No 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.

Letermovir is approved for use in cytomegalovirus-seropositive hematopoietic stem cell transplant recipients and is investigated in other transplant settings.Nonlinear pharmacokinetics (PKs) were observed in clinical studies after intravenous and oral dosing across a wide dose range, including the efficacious doses of 240 and 480 mg. A physiologically-based PK (PBPK) model for letermovir was built to develop a plausible explanation for the nonlinear PKs observed in clinical studies. In vitro studies suggested that letermovir elimination and distribution are mediated by saturable uridine glucuronosyltransferases (UGT)-metabolism and by saturable hepatic uptake via organic anion-transporting polypeptides (OATP) 1B. A sensitivity analysis of parameters describing the metabolism and distribution mechanisms indicated that the greater than dose-proportional increase in letermovir exposure is best described by a saturable OATP1B-mediated transport. This PBPK model was further used to evaluate the drug interaction potential between letermovir and everolimus, an immunosuppressant that may be co-administered with letermovir depending on regions. Because letermovir inhibits cytochrome P450 (CYP) 3A and everolimus is a known CYP3A substrate, an interaction when concomitantly administered is anticipated. The drug-drug interaction simulation confirmed that letermovir will likely increase everolimus are under the curve by 2.5-fold, consistent with the moderate increase in exposure observed with midazolam in the clinic. The output highlights the importance of drug monitoring, which is common clinical practice for everolimus to maintain safe and efficacious drug concentrations in the targeted patient population when concomitantly administered with letermovir.

Aim: To predict the impact of the different CYP2C9 and VKORC1 genotypes on warfarin–sorafenib interactions in whites and Asians. Materials & methods: The influences of the CYP2C9*1/*3 and VKORC1 -1639 A/A genotypes on increases in anticoagulation responses (International Normalized Ratio [INR]) in the presence of sorafenib were predicted using the population pharmacokinetic-pharmacodynamic (PK/PD) model in whites and Asians. Results: INRs were predicted to be 2.0–2.1- versus 1.8–1.9-times higher in the presence of sorafenib in the CYP2C9 ( *1/*1 vs *1/*3) groups than those for warfarin alone in both whites and Asians. INRs were also predicted to be 2.1–2.2- versus 1.9–2.1-times higher in the VKORC1 (GG or GA vs AA) groups. Conclusion: Warfarin–sorafenib interactions might be similar irrespective of CYP2C9 and VKORC1 genotypes or ethnicity.

Backgrounds: The anticoagulant activity of warfarin (R/S-WF) is due mainly to S-WF, which is primarily metabolized by CYP2C9. Previous reports have presented an increase in the International Normalized Ratio (INR) after concomitant administration of WF with sorafenib (SF), a tyrosine kinase inhibitor. However, few studies have focused on quantitative prediction of this INR increase. Objectives: We attempted to predict SF/S-WF concentrations, INR, and the optimal dose of WF in the presence of SF for Japanese patients, based on the metabolic interaction between WF and SF related to CYP2C9 inhibition. Methods: The previous population PK model of SF in the literature was employed to predict the SF concentration. The inhibition constant of SF for S-WF metabolism was determined in in vitro. The unbound fraction of SF in the liver was estimated using the published equation. The competitive inhibition model between WF and SF was incorporated into previously reported population PK-PD models of S-WF to predict the S-WF concentrations and INR. Based on these data, a population PK-PD model describing the interaction between WF and SF was developed using NONMEM. Clinical data and INR values were collected from the literature and used for the model evaluation. Results: The observed time course of INR retrieved from a patient given WF and SF was mostly within the 90% range of the predicted values. We predicted the SF/S-WF concentrations and INR after administration of WF (3 mg/d) alone and WF (3 mg/d) + SF (400 mg/d). It was found that the mean values of S-WF concentration and INR at steady state were 4.8 and 1.9 times greater in the presence of SF with WF, respectively, than those with WF alone. The predicted S-WF concentrations and INR after reduction in the WF dose in the presence of SF did not differ clinically among the regimens (WF 3 mg/d, WF 0.75 mg/d + SF 400 mg/d and WF 0.5 mg/d + SF 400 mg/d) (Figure 1). Conclusions: These results suggest that a reduction in the daily dose of WF (e.g., from 3 mg to 0.5 mg) might be mandatory when WF and SF are administered concomitantly.