Fig 1.
N = number of subjects.
Fig 2.
Participants recruitment flowchart.
FDA = Food and Drug Administration; Max = maximum; SMC = Safety Monitoring Committee.
Fig 3.
Structural formula of UV-4 Hydrochloride.
Chemical structure of N-(9’-methoxynonyl)-1-deoxynojirimycin hydrochloride (UV-4B).
Table 1.
Demographics and Baseline Characteristics.
Table 2.
Summary of Subjects with Treatment-Emergent Adverse Events by Severity.
Table 3.
Summary of Subjects with Treatment-Emergent Adverse Events with Incidence Greater Than 5% Among UV-4-Treated Subjects.
Table 4.
Number of Subjects with Related Treatment-Emergent Adverse Events by System Organ Class and Preferred Term.
Fig 4.
UV-4 plasma concentration-time profiles.
A. Geometric mean (±SD) UV-4 concentration-time profiles are shown by UV-4 dose on semilogarithmic scale. Absorption was rapid (median Tmax of 0.5 to 1 hour) and dose independent. Maximum exposure increased approximately in proportion with dose. UV-4 concentrations were quantifiable over the entire 48-hour collection interval following administration of 10 mg or higher dose levels. Following administration of 3 mg UV-4, UV-4 concentrations were quantifiable for 24 hours in 5 of 6 subjects, and for 36 hours in one subject. B. Arithmetic mean (±SD) UV-4 concentration-time profiles are shown by UV-4 dose on linear scale. The graphic represents an expansion of the first 12 hours of sampling to better illustrate UV-4 initial absorption and distribution characteristics.
Table 5.
Summary of Key UV-4 Pharmacokinetic Parameters.
Fig 5.
Individual and Geometric Mean of Cmax versus Administered Dose.
A. Individual and geometric mean of Cmax represented using log-scale. Overall Cmax appears to increase in a dose proportional manner. B. Individual and geometric mean of Dose Normalized Cmax (DNCmax) (linear scale). There is considerable overlap in the range of individual DNCmax values, with a trend of a slightly greater than proportional increase in Cmax over the 3 to 180 mg UV-4 dose range. The range and mean DNCmax values were similar across the 360 to 1000 mg dose range. Dose proportionality was assessed utilizing a power model, the slope was approximately 1.1 over either the 333-fold (3 to 1000 mg) or the 33-fold (30 to 1000 mg) UV-4 dose range. The 90% CI estimates of 333-fold (1.078, 1.133) and 33-fold (1.048, 1.157) were not fully contained within the pre-specified confidence bounds (0.94, 1.06). Overall Cmax appears to increase in a generally dose proportional manner, especially at the higher doses of 360 mg and above.
Fig 6.
Individual and Geometric Mean AUC(0-inf) versus Administered Dose.
A. Individual and geometric mean of AUC(0-inf) represented using log-scale. Overall AUC(0-inf) appears to increase in a generally dose proportional manner. B. Individual and geometric mean Dose Normalized AUC(0-inf) (DNAUC(0-inf)) (linear scale). AUC(0-inf) increased in a dose-proportional manner over the 3 to 1000 mg (333-fold) UV-4 dose range. Mean`and individual range of DNAUC(0-inf) of 3 mg group was slightly lower compared to the subsequent dose levels (10 to 1000 mg), for which the individual range and mean DNAUC(0-inf) values were similar. Dose proportionality was assessed utilizing a power model. The slope was 1.033 when dose proportionality was assessed over the 333-fold dose range, but the 90% CI estimates (1.013, 1.053) were not fully contained within the pre-specified confidence bounds (0.96, 1.04). When the dose proportionality assessment was repeated over a 33-fold dose range (30 to 1000 mg), the slope was 1.013 and the 90% CI estimates (0.9837, 1.042) were fully contained within the pre-specified confidence bounds (0.94, 1.06). These data indicate that increases of AUC(0-inf) were dose proportional over the 30 to 1000 mg dose range.