1 Introduction
Compound | IC50 (nM) | pIC50 (nM)a
| ||
---|---|---|---|---|
SGLT2 | SGLT1 | SGLT2 | SGLT1 | |
Empagliflozin | 3.1 | 8,300 | 8.50 ± 0.02 | 5.08 ± 0.03 |
Dapagliflozin | 1.2 | 1,400 | 8.94 ± 0.06 | 5.86 ± 0.07 |
Canagliflozin | 2.7 | 710 | 8.56 ± 0.02 | 6.15 ± 0.06 |
Ipragliflozin | 5.3 | 3,000 | 8.27 ± 0.04 | 5.53 ± 0.02 |
Tofogliflozin | 6.4 | 12,000 | 8.18 ± 0.12 | 4.92 ± 0.09 |
2 Clinical Pharmacokinetics
Study | Subject number (study details) | Empagliflozin dose (mg) |
Cmax (nmol/L) | AUC (nmol·h/L) |
tmax (h) |
t½ (h) | CLR (mL/min) |
---|---|---|---|---|---|---|---|
Healthy volunteers, single dose | |||||||
Seman et al. [19]a
|
n = 72 (6 active + 2 placebo per dose group); males | ||||||
6c
| 0.5 | 9.33 (3.73) | 61.2 (17.2)f
| 1.5 (1.0–3.0) | 5.6 (0.7) | 51.3 (11.5)g
| |
6 | 2.5 | 53.2 (6.23) | 393 (43.4)f
| 1.8 (1.0–3.0) | 8.6 (0.6) | 41.3 (9.1)g
| |
6 | 10 | 226 (46.0) | 1,730 (377)f
| 1.5 (1.0–2.0) | 13.1 (4.0) | 41.1 (4.1)g
| |
6 | 25 | 505 (130) | 3,830 (825)f
| 2.1 (1.0–3.0) | 10.2 (2.1) | 37.7 (9.4)g
| |
5c
| 50 | 1,110 (274) | 8,580 (1,680)f
| 1.5 (0.8–3.0) | 10.3 (1.8) | 32.1 (7.3)g
| |
5 | 50 (OGTT) | 951 (300) | 8,090 (1,240)f
| 1.5 (1.5–6.0) | 8.8 (1.9) | 35.5 (8.9)g
| |
5 | 100 | 2,500 (666) | 16,500 (2,390)f
| 1.0 (0.8–3.0) | 10.6 (2.5) | 40.7 (9.1)g
| |
6 | 200 | 3,490 (816) | 31,200 (6,260)f
| 1.8 (1.0–3.0) | 11.1 (2.6) | 45.6 (9.1)g
| |
6 | 400 | 6,060 (1,720) | 46,600 (10,200)f
| 2.0 (0.8–4.0) | 11.2 (3.6) | 49.5 (9.8)g
| |
6 | 800 | 7,950 (1,820) | 70,200 (9,510)f
| 1.5 (0.7–2.0) | 11.2 (1.6) | 47.3 (10.0)g
| |
Sarashina et al. [20]b
|
n = 48 (6 active + 2 placebo per dose group); Japanese males | ||||||
6 | 1 | 36.6 (23.9) | 266 (23.1)f
| 1.25 (1.00–2.00) | 7.76 (13.9) | 32.4 (20.2)g
| |
6 | 5 | 166 (26.6) | 1,140 (10.2)f
| 2.00 (0.75–2.00) | 9.60 (19.9) | 36.5 (9.57)g
| |
6 | 10 | 379 (19.4) | 2,670 (10.6)f
| 1.50 (1.00–3.00) | 9.88 (29.7) | 29.9 (16.2)g
| |
6 | 10 (OGTT) | 449 (28.9) | 3,000 (14.1)f
| 1.75 (0.75–4.00) | 7.78 (12.7) | 35.3 (10.2)g
| |
6 | 25 | 661 (10.4) | 6,180 (13.4)f
| 2.00 (1.00–4.00) | 11.7 (30.1) | 34.8 (16.8)g
| |
6 | 100 | 2,980 (31.2) | 22,800 (25.5)f
| 2.50 (0.75–4.00) | 11.6 (31.9) | 38.7 (19.0)g
| |
Patients with T2DM, multiple steady-state dose | |||||||
Heise et al. [22]a
|
n = 48 (36 active + 12 placebo); duration 8 daysd
| ||||||
9 | 2.5 (day 1, single dose) | 62.4 (12.3) | 402 (68) | 1.5 (0.7–1.5) | 11.4 (2.3) | 29.1 (15.1) | |
9 | 10 (day 1, single dose) | 245 (51.5) | 1,630 (231) | 1.5 (1.0–2.0) | 11.9 (1.4) | 24.5 (6.6) | |
