Management of drug interaction issues of Letermovir among patients undergoing hematopoietic stem cell transplantation
Keywords:
Letermovir, Drug interaction, CMV infection, ProphylaxisAbstract
Cytomegalovirus (CMV) reactivation can occur after an allogeneic hematopoietic stem cell transplantation (allo-HSCT) during immunosuppressive use, and reactivation can cause severe end-organ disease leading to death. Determining CMV prevention strategies depends on several factors such as CMV serostatus, chemotherapy regimen, side effect of antivirals or drug availability. Antiviral drugs effective against CMV include acyclovir, valacyclovir, ganciclovir, valganciclovir, foscarnet and cidofovir. To prevent CMV, antiviral drugs are administered for an extended period. They may cause patients to experience adverse effects such as bone marrow suppression, abnormal electrolyte balance and impaired renal function. A pre-emptive treatment approach has been used in an HSCT population to avoid bone marrow suppression by antivirals. Letermovir is a new antiviral inhibiting CMV viral terminase complex and viral replication. Letermovir was approved for CMV prophylaxis among adult CMV-seropositive recipients [R+] of an allo-HSCT in 2017. Despite good tolerability, Letermovir may cause many drug-drug interactions by inhibiting CYP3A4, CYP2C8, P-gp, OAT1B1/3 and inducing CYP2C19 and CYP2C9. Therefore, surveillance and management of concomitant medications should be undertaken to maximize the efficiency and safety of patients receiving Letermovir
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Crough T, Khanna R. Immunobiology of human cyto megalovirus: from bench to bedside. Clin Microbiol Rev. 2009;22:76–98.
Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127:2427–38.
Ljungman P, de la Camara R, Robin C, Crocchiolo R, Einsele H, Hill JA, et al. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). The Lancet Infectious Diseases. 2019;19:e260-e72.
Sangmala P. The Systematic Review of Economic Evaluation of Oral Valganciclovir and Intravenous Ganciclovir for Cytomegalovirus (CMV) Prevention and Treatment in Transplant Recipients.Journal of Health Systems Research. 2018;12:500-14.
Gagelmann N, Ljungman P, Styczynski J, Kröger N. Comparative efficacy and safety of different antiviral agents for cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplantation: a systematic review and meta-analysis. Biology of Blood and Marrow Transplantation. 2018;24:2101–9.
Chen K, Cheng MP, Hammond SP, Einsele H, Marty FM. Antiviral prophylaxis for cytomegalovirus infec tion in allogeneic hematopoietic cell transplantation. Blood Advances. 2018;2:2159–75.
Boeckh M, Nichols WG, Chemaly RF, Papanicolaou GA, Wingard JR, Xie H, et al. Valganciclovir for the prevention of complications of late cytomegalovirus infection after allogeneic hematopoietic cell trans plantation. Ann Intern Med. 2015;162:1–10.
Marty FM, Winston DJ, Chemaly RF, Mullane KM, Shore TB, Papanicolaou GA, et al. A randomized, double-blind, placebo-controlled phase 3 trial of oral brincidofovir for cytomegalovirus prophylaxis in allo geneic hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation. 2019;25:369–81.
PREVYMIS™ (Letermovir). Package insert. Merck & Co., Inc; 2017. 10. Kropeit D, McCormick D, Erb-Zohar K, Stobernack HP, Zimmermann H, Rübsamen-Schaeff H. Pharmacokinetics and Safety of Letermovir and Midazolam Coadministration in Healthy Subjects. Clin Pharmacol Drug Dev. 2022;11:16-24.
Wang YH, Chen D, Hartmann G, Cho CR, Menzel K. PBPK Modeling Strategy for Predicting Complex Drug Interactions of Letermovir as a Perpetrator in Support of Product Labeling. Clin Pharmacol Ther. 2019;105:515-23.
Scheuenpflug J, Kropeit D, Erb-Zohar K, Theis JGW, Stobernack HP, McCormick D, et al. The Effect of Oral Letermovir Administration on the Pharmacokinetics of a Single Oral Dose of P-Glycoprotein Substrate Digoxin in Healthy Volunteers. Clin Pharmacol Drug Dev. 2022;11:6-15.
Goldner T, Hewlett G, Ettischer N, Ruebsamen-Schaeff H, Zimmermann H, Lischka P. The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol. 2011;85:10884-93.
