LAUSR

Kropeit et al reported drug-drug interactions between letermovir and the immunosuppressive agents cyclosporin A and tacrolimus (Tac) in healthy subjects.1 According to this report, maximum drug concentration (Cmax) of Tac or total exposure to Tac increased by less than 2-fold after the oral administration of Tac (5 mg) plus letermovir (80 mg, twice daily). However, given that maximum drug concentration time (Tmax) and biological half-life (t1/2) of Tac were not affected by letermovir, it is speculated that the absorption of Tac was increased by this combination. However, there are no data on the effects of the coadministration of these drugs in hematopoietic stem cell transplantation (HSCT) patients. Here, we report 3 HSCT cases treated with letermovir. Blood concentrations of Tac were determined by the chemiluminescence magnetic microparticle immunoassay using the Architect-i1000 system (Abbott Laboratories, Abbott Park, Illinois) according to the manufacturer’s instructions. In case 1, before initiating letermovir treatment, we predicted that the blood concentration of Tac would be maintained at the target level by continued administration of the initial dose of Tac. However, the blood concentrations of Tac significantly increased on the second day after the administration of letermovir, even when Tac was administered as previously done. When combined with letermovir, the target level of Tac was achieved by a 33% reduction in the dose of Tac, and the blood concentrations became stable (Figure 1A). In case 2, based on the outcomes of case 1, we reduced the dose of Tac by 70% from the beginning of letermovir administration, and the blood concentration was carefullymonitored.When letermovir was switched to intravenous infusion because of difficulties in oral administration, Tac blood concentration sharply increased by 1.5 times, suggesting a 50% dose reduction (Figure 1B). In case 3, we administered letermovir from day 17 along with Tac and voriconazole (VRCZ). Although VRCZ also increased the concentration of TAC by inhibiting cytochrome P450 (CYP) 3A4 and letermovir, the blood concentration of TAC did not fluctuate greatly because its dose was reduced by 70 % (Figure 1C). Our study suggests that letermovir inhibited CYP3A4 and increased the Tac blood concentration by 1.5to 2-fold regardless of the route of administration. Tac concentration increased the next day following the oral administration of letermovir, and the maximum concentration was observed within 5-6 days. When Tac concentrations were maintained at 10-20 ng/mL immediately after HSCT, the blood concentration of the drug doubled, which is dangerous. To avoid this, Tac should be administered with consideration of drug-drug interaction, particularly based on the assumption that CYP3A4 inhibitory action occurs from the next day after oral administration of letermovir. There should be careful monitoring of the combined use of letermovir and Tac in cases in which Tac blood concentration is at a high level immediately after HSCT.