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

Abstract

1263W94 [maribavir; 5,6-dichloro-2-(isopropylamino)-1, ␤-L-ribofuranosyl-1-H-benzimidazole], a novel benzimidazole compound, has been demonstrated to potently and selectively inhibit human cytomegalovirus replication in vitro and to have favorable safety profiles in animal species. Two phase I trials evaluated the safety and pharmacokinetics of escalating single doses of 1263W94 in 13 healthy subjects (dose, 50 to 1,600 mg) and 17 human immunodeficiency virus (HIV)-infected subjects (dose, 100 to 1,600 mg). No severe safety concerns were observed in the evaluation of adverse events, vital signs, electrocardiograms, and clinical laboratory tests following administration of a single dose of 1263W94. The most frequently reported adverse events in both populations were taste disturbance (80%) and headache (53%). 1263W94 was rapidly absorbed following oral administration, with peak concentrations in plasma (C max ) occurring 1 to 3 h after dosing. The increases in the C max of 1263W94 and the area under the concentration-time curve from time zero to infinity (AUC 0-ؕ ) for 1263W94 were dose dependent; C max increased slightly less than proportionally to the dose, and AUC 0-ؕ increased slightly more than proportionally to the dose. 1263W94 was rapidly eliminated, with a mean half-life in plasma of 3 to 5 h; the half-life was independent of the dose level. Less than 2% of the 1263W94 dose administered was eliminated unchanged in urine. The principal metabolite of 1263W94 was 4469W94 (which is derived by N-dealkylation of 1263W94 via CYP3A4), which accounted for 30 to 40% of the dose in urine. Greater than 98% of the 1263W94 in plasma is bound to proteins, and the extent of binding appears to be constant over the dose range of 200 to 1,600 mg. In the trial with HIV-infected subjects, consumption of a high-fat meal decreased the 1263W94 AUC 0-ؕ and C max in plasma by ϳ30%.

Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase

“…Maribavir, a specific inhibitor of UL97 kinase activity, is currently being evaluated for approval as an antiviral agent against HCMV disease (10,11,47,48). Thus, the results presented here help establish a likely mechanism by which inhibition of UL97 may provide its therapeutic efficacy in patients (11,48).…”

Human Cytomegalovirus Protein Kinase UL97 Forms a Complex with the Tegument Phosphoprotein pp65

“…Nonetheless, UL97 is a protein serine-threonine kinase (22). Maribavir, a specific inhibitor of UL97 protein kinase activity (6,8), greatly inhibits viral replication and has shown promise as an anti-HCMV therapeutic agent in clinical trials (30,56). Therefore, UL97 is an important antiviral drug target.…”

Protein Array Identification of Substrates of the Epstein-Barr Virus Protein Kinase BGLF4

“…The protein kinases phosphorylate both viral and host proteins (16,21,42) and are necessary for efficient virus lytic replication. Consequently, these kinases have been of interest as potential targets for antiviral drug development (37), and the compound 1263W94 (maribavir), which inhibits the cytomegalovirus UL97 protein (3), has been used in phase I clinical trials (27,31,47).…”