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Antimicrobial Agents and Chemotherapy, September 2002, p. 2969-2976, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.2969-2976.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Phase I Dose Escalation Trial Evaluating the Pharmacokinetics, Anti-Human Cytomegalovirus (HCMV) Activity, and Safety of 1263W94 in Human Immunodeficiency Virus-Infected Men with Asymptomatic HCMV Shedding

Jacob P. Lalezari,1 Judith A. Aberg,2,{dagger} Laurene H. Wang,3,{ddagger} Mary Beth Wire,3* Richard Miner,4 Wendy Snowden,5 Christine L. Talarico,3 Shuching Shaw,3 Mark A. Jacobson,2 and W. Lawrence Drew4

Quest Clinical Research,1 Mount Zion Medical Center,4 San Francisco General Hospital, San Francisco, California,2 GlaxoSmithKline, Research Triangle Park, North Carolina,3 GlaxoSmithKline, Stevenage, United Kingdom5

Received 10 December 2001/ Returned for modification 26 February 2002/ Accepted 30 May 2002

1263W94 [maribavir; 5,6-dichloro-2-(isopropylamino)-1,ß-L-ribofuranosyl-1-H-benzimidazole] is a novel benzimidazole compound for treatment of human cytomegalovirus (HCMV) infection and disease, with potent in vitro activity against HCMV and good oral bioavailability. A phase I study was conducted to determine the pharmacokinetics (PK), anti-HCMV activity, and safety of 1263W94 administered as multiple oral doses to human immunodeficiency virus type 1-infected adult male subjects with asymptomatic HCMV shedding. Subjects received one of six dosage regimens (100, 200, or 400 mg three times a day, or 600, 900, or 1,200 mg twice a day) or a placebo for 28 days. 1263W94 demonstrated linear PK, with steady-state plasma 1263W94 profiles predictable based on single-dose data. 1263W94 was rapidly absorbed following oral dosing, and values for the maximum concentration of the drug in plasma and the area under the concentration-time curve increased in proportion to the dose. 1263W94 demonstrated in vivo anti-HCMV activity in semen at all of the dosage regimens tested, with mean reductions in semen HCMV titers of 2.9 to 3.7 log10 PFU/ml among the four regimens evaluated for anti-HCMV activity. 1263W94 was generally well tolerated; taste disturbance was the most frequently reported adverse event over the 28-day dosing period.

* Corresponding author. Mailing address: Clinical Pharmacology and Experimental Medicine, GlaxoSmithKline, 5 Moore Dr., 17.2214.2b, Research Triangle Park, NC 27709. Phone: (919) 483-2100. Fax: (919) 483-8948. E-mail: mbm27778{at}gsk.com.

{dagger} Present address: Washington University School of Medicine, St. Louis, MO 63141.

{ddagger} Present address: Triangle Pharmaceuticals, Durham, NC 27707.

Antimicrobial Agents and Chemotherapy, September 2002, p. 2969-2976, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.2969-2976.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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