176161-24-3

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.

Treatment of cytomegalovirus infections (antiviral).

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.

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).