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.
1263W94 [maribavir; 5,6-dichloro-2-(isopropylamino)-1,beta-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 log(10) 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.
Lalezari
Jacob P
JP
Quest Clinical Research, San Francisco, California, USA.
Aberg
Judith A
JA
Wang
Laurene H
LH
Wire
Mary Beth
MB
Miner
Richard
R
Snowden
Wendy
W
Talarico
Christine L
CL
Shaw
Shuching
S
Jacobson
Mark A
MA
Drew
W Lawrence
WL
D000328:Adult; D019540:Area Under Curve; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002478:Cells, Cultured; D003470:Culture Media; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000821:virology; D004279:DNA, Viral / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012263:Ribonucleosides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012661:Semen / Q000821:virology; D014556:Urine / Q000821:virology; D010948:Viral Plaque Assay; D017201:Virus Shedding; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives
D001562:Benzimidazoles; D003470:Culture Media; D004279:DNA, Viral; D012263:Ribonucleosides; C400401:maribavir; D004004:Dichlororibofuranosylbenzimidazole