BENZIMIDAVIR

Absorption

Population pharmacokinetic modeling in patients receiving maribavir 400mg twice daily showed an AUC0-tau and Cmax of 128 μg.h/mL and 17.2 μg/mL, respectively. It has a median Tmax of one to three hours.

Toxicity

Data are limited regarding overdosage with maribavir. As there is no specific antidote for maribavir overdose, patients suspected of overdosage should be monitored closely for adverse reactions and treated symptomatically as clinically indicated. As maribavir is extensively protein-bound in plasma, dialysis is unlikely to be of benefit.

Description

Maribavir is an orally bioavailable benzimidazole L-riboside antiviral, with a spectrum of activity essentially limited to human cytomegalovirus (CMV) and Epstein–Barr virus (EBV). It is an inhibitor of the CMV UL97 kinase. As of 2008, maribavir was in phase III clinical trials for prevention of CMV infection in transplant recipients at risk. Earlier phase I and II trials of maribavir showed anti-CMV activity with an acceptable adverse effect profile. Investigational drug code names include 1263W94, BW1263-W94, GW257406X, and VP41263, reflecting changes in ownership during drug development. As of early 2009, the drug was being developed under ‘‘fast track’’ status granted by the US Food and Drug Administration, but the apparent failure of maribar prophylaxis to prevent CMV infection in stem cell transplant recipients in the definitive phase III clinical trial resulted in the sponsor halting ongoing clinical development.

The Uses of BENZIMIDAVIR

Treatment of cytomegalovirus infections (antiviral).

Background

Maribavir is an inhibitor of the cytomegalovirus (CMV; HHV5) pUL97 kinase which is used to treat CMV infections in patients post-transplantation. Most standard CMV therapies, such as ganciclovir or foscarnet, target CMV DNA polymerase - while generally effective, these medications tend to promote the development of CMV resistance to DNA polymerase-based therapies, and their use is often limited by toxicities like myelosuppression and renal injury. Maribavir is novel in that it instead targets the CMV pUL97 kinase, thereby providing an effective alternative treatment option in cases of resistant infections.
Maribavir was approved by the FDA in November 2021, under the name Livtencity (Takeda), for the treatment of resistant CMV infections in post-transplant patients. The drug was also approved by Health Canada in September 2022 and by European Commission in November 2022.

Indications

Maribavir is indicated for the treatment of post-transplant cytomegalovirus (CMV) infection (following hematopoietic stem cell transplant or solid organ transplant) which is refractory to standard treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet.
In the US, patients receiving the treatment should weigh more than 35 kg and be at least 12 years old. In Canada and Europe, maribavir is only approved in adults.

Mechanism of action

Maribavir inhibits the CMV UL97 kinase, an enzyme which is required for the normal replication of the virus . In the absence of functioning UL97 kinase, viral replication is severely impaired in vitro, with an abnormal cell culture cytopathic effect characterized by the nuclear aggregation of excess amorphous viral proteins, mainly the tegument protein pp65. Impaired UL97 function appears to cause a defect in viral encapsidation and/or egress of viral particles from the nucleus. In addition, viral DNA synthesis may also be reduced. CMV replication is not completely shut off in the absence of the UL97 kinase; the widely varying maribavir IC50s under different assay conditions suggest that host cells can variably substitute for the normal function of UL97, a factor that may affect the therapeutic potency of maribavir in vivo.

Pharmacokinetics

Maribavir exerts its antiviral efficacy via an alternative target as compared to traditional CMV antivirals and is thus useful in the treatment of CMV infections that have proven resistant to standard therapy.
Maribavir should not be used concomitantly with ganciclovir or valganciclovir, as these molecules both require activation via CMV pUL97 in order to exert their antiviral effect. Taking them alongside maribavir - an inhibitor of this same kinase - will therefore significantly reduce their antiviral activity.

Drug interactions

Since CYP3A4 appears to be the major maribavir-metabolizing enzyme, there are potential drug interactions with CYP3A4 inhibitors, such as azole antifungals, macrolide antibiotics, and HIV protease inhibitors, or CYP3A4 inducers, such as rifampicin or efavirenz. There are insufficient data to assess the clinical significance of this interaction. Phase I clinical trials examined the pharmacokinetics of maribavir in HIV-infected subjects, many of whom were concomitantly using antifungals and protease inhibitors. Overall, the pharmacokinetic data were not significantly different from those of healthy individuals not on these drugs. In healthy adults, oral administration of ketoconazole, a potent CYP3A4 inhibitor, resulted in a 35% decrease in the clearance of maribavir, which is not expected to have adverse consequences because of the low observed toxicity of maribavir. Further studies are required to assess potential impairment of antiviral activity by CYP3A4 inducers. Maribavir may have some inhibitory effect on cytochrome P450 isozymes, CYP2C19 and CYP2D6, as assessed after administration of multiple concurrently administered drug probes, including omeprazole (2C19) and dextromethorphan (2D6).

Metabolism

Maribavir is extensively metabolized following oral administration, primarily by CYP3A4 and, to a lesser extent, by CYP1A2. Its major circulating metabolite is VP 44469, an inactive N-dealkylated metabolite.