Pharmacokinetics and safety of the anti‐human cytomegalovirus drug letermovir in subjects with hepatic impairment

Kropeit, Dirk; McCormick, David; Erb‐Zohar, Katharina; Моисеев, В С; Kobalava, Zhanna; Stobernack, Hans‐Peter; Zimmermann, Holger; Rübsamen‐Schaeff, Helga

doi:10.1111/bcp.13376

Cited by 29 publications

(17 citation statements)

References 15 publications

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“…Letermovir is contraindicated in persons receiving ergot alkaloids and in persons receiving certain statins along with cyclosporine [17]. Although letermovir is well tolerated in the setting of mild-to-moderate hepatic and renal impairment, it should be used with caution in severe hepatic impairment (ChildPugh Class C) and insufficient data exist to guide dose adjustments if the creatinine clearance is < 10 mL/min [18,19].…”

Section: Mechanism Of Action and Pharmacologymentioning

confidence: 99%

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

Hakki

2020

Curr Hematol Malig Rep

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Purpose of Review CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often limited by toxicities and resistance. Agents with novel mechanisms and favorable toxicity profiles are critically needed. We review recent developments in CMV antivirals and immune-based approaches to mitigating CMV infection. Recent Findings Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, is currently in two phase 3 treatment studies. Adoptive immunotherapy using third-party T cells has proven safe and effective in preliminary studies. Vaccine development continues, with several promising candidates currently under study. Summary No longer limited to DNA polymerase inhibitors, the prevention and treatment of CMV infections in the HCT recipient is a rapidly evolving field which should translate into improvements in CMV-related outcomes.

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Section: Mechanism Of Action and Pharmacologymentioning

confidence: 99%

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

Hakki

2020

Curr Hematol Malig Rep

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“…15 Letermovir undergoes hepatic metabolism and is excreted primarily via the liver by bile (this is further described, along with its other pharmacokinetic properties, below); therefore, impaired hepatic function may affect letermovir concentration and exposure. In a phase I trial by Kropeit and colleagues, 27 patients with moderate (Child Pugh Class B) and severe (Child Pugh Class C) hepatic impairment were found to have a 1.6-and 3.8-fold increase in the area under the receiver operating characteristic curve (AUC), respectively, compared with healthy subjects. 27 Although generally well tolerated, lower dosages of letermovir were used compared with the determined therapeutic dose.…”

Section: Dosing and Administrationmentioning

confidence: 99%

Letermovir and its role in the prevention of cytomegalovirus infection in seropositive patients receiving an allogeneic hematopoietic cell transplant

Shigle

Handy

2020

Therapeutic Advances in Hematology

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Cytomegalovirus (CMV) reactivation is one of the most common infections affecting allogeneic hematopoietic cell transplant recipients. Although available anti-CMV therapies have been evaluated for the prevention of CMV reactivation, their toxicity profile makes them unfavorable for use as primary prophylaxis; thus, they are routinely reserved for the treatment of CMV viremia or CMV end-organ disease. Pre-emptive CMV monitoring strategies have been widely accepted, and although they have been helpful in early detection, they have not affected the overall morbidity and mortality associated with CMV. Letermovir is a novel agent that was approved for primary prophylaxis in CMV-seropositive adult allogeneic hematopoietic cell transplant recipients. This review focuses on letermovir’s novel mechanism; clinical trials supporting its United States Food and Drug Administration (FDA) approval and subsequent follow-up analyses; clinical considerations, with an emphasis on pharmacology; and lessons learned from solid organ transplant recipients, as well as potential future directions.

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“…Although no compounds currently target pUL104, several compounds have been described that prevent encapsidation by inhibiting the viral terminase . Letermovir, a CMV‐specific terminase inhibitor in late stage development, showed no cross resistance with viral strains resistant to currently available drugs and few side effects in clinical trials . Letermovir provides proof of principle that nonnucleoside, small molecule compounds that inhibit DNA encapsidation are viable drug candidates.…”

Section: Human Cytomegalovirusmentioning

confidence: 99%

Human herpesvirus portal proteins: Structure, function, and antiviral prospects

Kornfeind

Visalli

2018

Reviews in Medical Virology

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Herpesviruses (Herpesvirales) and tailed bacteriophages (Caudovirales) package their dsDNA genomes through an evolutionarily conserved mechanism. Much is known about the biochemistry and structural biology of phage portal proteins and the DNA encapsidation (viral genome cleavage and packaging) process. Although not at the same level of detail, studies on HSV-1, CMV, VZV, and HHV-8 have revealed important information on the function and structure of herpesvirus portal proteins. During dsDNA phage and herpesviral genome replication, concatamers of viral dsDNA are cleaved into single length units by a virus-encoded terminase and packaged into preformed procapsids through a channel located at a single capsid vertex (portal). Oligomeric portals are formed by the interaction of identical portal protein monomers. Comparing portal protein primary aa sequences between phage and herpesviruses reveals little to no sequence similarity. In contrast, the secondary and tertiary structures of known portals are remarkable. In all cases, function is highly conserved in that portals are essential for DNA packaging and also play a role in releasing viral genomic DNA during infection. Preclinical studies have described small molecules that target the HSV-1 and VZV portals and prevent viral replication by inhibiting encapsidation. This review summarizes what is known concerning the structure and function of herpesvirus portal proteins primarily based on their conserved bacteriophage counterparts and the potential to develop novel portal-specific DNA encapsidation inhibitors.

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Pharmacokinetics and safety of the anti‐human cytomegalovirus drug letermovir in subjects with hepatic impairment

Abstract: Moderate hepatic impairment increased exposure to letermovir <2-fold, while severe hepatic impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment.

Cited by 29 publications

References 15 publications

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

Letermovir and its role in the prevention of cytomegalovirus infection in seropositive patients receiving an allogeneic hematopoietic cell transplant

Human herpesvirus portal proteins: Structure, function, and antiviral prospects

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