Lischka P, Hewlett G, Wunberg T, Baumeister J, Paulsen D, Goldner T, et al. In Vitro and In Vivo Activities of the Novel Anticytomegalovirus Compound AIC246. Antimicrobial Agents and Chemotherapy. 2010;54:1290-7.
Kaul DR, Stoelben S, Cober E, Ojo T, Sandusky E, Lischka P, et al. First Report of Successful Treatment of Multidrug-Resistant Cytomegalovirus Disease with the Novel Anti-CMV Compound AIC246. American Journal of Transplantation. 2011;11:1079-84.
Chemaly RF, Ullmann AJ, Stoelben S, Richard MP, Bornhäuser M, Groth C, et al. Letermovir for Cytomegalovirus Prophylaxis in Hematopoietic-Cell Transplantation. New England Journal of Medicine. 2014;370:1781-9.
Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. New England Journal of Medicine. 2017;377:2433-44.
Kropeit D, von Richter O, Stobernack HP, Rübsamen-Schaeff H, Zimmermann H. Pharmacokinetics and Safety of Letermovir Coadministered With Cyclosporine A or Tacrolimus in Healthy Subjects. Clin Pharmacol Drug Dev. 2018;7:9-21.
Hedvat J, Choe JY, Salerno DM, Scheffert JL, Kovac D, Anamisis A, et al. Managing the significant drug-drug interaction between tacrolimus and Letermovir in solid organ transplant recipients. Clin Transplant. 2021;35:e14213.
McCrea JB, Macha S, Adedoyin A, Marshall W, Menzel K, Cho CR, et al. Pharmacokinetic Drug-Drug Interactions Between Letermovir and the Immunosuppressants Cyclosporine, Tacrolimus, Sirolimus, and Mycophenolate Mofetil. J Clin Pharmacol. 2019;59:1331-9.
Brüggemann RJ, Alffenaar JW, Blijlevens NM, Billaud EM, Kosterink JG, Verweij PE, et al. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis. 2009;48:1441-58.
Marshall WL, McCrea JB, Macha S, Menzel K, Liu F, van Schanke A, et al. Pharmacokinetics and Tolerability of Letermovir Coadministered With Azole Antifungals (Posaconazole or Voriconazole) in Healthy Subjects. J Clin Pharmacol. 2018;58:897-904.
Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos. 2003;31:540-7.
Duong A, Sweet A, Jain R, Hill JA, Pergam SA, Boeckh M, et al. Clinically significant drug interaction: Letermovir and voriconazole. J Antimicrob Chemother. 2020;75:775-7.
Miceli MH, Kauffman CA. Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent. Clinical Infectious Diseases. 2015;61:1558-65.
Terrier J, Zanella MC, Masouridi-Levrat S, Kronig I, Chalandon Y, Vernaz N, et al. Clinical and Pharmacological Considerations for Concomitant Administration of Posaconazole and Isavuconazole with Letermovir. Antimicrob Agents Chemother. 2021;65:e00274-21.
Adedoyin A, Fancourt C, Menzel K, Zhao T, Tomek C, Panebianco D, et al. Assessment of Pharmacokinetic Interaction Between Letermovir and Fluconazole in Healthy Participants. Clinical Pharmacology in Drug Development. 2021;10:198-206.
McCrea JB, Menzel K, Fancourt C, Witter R, Zhao T, Robbins JA, et al. Evaluation of the inhibitory effects of itraconazole on Letermovir. Br J Clin Pharmacol. 2023,89:2122-30.
Morrison VA. Echinocandin antifungals: review and update. Expert Rev Anti Infect Ther. 2006;4:325-42.
Bergan T. Pharmacokinetics of beta-lactam antibiotics. Scand J Infect Dis Suppl. 1984;42:83-98.
Lode H, Höffken G, Boeckk M, Deppermann N, Borner K, Koeppe P. Quinolone pharmacokinetics and metabolism. Journal of Antimicrobial Chemotherapy. 1990;26(suppl_B):41-9.
Menzel K, McCrea JB, Fancourt C, Witter R, Zhao T, Stoch SA, et al. A drug-drug interaction study with Letermovir and acyclovir in healthy participants. Br J Clin Pharmacol. 2023;89:1690-4.
Brown F, Banken L, Saywell K, Arum I. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers. Clin Pharmacokinet. 1999;37:167-76.
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