Division of Infectious Diseases, University Hospital of Genevagrid.150338.c, Geneva, Switzerland.
Division of Hematology, Bone Marrow Transplant Unit, University Hospital of Genevagrid.150338.c and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Antimicrob Agents Chemother. 2022 Aug 16;66(8):e0065722. doi: 10.1128/aac.00657-22. Epub 2022 Jul 25.
With balanced safety-efficacy profile, letermovir anti-cytomegalovirus (CMV) prophylaxis is used in hematopoietic stem cell transplant recipients (HSCTR). We assessed feasibility and usefulness of letermovir therapeutic drug monitoring (TDM) in HSCTR. We performed a prospective observational study on letermovir-TDM including 40 consecutive adult CMV-seropositive allogeneic-HSCTR who received orally (PO) administered letermovir. Minimal blood concentrations of letermovir (C) were measured on days 3 and 7 postletermovir initiation and weekly thereafter. Letermovir-C remained stable during the first 70 days post-HSCT at a median of 286 μg/L (interquartile range, 131 to 591 μg/L), with large interpatient/intrapatient variability. No associations between breakthrough clinically significant CMV infection or detectable CMV DNAemia and letermovir-C were observed. Patients with letermovir-associated adverse events had higher letermovir-C than patients without (400 versus 266 μg/L, = 0.02). Letermovir-C was similar in patients with or without gastrointestinal symptoms (280 versus 300 μg/L, 0.49). Acute grade ≥2 GvHD was associated with higher letermovir-C (479 versus 248 μg/L, = 0.001), including gastrointestinal GvHD (499 versus 263 μg/L, = 0.004). Concomitantly administered posaconazole and cyclosporine were associated with higher letermovir-C (707 versus 259 μg/L, < 0.001 and 437 versus 248 μg/L, = 0.01, respectively). In multivariable analysis, both posaconazole (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.4 to 9.7; < 0.0001) and cyclosporine-adjusted letermovir dose at 240 mg daily (OR, 3.5; 95% CI, 1.4 to 9.0; = 0.01) were independently associated with higher letermovir-C. In conclusion, administration of PO letermovir led to measurable and relatively stable letermovir-C, without noticeable associations with clinical efficacy. Letermovir exposure was not affected by gastrointestinal symptoms, but with posaconazole and cyclosporine administration. Associations between letermovir and concomitantly administered agents and adverse events warrant additional clinical studies.
来特莫韦具有平衡的安全性和疗效，用于造血干细胞移植受者（HSCTR）的抗巨细胞病毒（CMV）预防。我们评估了来特莫韦治疗药物监测（TDM）在 HSCTR 中的可行性和实用性。我们对 40 例连续接受口服（PO）来特莫韦治疗的 CMV 阳性同种异体 HSCTR 进行了前瞻性观察研究。在来特莫韦开始后第 3 天和第 7 天以及此后每周测量来特莫韦的最小血药浓度（C）。在 HSCT 后 70 天内，来特莫韦-C 中位数保持稳定，为 286μg/L（四分位距，131 至 591μg/L），个体间/个体内变异性较大。未观察到来特莫韦-C 与突破性临床显著 CMV 感染或可检测到的 CMV DNA 血症之间存在关联。发生来特莫韦相关不良事件的患者的来特莫韦-C 高于无不良事件的患者（400 与 266μg/L，=0.02）。有胃肠道症状与无胃肠道症状的患者来特莫韦-C 相似（280 与 300μg/L，0.49）。急性≥2 级移植物抗宿主病（GVHD）与较高的来特莫韦-C 相关（479 与 248μg/L，=0.001），包括胃肠道 GVHD（499 与 263μg/L，=0.004）。同时给予泊沙康唑和环孢素与较高的来特莫韦-C 相关（707 与 259μg/L，<0.001 和 437 与 248μg/L，=0.01）。在多变量分析中，泊沙康唑（比值比[OR]，4.9；95%置信区间[CI]，2.4 至 9.7；<0.0001）和环孢素调整后的来特莫韦剂量为 240mg/天（OR，3.5；95%CI，1.4 至 9.0；=0.01）与较高的来特莫韦-C 独立相关。总之，PO 来特莫韦的给药导致可测量和相对稳定的来特莫韦-C，与临床疗效无明显关联。胃肠道症状不会影响来特莫韦的暴露，但会影响泊沙康唑和环孢素的给药。来特莫韦与同时给予的药物和不良事件之间的关联需要进一步的临床研究。
