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

Abstract

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.

FIG. 1.

Plots of dose versus plasma 1263W94 AUC_∞ (a) and AUC_24,ss (b).

FIG. 2.

(a) Median concentration-time profiles of HCMV in semen, measured in PFU per milliliter by using plaque assays. Symbols: ○, 100 mg t.i.d. (n = 7); ▪, 200 mg t.i.d. (n = 5); ♦, 400 mg t.i.d. (n = 6); ▵, 600 mg b.i.d. (n = 6). (b) Median concentration-time profiles of HCMV DNA in semen, measured in log₁₀ copies per milliliter by using PCR analysis. Symbols: ○, 100 mg t.i.d. (n = 7); ▪, 200 mg t.i.d. (n = 4); ♦, 400 mg t.i.d. (n = 5); ▵, 600 mg b.i.d. (n = 2).