PL8177 is a melanocortin agonist being developed to treat inflammatory conditions. |
PL8177 had consistent pharmacokinetics and low accumulation with repeated dosing, supporting further development. |
1 Introduction
2 Methods
2.1 Preclinical Studies
2.1.1 Mouse
2.1.2 Rat
2.1.3 Dog
2.2 Healthy Volunteers
2.2.1 Subjects
2.2.2 Study Design
2.2.3 Analysis
2.3 Liquid Chromatography–Mass Spectrometry
3 Results
3.1 Preclinical Studies
3.1.1 Mouse
Parameter | Dose | ||
---|---|---|---|
3 mg/kg sc | 1 mg/kg sc | 1 mg/kg iv | |
A. Mouse | |||
AUC∞, ng·h/mL | 1727 | 476 | 753 |
Cmax, ng/mL | 2440 | 703 | NC |
CL/F, mL/min/kg | 22 | NC | NC |
t½, h | 0.5 | 0.26 | 0.2 |
tmax, h | 0.25 | 0.083 | NC |
F | – | 0.63 | – |
Dose mg/kg | Sex | tmax, h | Cmax (SE), ng/mL | AUClast (SE), ng·h/mL | t½, h | AUC∞, ng·h/mL | Vd/F, L/kg | CL/F, mL/min/kg |
---|---|---|---|---|---|---|---|---|
B. Rat PL8177 | ||||||||
Day 1 | ||||||||
1.0 | F | 0.5 | 516 (41.7) | 880 (59.4) | 0.749 | 907 | 1.19 | 18.4 |
M | 0.5 | 525 (86.7) | 1030 (78.4) | 0.868 | 1080 | 1.15 | 15.4 | |
5.0 | F | 0.5 | 1080 (36.8) | 4030 (122.0) | 5.91 | 4200 | 10.1 | 19.8 |
M | 1.0 | 1180 (59.7) | 4300 (146.0) | 6.12 | 4510 | 9.78 | 18.5 | |
25.0 | F | 0.25 | 782 (60.8) | 4920 (181.0) | NC | NC | NC | NC |
M | 0.5 | 666 (80.0) | 4930 (183.0) | NC | NC | NC | NC | |
Day 14a | ||||||||
1.0 | F | 0.5 | 525 (5.82) | 712 (46.7) | NC | NC | NC | NC |
M | 0.5 | 572 (65.4) | 708 (111.0) | NC | NC | NC | NC | |
5.0 | F | 1.0 | 1000 (91.6) | 1480 (71.8) | NC | NC | NC | NC |
M | 1.0 | 1100 (28.05) | 1640 (59.6) | NC | NC | NC | NC | |
25.0 | F | 0.5 | 1190 (94.8) | 1710 (56.5) | NC | NC | NC | NC |
M | 1.0 | 1140 (124.0) | 1860 (103.0) | NC | NC | NC | NC | |
Day 28 | ||||||||
1.0 | F | 0.5 | 695 (138.0) | 818 (73.5) | 0.624 | 829 | 1.08 | 20.1 |
M | 0.5 | 594 (64.6) | 933 (51.3) | 0.661 | 952 | 1.00 | 17.5 | |
5.0 | F | 0.25 | 1060 (158.0) | 3750 (247.0) | 9.29 | 4300 | 15.6 | 19.4 |
M | 0.5 | 1080 (253.0) | 4550 (194.0) | 8.78 | 5160 | 12.3 | 16.2 | |
25.0 | F | 0.5 | 1180 (127.0) | 11,900 (406.0) | NC | NC | NC | NC |
M | 0.25 | 1050 (71.6) | 12,600 (181.0) | NC | NC | NC | NC |
Dose, mg/kg | Sex | tmax (SD), h | Cmax (SD), ng/mL | Cmax/dose (SD) | AUClast (SD), ng·h/mL |
---|---|---|---|---|---|
C. Dog PL8177 | |||||
Day 1 | |||||
1.5 | F | 1.3 (0.5) | 106 (43.5) | 70.5 (29.0) | 271 (93.1) |
M | 1.1 (0.63) | 116 (30.2) | 77.4 (20.2) | 247 (16.2) | |
8.0 | F | 1.0 (0) | 615 (124) | 76.9 (15.5) | 1560 (141) |
M | 0.75 (0.29) | 400 (117) | 50.0 (14.7) | 1280 (217) | |
40.0 | F | 0.56 (0.31) | 1010 (398) | 25.2 (9.94) | 3610 (792) |
M | 0.88 (0.25) | 633 (257) | 15.8 (6.42) | 2640 (306) | |
Day 14 | |||||
1.5 | F | 1.0 (0) | 128 (59.9) | 85.6 (39.9) | 258 (104) |
