Preclinical and Toxicology Studies of 1263W94, a Potent and Selective Inhibitor of Human Cytomegalovirus Replication

Abstract

1263W94 is a novel benzimidazole compound being developed for treatment of human cytomegalovirus infection. No adverse pharmacological effects were demonstrated in safety pharmacology studies with 1263W94. The minimal-effect dose in a 1-month rat study was 100 mg/kg/day, and the no-effect dose in a 1-month monkey study was 180 mg/kg/day. Toxic effects were limited to increases in liver weights, neutrophils, and monocytes at higher doses in female rats. 1263W94 was not genotoxic in the Ames or micronucleus assays. In the mouse lymphoma assay, 1263W94 was mutagenic in the absence of the rat liver S-9 metabolic activation system, with equivocal results in the presence of the S-9 mix. Mean oral bioavailability of 1263W94 was >90% in rats and ϳ50% in monkeys. Clearance in rats and monkeys was primarily by biliary secretion, with evidence of enterohepatic recirculation. In 1-month studies in rats and monkeys, mean peak concentrations and exposures to 1263W94 increased in near proportion to dose. Metabolism of 1263W94 to its primary metabolite, an N-dealkylated analog, appeared to be mediated via the isozyme CYP3A4 in humans. 1263W94 was primarily distributed in the gastrointestinal tract of rats but did not cross the blood-brain barrier. In monkeys, 1263W94 levels in the brain, cerebrospinal fluid, and vitreous humor ranged from 4 to 20%, 1 to 2%, and <1%, of corresponding concentrations in plasma, respectively. The high level of binding by 1263W94 to human plasma proteins (primarily albumin) was readily reversible, with less protein binding seen in the monkey, rat, and mouse. Results of these studies demonstrate a favorable safety profile for 1263W94.

Resistance of Human Cytomegalovirus to the Benzimidazole l -Ribonucleoside Maribavir Maps to UL27

“…Unlike TCRB, it is active against Epstein-Barr virus (42). Preclinical safety and pharmacokinetic studies with maribavir found it was well tolerated and established that the drug has good oral bioavailability and low toxicity compared to currently available HCMV drugs (21,25). Human studies yielded a good safety profile and established that maribavir reduced titers of HCMV in semen and urine from patients in a phase I/II clinical trial (25).…”

Phase I Safety and Pharmacokinetic Trials of 1263W94, a Novel Oral Anti-Human Cytomegalovirus Agent, in Healthy and Human Immunodeficiency Virus-Infected Subjects

“…1263W94 has been shown to have minimal cytotoxicity against bone marrow progenitors and various human leukemic cell lines in vitro (1,2) and limited toxicity in rats and monkeys (6). 1263W94 was rapidly and well absorbed in animals, with absolute oral bioavailabilities of ϳ90% in rats and ϳ50% in monkeys (6).…”

Mutations in the Human Cytomegalovirus UL27 Gene That Confer Resistance to Maribavir

“…Another subset of benzimidazoles is exemplified by the L-ribose derivative maribavir (1263W94). The drug is a potent inhibitor of CMV and Epstein-Barr virus, including CMV strains resistant to currently available drugs (4,9). Maribavir has good oral bioavailability, with few limiting side effects noted in a phase I clinical trial, which showed marked reduction in CMV shedding in semen at 4 weeks in human immunodeficiency virus-infected subjects (13).…”