letermovir in phase I studies. The simulated versus observed PK parameters of letermovir over the dose range were numerically compared. The model should describe the dose nonlinearity, and the approximately two‐fold AUC exposure difference observed in Japanese subjects 6 . Thus, the AUC ratio (= simulated geometric mean exposure/observed arithmetic or geometric mean exposure) was targeted to fall within a predefined criteria of a two‐fold range. The ratio of simulated to observed C max after oral dosing was optimized to be less than two‐fold because the final PBPK model was intended to be used as the perpetrator model for CYP3A inhibition.…”

“…and oral formulation and exhibited greater than dose‐proportional increases in exposure after single and multiple i.v. and oral dosing in healthy subjects 4–6 . In vitro studies showed that letermovir is a substrate for the efflux transporter P‐glycoprotein (P‐gp) and the hepatic uptake transporters OATP1B1 and 1B3 and the metabolizing enzymes CYP3A, UGT1A1, and UGT1A3 7 .…”

Evaluation of the inhibitory effects of itraconazole on letermovir

“…Letermovir has high oral bioavailability (94% based on population pharmacokinetic [PK] analysis in healthy subjects) 6 and is rapidly absorbed with maximum plasma concentration ( C max ) reached 1.5–3 h after dosing 1 . Following peak concentrations, letermovir plasma levels decline in a biphasic manner 7 . Steady state is reached in 9–10 days, and the steady‐state terminal half‐life ( t ½ ) is approximately 12 h. Letermovir is eliminated primarily as unchanged parent in faeces and is partly eliminated by glucuronidation mediated by UDP‐glucuronosyltransferase (UGT)1A1 or UGT1A3 8 …”

Letermovir vs Valganciclovir for Cytomegalovirus Prophylaxis After Kidney Transplant

“…Letermovir, a substrate of organic anion-transporting polypeptide 1B1/3, acts as a moderate inhibitor of cytochrome P450 3A (CYP3A) . Letermovir has number of drug-drug interactions, and of substantial concern are its interactions with immunosuppressant agents, particularly those that are substrates of CYP3A.…”

“…Letermovir has number of drug-drug interactions, and of substantial concern are its interactions with immunosuppressant agents, particularly those that are substrates of CYP3A. When letermovir was coadministered with calcineurin inhibitors and mammalian target of rapamycin inhibitors, there was a marked increase in the plasma concentrations of these drugs . However, the available data on use of letermovir in solid organ transplant recipients remain limited.…”