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Antimicrobial Agents and Chemotherapy, April 2003, p. 1334-1342, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1334-1342.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Laurene H. Wang,1,{dagger} Richard W. Peck,2 Yin Yin,1 Jane Allanson,2 Rebecca Wiggs,2 and Mary Beth Wire1*

GlaxoSmithKline, Research Triangle Park, North Carolina,1 GlaxoSmithKline Research and Development, Greenford, Middlesex, United Kingdom2

Received 8 May 2002/ Returned for modification 22 July 2002/ Accepted 14 January 2003

1263W94 [maribavir; 5,6-dichloro-2-(isopropylamino)-1, ß-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 (Cmax) occurring 1 to 3 h after dosing. The increases in the Cmax of 1263W94 and the area under the concentration-time curve from time zero to infinity (AUC0-{infty}) for 1263W94 were dose dependent; Cmax increased slightly less than proportionally to the dose, and AUC0-{infty} 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 AUC0-{infty} and Cmax in plasma by ~30%.

* Corresponding author. Mailing address: Clinical Pharmacology, GlaxoSmithKline, 5 Moore Dr., 17.2214.2B, Research Triangle Park, NC 27709. Phone: (919) 483-5852. Fax: (919) 483-8948. E-mail: mbm27778{at}gsk.com.

{dagger} Present address: Triangle Pharmaceuticals, Inc., Durham, N.C.

Antimicrobial Agents and Chemotherapy, April 2003, p. 1334-1342, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1334-1342.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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