Therapeutic Drug Monitoring of Orally Administered Letermovir Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Article Article scientifique Article Therapeutic Drug Monitoring of Orally Administered Letermovir Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients eng 2022-07-25 2022-08-16 author Royston Lena 0000-0003-2367-7682 Division of Infectious Diseases, University Hospital of Genevagrid.150338.c, Geneva, Switzerland. 658907 author Masouridi Levrat Stavroula Division of Hematology, Bone Marrow Transplant Unit, University Hospital of Genevagrid.150338.c and Faculty of Medicine, University of Geneva, Geneva, Switzerland. 844685 author Gotta Verena Division of Pediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, Basel, Switzerland. author Royston Eva Division of Hematology, Bone Marrow Transplant Unit, University Hospital of Genevagrid.150338.c and Faculty of Medicine, University of Geneva, Geneva, Switzerland. 729726 author Pressacco Brossier Caroline Division of Infectious Diseases, University Hospital of Genevagrid.150338.c, Geneva, Switzerland. 742780 author Abid Yasmine Division of Infectious Diseases, University Hospital of Genevagrid.150338.c, Geneva, Switzerland. 805902 author Tonoli David Division of Laboratory Medicine, University Hospital of Genevagrid.150338.c, Geneva, Switzerland. 664012 author Karmime Abderrahim Division of Laboratory Medicine, University Hospital of Genevagrid.150338.c, Geneva, Switzerland. 29133 author Jayo Murielle Division of Laboratory Medicine, University Hospital of Genevagrid.150338.c, Geneva, Switzerland. 114495 author Van Delden Christian Division of Infectious Diseases, University Hospital of Genevagrid.150338.c, Geneva, Switzerland. 24088 Département de médecine (DEMED) author Lescuyer Pierre 0000-0001-6986-8738 Division of Laboratory Medicine, University Hospital of Genevagrid.150338.c, Geneva, Switzerland. 562350 author Pfister Marc Division of Pediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, Basel, Switzerland. author Chalandon Yves 0000-0001-9341-8104 Division of Hematology, Bone Marrow Transplant Unit, University Hospital of Genevagrid.150338.c and Faculty of Medicine, University of Geneva, Geneva, Switzerland. 644957 Département de médecine (DEMED) author Neofytos Dionysios 0000-0001-6970-2869 Division of Infectious Diseases, University Hospital of Genevagrid.150338.c, Geneva, Switzerland. 911674 Département de médecine (DEMED) e0065722 10.1128/aac.00657-22 35876579 0066-4804 PMC9380536 https://journals.asm.org/doi/10.1128/aac.00657-22 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 (Ctrough) were measured on days 3 and 7 postletermovir initiation and weekly thereafter. Letermovir-Ctrough 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-Ctrough were observed. Patients with letermovir-associated adverse events had higher letermovir-Ctrough than patients without (400 versus 266 μg/L, P = 0.02). Letermovir-Ctrough was similar in patients with or without gastrointestinal symptoms (280 versus 300 μg/L, P = 0.49). Acute grade ≥2 GvHD was associated with higher letermovir-Ctrough (479 versus 248 μg/L, P = 0.001), including gastrointestinal GvHD (499 versus 263 μg/L, P = 0.004). Concomitantly administered posaconazole and cyclosporine were associated with higher letermovir-Ctrough (707 versus 259 μg/L, P < 0.001 and 437 versus 248 μg/L, P = 0.01, respectively). In multivariable analysis, both posaconazole (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.4 to 9.7; P < 0.0001) and cyclosporine-adjusted letermovir dose at 240 mg daily (OR, 3.5; 95% CI, 1.4 to 9.0; P = 0.01) were independently associated with higher letermovir-Ctrough. In conclusion, administration of PO letermovir led to measurable and relatively stable letermovir-Ctrough, 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. CMV Allogeneic hematopoietic stem cell transplant recipients Cytomegalovirus Letermovir Prophylaxis Therapeutic drug monitoring Acetates Adult Antiviral Agents Cyclosporins / therapeutic use Cytomegalovirus Infections / drug therapy Cytomegalovirus Infections / prevention & control Drug Monitoring Graft vs Host Disease / etiology Hematopoietic Stem Cell Transplantation / adverse effects Humans Quinazolines Transplant Recipients Dewey 616 56 Département de médecine 221 false 211 Auto-immunité, inflammation et athérosclérose 270 1216 Leucémie et transplantation allogénique de cellules souches hématopoïétiques 982 235 Perception du Quorum et gènes de virulence 301 Antimicrobial agents and chemotherapy 66 8 f5f76672-77e1-4912-a636-0e3dcfee5d16 Article (Published version) Public Article-scientifique-from-europePmc.pdf 1525248 application/pdf CC BY-4.0 31023bbb68974ddaa61596a1bc4e35244ba01967201170caf63303f21d380d68 31182428-0ca2-47bd-ac66-09974acbbbc0 Appendix Public aac.00657-22-s0001.pdf 109817 application/pdf Figure S1 e27638fadd904df2c1d2660aad44ba08f903b26fa657cdf748ad804732de6bea openAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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