Role of Letermovir Therapeutic Drug Monitoring for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation Recipients: a Prospective Study

Overview

Journal Eur J Clin Microbiol Infect Dis

Publisher Springer

Specialties Infectious Diseases
Microbiology

Date 2024 Nov 9

PMID 39520621

Authors

Yulan Qiu

Xiaoning Wang

Juan Ren

Yijing Zhang

Chuqi Bai

Sasa Hu

Taotao Wang

Jiaojiao Chen

Chuhui Wang

Pengcheng He

Yalin Dong

Affiliations

Soon will be listed here.

Abstract

Purpose: The role of therapeutic drug monitoring (TDM) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receiving letermovir has not yet been clarified. This study is to explore letermovir trough concentration (C) correlation with its clinical efficacy and adverse events, and factors affecting its plasma concentrations.

Methods: A prospective, non-interventional study was performed in allo-HSCT recipients receiving letermovir prophylaxis. Plasma concentrations were determined using high-performance liquid chromatography-tandem mass spectrometry. Data analysis was performed using logistic regression, linear regression, and classification and regression tree (CART) models.

Results: 701 trough concentrations from 71 recipients were included, uncovering pronounced intra- and inter-individual variability in letermovir C. During 24-week follow-up, CMV infection incidence was 16.4%. A significant correlation was identified between letermovir C and its clinical efficacy, and the CART model showed an increased risk of CMV infection when C ≤ 2731 ng/mL. However, no clear correlation was found between C and adverse events. Gastrointestinal graft-versus-host disease, cyclosporine C, gender, and concomitant medications, including mycophenolate mofetil, ondansetron, caspofungin, and methylprednisolone, may impact letermovir C. Additionally, coadministration with cyclosporine injection significantly decreased median letermovir C compared with cyclosporine capsules (2311 vs. 3386 ng/mL). Moreover, with the extension of time post-transplant, trough concentrations of both cyclosporine and letermovir significantly decreased.

Conclusion: TDM for letermovir may be beneficial in allo-HSCT recipients considering the variability in letermovir C and its correlation with clinical efficacy. Moreover, drug interactions and the effects of changes in cyclosporine dosage forms or concentrations require careful monitoring for their effect on letermovir C.

References

Chang Y, Pei X, Huang X . Haematopoietic stem-cell transplantation in China in the era of targeted therapies: current advances, challenges, and future directions. Lancet Haematol. 2022; 9(12):e919-e929. DOI: 10.1016/S2352-3026(22)00293-9. View

Green M, Leisenring W, Xie H, Mast T, Cui Y, Sandmaier B . Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol. 2016; 3(3):e119-27. PMC: 4914379. DOI: 10.1016/S2352-3026(15)00289-6. View

Marr K, Carter R, Boeckh M, Martin P, Corey L . Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood. 2002; 100(13):4358-66. DOI: 10.1182/blood-2002-05-1496. View

Piret J, Boivin G . Clinical development of letermovir and maribavir: Overview of human cytomegalovirus drug resistance. Antiviral Res. 2019; 163:91-105. DOI: 10.1016/j.antiviral.2019.01.011. View

Prohn M, Viberg A, Zhang D, Dykstra K, Davis C, Macha S . Population pharmacokinetics of letermovir following oral and intravenous administration in healthy participants and allogeneic hematopoietic cell transplantation recipients. CPT Pharmacometrics Syst Pharmacol. 2021; 10(3):255-267. PMC: 7965833. DOI: 10.1002/psp4.12593. View

Prohn M, Cho C, Viberg A, Dykstra K, Davis C, Sabato P . Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients. Clin Pharmacol Ther. 2021; 111(2):485-495. DOI: 10.1002/cpt.2456. View

Royston L, Masouridi-Levrat S, Gotta V, Royston E, Pressacco-Brossier C, Abi Aad Y . Therapeutic Drug Monitoring of Orally Administered Letermovir Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients. Antimicrob Agents Chemother. 2022; 66(8):e0065722. PMC: 9380536. DOI: 10.1128/aac.00657-22. View

Menzel K, Kothare P, McCrea J, Chu X, Kropeit D . Absorption, Metabolism, Distribution, and Excretion of Letermovir. Curr Drug Metab. 2021; 22(10):784-794. DOI: 10.2174/1389200222666210223112826. View

Ljungman P, Boeckh M, Hirsch H, Josephson F, Lundgren J, Nichols G . Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2016; 64(1):87-91. DOI: 10.1093/cid/ciw668. View

10.

Isberner N, Aghai F, Schirmer D, Kraus S, Grigoleit G, Klinker H . Quantification of letermovir in human serum using high-performance liquid chromatography with diode array detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2020; 1159:122399. DOI: 10.1016/j.jchromb.2020.122399. View

11.

Manczak B, Verdier M, Dewulf J, Lemaitre F, Haufroid V, Hantson P . Lactic acidosis after allogeneic haematopoietic stem cell transplantation potentially related to letermovir. Br J Clin Pharmacol. 2023; 89(5):1686-1689. DOI: 10.1111/bcp.15686. View

12.

Marty F, Ljungman P, Chemaly R, Maertens J, Dadwal S, Duarte R . Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017; 377(25):2433-2444. DOI: 10.1056/NEJMoa1706640. View

13.

Geswein L . Letermovir associated hepatic transaminitis: A case report. J Oncol Pharm Pract. 2018; 25(5):1235-1238. DOI: 10.1177/1078155218783245. View

14.

Strenger V, Sperl D, Kubesch K, Donnerer J, Schwinger W, Zach K . Letermovir in paediatric HSCT recipients. J Antimicrob Chemother. 2019; 74(9):2820-2821. DOI: 10.1093/jac/dkz218. View

15.

Chemaly R, Ullmann A, Stoelben S, Richard M, Bornhauser M, Groth C . Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med. 2014; 370(19):1781-9. DOI: 10.1056/NEJMoa1309533. View

16.

Chalasani N, Bonkovsky H, Fontana R, Lee W, Stolz A, Talwalkar J . Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. Gastroenterology. 2015; 148(7):1340-52.e7. PMC: 4446235. DOI: 10.1053/j.gastro.2015.03.006. View

17.

Deleenheer B, Spriet I, Maertens J . Pharmacokinetic drug evaluation of letermovir prophylaxis for cytomegalovirus in hematopoietic stem cell transplantation. Expert Opin Drug Metab Toxicol. 2018; 14(12):1197-1207. DOI: 10.1080/17425255.2018.1550485. View

18.

Muller J, Keiser M, Drozdzik M, Oswald S . Expression, regulation and function of intestinal drug transporters: an update. Biol Chem. 2016; 398(2):175-192. DOI: 10.1515/hsz-2016-0259. View

19.

Oswald S . Organic Anion Transporting Polypeptide (OATP) transporter expression, localization and function in the human intestine. Pharmacol Ther. 2018; 195:39-53. DOI: 10.1016/j.pharmthera.2018.10.007. View

20.

McCrea J, Menzel K, Fancourt C, Witter R, Zhao T, Robbins J . Evaluation of the inhibitory effects of itraconazole on letermovir. Br J Clin Pharmacol. 2023; 89(7):2122-2130. DOI: 10.1111/bcp.15677. View