9 | 25 (day 1, single dose) | 606 (147) | 4,310 (1,040) | 1.5 (1.0–4.0) | 10.8 (2.0) | 21.1 (11.1) | |
9 | 100 (day 1, single dose) | 2,750 (701) | 20,000 (3,640) | 3.0 (1.0–4.0) | 13.6 (3.7) | 15.0 (5.9) | |
9 | 2.5 (day 9, steady state) | 68.5 (16.8) | 471 (108) | 1.5 (1.0–2.0) | 10.3 (1.9) | 33.3 (18.4) | |
8 | 10 (day 9, steady state) | 283 (90.1) | 2,030 (362) | 1.5 (1.0–2.0) | 14.3 (2.4) | 34.4 (18.4) | |
9 | 25 (day 9, steady state) | 630 (106) | 4,990 (1,080) | 2.0 (0.7–4.2) | 10.7 (2.1) | 23.5 (8.7) | |
8 | 100 (day 9, steady state) | 2,750 (605) | 22,800 (5,700) | 1.75 (1.0–4.0) | 18.8 (10.5) | 27.4 (16.9) | |
Heise et al. [23]b
|
n = 78 (including 16 placebo); duration 28 dayse
| ||||||
16 | 10 (day 1, single dose) | 309 (45.2) | 1,550 (16.2) | 1.5 (1.0–2.5) | 8.8 (13.0) | 30.1 (25.1) | |
16 | 25 (day 1, single dose) | 722 (20.0) | 3,930 (22.9) | 1.5 (0.8–2.0) | 8.2 (14.9) | 32.4 (28.1) | |
30 | 100 (day 1, single dose) | 2,630 (25.8) | 15,900 (21.2) | 1.5 (0.8–3.0) | 8.7 (18.7) | 33.0 (39.3) | |
16 | 10 (day 28, steady state) | 259 (24.8) | 1,870 (15.9) | 1.5 (1.0–4.0) | 13.2 (44.7) | 37.0 (31.1) | |
16 | 25 (day 28, steady state) | 687 (18.4) | 4,740 (21.2) | 1.5 (0.8–3.0) | 13.3 (32.6) | 36.2 (26.3) | |
30 | 100 (day 28, steady state) | 2,390 (28.1) | 18,700 (25.2) | 1.5 (0.8–6.0) | 16.5 (47.9) | 36.5 (35.2) | |
Special populations, single dose | |||||||
Macha et al. [26]b
|
n = 36; mild–severe hepatic impairment, plus controls (normal hepatic function) | ||||||
12, normal | 50 | 1,370 (33.9) | 10,800 (22.6)f
| 2.0 (1.0–4.0) | 19.9 (43.1) | 28.7 (30.3)g
| |
8, mild | 50 | 1,430 (36.8) | 13,800 (38.6)f
| 1.5 (0.7–4.0) | 18.1 (25.9) | 23.7 (48.0)g
| |
8, moderate | 50 | 1,660 (26.4) | 16,100 (26.2)f
| 2.0 (0.7–2.5) | 17.1 (45.9) | 19.9 (36.8)g
| |
8, severe | 50 | 1,970 (22.1) | 19,000 (27.1)f
| 1.5 (0.7–2.5) | 17.7 (67.4) | 21.3 (37.1)g
| |
Macha et al. [24]b
|
n = 40; mild–severe renal impairment, renal failure/ESRD, plus controls (normal renal function) | ||||||
8, normal | 50 | 1,240 (23.5) | 10,600 (16.4)f
| 1.0 (1.0–3.0) | 19.9 (58.8) | 28.5 (20.5)h
| |
9, mild | 50 | 1,500 (29.4) | 12,700 (20.8)f
| 2.5 (2.0–4.0) | 24.6 (84.5) | 18.6 (46.9)h
| |
7, moderate | 50 | 1,290 (37.9) | 13,000 (25.1)f
| 2.0 (1.5–3.0) | 23.8 (87.9) | 11.8 (69.6)h
| |
8, severe | 50 | 1,520 (31.6) | 17,700 (17.8)f
| 2.0 (0.7–4.0) | 27.9 (76.8) | 4.0 (30.6)h
| |
8, renal failure/ESRD | 50 | 1,290 (27.5) | 16,600 (38.7)f
| 2.5 (1.5–3.0) | 22.0 (74.3) | 0.5 (59.1)h
|
2.1 Healthy Subjects
2.2 Patients with Type 2 Diabetes Mellitus
3 Clinical Pharmacodynamics
