Drug–drug interaction between letermovir and ciclosporin in allogeneic haematopoietic cell transplantation recipients

Letermovir, a cytomegalovirus prophylactic agent, is widely used in allogeneic HSCT recipients. As an inhibitor of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), it may interact with ciclosporin A (CsA), potentially impacting its pharmacokinetics. Inflammation can impair CYP3A-mediated drug metabolism, with severe inflammation reducing CsA metabolism. However, current data on the drug-drug interaction (DDI) between CsA and letermovir as a perpetrator are limited to healthy volunteers and lack evaluation in HSCT patients, particularly under minimal inflammation conditions, where such DDIs may occur. This retrospective, observational, single-centre study included seven adult HSCT recipients who received CsA and letermovir concurrently with no-to-mild inflammation (C-reactive protein ≤40 mg/L). CsA concentration/dose (C/D) ratios were calculated before and after letermovir initiation. Changes in CsA pharmacokinetics were analysed using Wilcoxon signed-rank tests. A 240 mg dose of letermovir once daily significantly increased the median CsA C/D ratio from 0.39 to 0.90 (P = 0.0156) and the median CsA trough concentration from 136 µg/L to 240 µg/L (P = 0.0156). These changes were attributed to CYP3A4 inhibition by letermovir, given the stable no-to-mild inflammatory status and the lack of additional DDI. Letermovir significantly decreased CsA metabolism in HSCT patients through CYP3A4 inhibition, with clinical implications for dosing precision. Close therapeutic drug monitoring (generally twice weekly) is therefore recommended during letermovir initiation and discontinuation to mitigate risks of subtherapeutic levels or toxicity. This study highlights the significance of assessing DDIs in HSCT, where inflammation modulates metabolic interactions resulting in a complex interplay such as a disease-drug-drug interaction (D-DDI).