Lack of a Significant Pharmacokinetic Interaction between Letermovir and Calcineurin Inhibitors in Allogeneic HCT Recipients

Abstract

Background Letermovir (LET) is approved for the prophylaxis of cytomegalovirus (CMV) in allogeneic hematopoietic cell transplantation (allo-HCT) patients. LET is a weak-moderate CYP3A4 inhibitor, which may impact calcineurin inhibitor (CNI) levels. In the phase 1 trial, LET caused an increase in maximum plasma concentrations (Cmax) of CSA and tacrolimus by 37% and 70%, respectively. There are no data to correlate how the Cmax increase in the presence of LET may affect CNI trough levels. Methods A retrospective review was conducted to evaluate the effect of LET on CNI trough levels and determine if empiric dose adjustments are needed. Patients ≥ 18 years were included if they received an allo-HCT with a CNI from February to June 2018 and received LET 480 mg daily or 240mg daily for tacrolimus- or CSA-based GVHD prophylaxis, respectively. The primary endpoint was percent change in concentration to dose (C/D) ratio over the 7-day period after initiation of LET. The C/D ratio allows for an analysis of the effect on trough levels at any given dose, which we would expect to rise upon initiation of LET due to CYP inhibition. LET reaches steady state in 36-60 hours; therefore, C/D percent changes were evaluated both from baseline to 4 days post-LET and from day 4 to day 7. Results Thirty-four patients (median age 53, range 24-75) were included in the analysis, with 24 (70.6%) patients receiving a tacrolimus-based graft-versus-host disease (GVHD) prophylaxis and 10 (29.4%) patients receiving CSA-based GVHD prophylaxis. There were 8 (24%) umbilical cord blood transplants, 10 (29%) haploidentical HCTs, and 16 (47%) conventional HCTs, with 14 patients (41%) receiving myeloablative conditioning. LET was initiated on a median of day 7 (range 6-30) post-HCT, and 23 patients (68%) received the drug orally. In the 10 patients who received CSA, there was an average of 3.8 (range 1-6) dose changes over 7 days. From baseline to 4 days post-LET, the mean percent change in C/D ratio was +15.9%, with a subsequent -10.0% change in C/D ratio from day 4 to day 7. In the 24 patients who received tacrolimus, there was an average of 2.2 (range 0-5) dose changes over 7 days. From baseline to 4 days post-LET, the mean percent change in C/D ratio was +20.4%, with a subsequent -18.9% change in C/D ratio from day 4 to day 7. Days 0 to 7 trough levels for all patients are displayed in Figures 1 and 2. Conclusion An empiric dose reduction in CNIs upon initiation of LET does not appear to be warranted based on this pilot study. An increase in trough levels is seen within 4 days after initiation of LET; however, the increase seems marginal and is compensated for by adjusting doses based on levels, which is the standard of care. Larger studies are needed to assess additional factors that may affect this drug-drug interaction.