3.1 Effects on Urinary Glucose Excretion
3.2 Effects on Plasma Glucose Concentration
4 Pharmacokinetics and Pharmacodynamics in Special Populations
4.1 Renal Impairment
4.2 Hepatic Impairment
5 Drug–Drug Interaction Studies
Study |
n
| EMPA, dose (mg) | Coadmin drug, dose | Effect of EMPA on coadmin drug exposurea
| Effect of coadmin drug on EMPA exposurea
| Dosing recommendations | |||
---|---|---|---|---|---|---|---|---|---|
C
max
| AUCτ,ss
|
C
max
| AUCτ,ss
| EMPA | Coadmin drug | ||||
Macha et al. [28] | 16 | 50 | Metformin, 1,000 mg | 103.6 (96.5–111.2) | 100.7 (95.9–105.6) | 100.5 (88.8–113.7) | 96.9 (92.3–101.7) | No change | No change |
Brand et al. [29] | 16 | 50 | Sitagliptin, 100 mg | 108.5 (100.7–116.9) | 103.1 (98.9–107.3) | 107.6 (97.0–119.4) | 110.4 (103.9–117.3) | No change | No change |
Friedrich et al. [30] | 16 | 50 | Linagliptin, 5 mg | 101 (87–119) | 103 (96–111) | 88 (79–99) | 102 (97–107) | No change | No change |
Macha et al. [31] | 16 | 50 | Glimepiride, 1 mg | 104.2 (89.5–121.3) | 93.3 (86.1–101.0)b
| 95.6 (88.2–103.5) | 95.2 (92.0–98.5) | No change | No change |
Macha et al. [32] | 18 | 25 | Warfarin, 25 mg |
R 97.89 (91.12–105.15) |
R 98.49 (95.29–101.80)b
| 100.64 (89.79–112.80) | 100.89 (96.86–105.10) | No change | No change |
S 98.88 (91.84–106.47) |
S 95.88 (93.40–98.43)b
| No change | No change | ||||||
Giessmann et al. [27] | 11 | 25 | HCTZ, 25 mg | 101.77 (88.63–116.85) | 96.27 (89.08–104.05) | 102.8 (88.6–119.3) | 107.1 (97.1–118.1) | No change | No change |
10 | 25 | Torasemide, 5 mg | 104.43 (93.81–116.25) | 101.44 (99.06–103.88) | 107.5 (97.9–118.0) | 107.8 (100.1–116.1) | No change | No change | |
Macha et al. [33] | 16 | 25 | Verapamil, 120 mg | Not stated | Not stated | 92.39 (85.38–99.37) | 102.95 (98.57–107.20)b
| No change | No change |
Macha et al. [33] | 23 | 25 | Ramipril, 2.5–5 mgc
| 103.61 (89.73–119.64) | 108.14 (100.51–116.35) | 104.47 (97.65–111.77) | 96.55 (93.05–100.18) | No change | No change |
Macha et al. [33] | 20 | 25 | Digoxin, 0.5 mg | 113.94 (99.33–130.70) | 106.11 (96.71–116.41)b
| Not stated | Not stated | No change | No change |
Macha et al. [34] | 18 | 25 | Simvastatin, 40 mg | 97.18 (76.30–123.77) | 101.26 (80.06–128.07)b
| 109.49 (96.91–123.69) | 102.05 (98.90–105.29)b
| No change | No change |
Macha et al. [35] | 18 | 25 | Ethinylestradiol, 30 μg | 99.2 (93.4–105.4) | 102.8 (97.6–108.4) | Not stated | Not stated | No change | No change |
25 | Levonorgestrel, 150 μg | 105.8 (99.5–112.6) | 101.9 (98.5–105.5) | Not stated | Not stated | No change | No change |