Results
Demographics
In the single-dose arm, a total of 61 subjects were enrolled, and 60
subjects completed the study. The mean (± standard deviation) age, body
weight and BMI of the randomized subjects were 30.75 ± 6.89 years, 71.06
± 7.48 kg, and 23.43 ± 2.06 kg/m2, respectively.
In the multiple-dose arm, 62 subjects were enrolled, and 60 subjects
completed the study. The mean (± standard deviation) age, body weight
and BMI of the randomized subjects were 30.84 ± 5.43 years, 70.72 ± 7.15
kg, and 23.47 ± 2.07 kg/m2, respectively. The
demographic characteristics were comparable among the dose groups for
both single and multiple arms.
Pharmacodynamics
In the single dose arm, UGE0-24h and
UGElast increased in a dose-dependent manner in the
range of 0.2 to 1.0 mg. UGE0-24h tended to be saturated
in the range of 1.0 mg to 5.0 mg of DWP16001, which was similar to that
of dapagliflozin 10 mg. Meanwhile, UGElast was higher
over 1.0 mg of DWP16001 than that of dapagliflozin (Figure 1,2 Table 1).
In the multiple dose arm, daily UGE reached a plateau at 50 - 60 g/day
at the steady state. The UGE was
higher with all doses of DWP16001 and dapagliflozin 10 mg compared with
placebo (Table S1). The mean UGE over 24 hours at steady state of 0.1
mg, 0.3 mg, 0.5 mg, 1.0 mg, and 2.0 mg DWP16001 were 36.1 g, 48.3 g,
55.1 g, 56.8 g, and 53.4 g, respectively, and the corresponding value of
dapagliflozin 10 mg was 40.5 g (Figure 1,2, Table 1).
In the OGTT after dosing for 14 consecutive days of DWP16001, the
Emax of the plasma glucose was lower than that of
baseline. The mean Emax changed from baseline of 0.1 mg,
0.3 mg, 0.5 mg, 1.0 mg and 2.0 mg DWP16001 were -27.5, -32.8, -7.8,
-23.9 and -17.4 mg/dL, respectively. These values were different from
-2.2 mg/dL of placebo, but similar to -21.6 mg/dL of dapagliflozin 10
mg. A similar pattern was observed for AUEC0-4h after
OGTT. The mean AUEC0-4h changed from baseline was
positive in placebo (4.3 mg*h/dL) , whereas 0.1 mg, 0.3 mg, 0.5 mg, 1.0
mg, 2.0 mg DWP16001 were -46.8, -55.6, -40.1, -54.0 and -21.9 mg*h/dL,
respectively. Postprandial insulin showed a decreasing tendency after
multiple doses, but it was not statistically significant
(Figure S1, Table S2).
Pharmacokinetics
DWP16001 was rapidly absorbed after a single dose with
Tmax between 1 and 3 h post-dose. After reached a
Tmax, plasma concentration of DWP16001 fell in a
biphasic manner with the elimination half-life of 11 to 28 hours (Figure
3). The t1/2 was tended to decrease as the dose of
DWP16001 increased (Table 2).
After multiple doses, the time-plasma concentration was similar to that
of the single-dose arm. The mean Tmax and
t1/2 at steady state were within a range of 1 to 2 hours
and 17 to 23 hours, respectively. After multiple administrations, the
95% CIs of the slope of the log-transformed Cmax,ss and
AUCtau,ss included 1.0 (0.98–1.10 and 0.98–1.09,
respectively), thus considered dose-proportional. The mean accumulation
index was approximately 1.6 to 1.9 over the range of 0.1 mg to 2.0 mg of
DWP16001. Less than 3 % of DWP16001 was excreted unchanged in the urine
at all doses (Table 2). The metabolic ratio of M1 ranged from 0.20 to
0.25. M2 was detected in very low amounts compared to the parent
molecules in all dose groups (Table S3).
PK-PD relationship
Drug exposure and UGE showed a clear exposure-response relationship. The
AUCtau and UGE over 24 h after the last dose were
correlated, with a Spearman correlation coefficient of 0.4061
(p=0.0002). The PK-PD relationship was well-explained by a sigmoid
Emax model, and the E0,
Emax, EC50, EC90, and γ
were calculated to be 0.1 g, 58.8 g, 31.8 μg·h/L, 58.4 μg·h/L, and 3.6,
respectively (Figure 4).
Effect of Food
After a high-fat meal was provided, the median Tmax was
prolonged from 1.3 to 2.5 hours, and the Cmax was
decreased approximately 43 % (GMR [90% CIs]: 0.57
[0.45–0.72]), compared to that of fasting state (Figure 5).
However, the AUCinf was similar between fed and fasting
state (GMR [90% CIs]: 0.97 [0.82–1.16]). The UGE was
comparable between fed and fasting state; GMR [90% CIs] of
UGE0-24h and UGElast were 0.80
[0.66–0.97] and 0.90 [0.68–1.19], respectively.
Safety and Tolerability
DWP16001 was found to be safe and tolerable in all dose groups, both in
single- and multiple-dose administration. In the single-dose arm,
treatment-emergent adverse events (TEAEs) were reported in 12 cases by 5
subjects who received DWP16001. In the multiple-dose arm, 27 cases were
reported in 13 subjects who received DWP16001, and four cases were
reported in three subjects who received placebo. Adverse drug reactions
(ADRs) that were determined to have a causal relationship with the
investigational product were reported in two cases from one subject in
the single-dose group and 22 cases from 12 subjects in the multiple-dose
group (Table 3). The most frequently reported ADRs were abdominal pain,
headache, and rhinorrhea. Abdominal pain was reported by three subjects
(1 in the 0.1 mg group and 2 in the 1.0 mg group). All TEAEs were mild
and spontaneously resolved. There were no serious adverse events, and no
subject withdrew from the study owing to adverse events.
No other clinically significant
changes were observed in the clinical laboratory tests, vital signs,
ECGs, or physical examinations.
Renal tubular marker [N-acetyl-β-D-glucosaminidase (NAG) and
β2-microglobulin (B2M)] tests were conducted in the multiple-dose arm.
Only one subject (DWP16001 2.0 mg group) had an increased B2M by more
than 0.5 µg/mL compared to the baseline, but it was found to be closer
to the baseline level in a post-study visit. The mean change in NAG and
B2M concentrations showed no significant increase across the different
dose groups (Table S4).