M | 1.0 (0) | 129 (23.9) | 86.0 (15.9) | 239 (27.3) | |
8.0 | F | 0.63 (0.25) | 547 (52.4) | 68.4 (6.55) | 1650 (231) |
M | 0.50 (0) | 359 (71.1) | 44.9 (8.89) | 1200 (108) | |
40.0 | F | 0.38 (0.14) | 1280 (305) | 31.9 (7.61) | 6220 (1250) |
M | 0.50 (0) | 850 (196) | 21.2 (4.89) | 4760 (503) | |
Day 28 | |||||
1.5 | F | 1.0 (0) | 96 (26.9) | 64.0 (17.9) | 210 (67.4) |
M | 0.75 (0.29) | 98 (12.8) | 65.3 (8.51) | 194 (17.8) | |
8.0 | F | 0.63 (0.25) | 389 (114) | 48.6 (14.3) | 1250 (128) |
M | 0.63 (0.25) | 275 (77.7) | 34.4 (9.72) | 1070 (159) | |
40.0 | F | 0.38 (0.14) | 1260 (407) | 31.5 (10.2) | 6620 (842) |
M | 0.44 (0.13) | 860 (131) | 21.5 (13.28) | 4620 (250) |
3.1.2 Rat
3.1.3 Dog
3.2 Human Studies
Dose, mg | Statistic | Cmax, ng/mL | AUC0–t, ng·h/mL | AUC∞, ng·h/mL | CL/F, L/h | t½, h | tmax, h | Vd/F, L | Cmax/dose, ng/mL/mg | AUC∞/dose, ng·h /mL/mg |
---|---|---|---|---|---|---|---|---|---|---|
5.0 | n | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 |
Mean (SD) | 87.8 (31.1) | 226 (36.0) | 240 (37.1) | 21.3 (3.6) | 16.3 (2.9) | 502 (133) | 17.6 (6.2) | 48.0 (7.4) | ||
Median | 80.9 | 235 | 246 | 20.3 | 17.3 | 0.8 | 496 | 16.2 | 49.2 | |
Geometric mean | 83.4 | 224 | 237 | 21.1 | 16.1 | 488 | 16.7 | 47.5 | ||
3.0 | n | 6 | 6 | 6 | 6 | 6 | 6 | 4 | 6 | 4 |
Mean (SD) | 54.4 (11.3) | 138 (18.9) | 158 (19.4) | 19.3 (2.5) | 19.5 (17.5) | 375 (154) | 18.1 (3.8) | 51.3 (7.7) | ||
Median | 49.1 | 138 | 163 | 18.4 | 12.3 | 0.6 | 394 | 16.4 | 51.1 | |
Geometric mean | 53.5 | 137 | 157 | 19.1 | 15.2 | 348 | 17.8 | 50.9 | ||
1.0 | n | 6 | 6 | 6 | 6 | 6 | 6 | 3 | 6 | 3 |
Mean (SD) | 17.4 (5.0) | 40.3 (9.4) | 46.2 (12) | 22.9 (5.9) | 6.7 (3.1) | 173 (35.1) | 17.4 (5.0) | 35.4 (1.8) | ||
Median | 18.3 | 39.2 | 45.5 | 22.7 | 6 | 0.6 | 186 | 18.3 | 34.5 | |
Geometric mean | 16.7 | 39.4 | 44.9 | 22.3 | 6.1 | 171 | 16.7 | 35.4 | ||
0.5 | n | 4 | 4 | 4 | 4 | 4 | 4 | 2 | 4 | 2 |
Mean (SD) | 8.2 (3.7) | 19.9 (14.9) | 22.4 (15.8) | 28.6 (12.0) | 2.8 (1.2) | 74.4 (9.7) | 16.4 (7.5) | 59.9 (45.8) | ||
Median | 7.2 | 13.3 | 15 | 33.6 | 2.6 | 0.5 | 74.4 | 14.3 | 59.9 | |
Geometric mean | 7.6 | 16.8 | 19.4 | 25.8 | 2.6 | 74.1 | 15.3 | 50.4 | ||
0.1 | n | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 |
Mean (SD) | 2.3 (1.0) | 2.7 (0.8) | 3.5 (0.8) | 29.8 (7.2) | 0.9 (0.3) | 36.1 (9.3) | 23.4 (10.1) | 34.9 (7.82) | ||
Median | 1.9 | 2.6 | 3.5 | 28.5 | 0.8 | 0.6 | 36.6 | 18.9 | 35.3 | |
Geometric mean | 2.2 | 2.6 | 3.4 | 29.2 | 0.8 | 35.1 | 22.1 | 34.2 |
Dose, mg | Statistic | Cmax, ng/mL | AUC0–t, ng·h/mL | AUC∞, ng·h/mL | CL/F, L/h | t½, h | tmax, h | Vd/F, L | Cmax/dose, ng/mL/mg | AUC∞/dose, ng·h/mL/mg |
---|---|---|---|---|---|---|---|---|---|---|
1.0 | n | 8 | 8 | 6 | 6 | 6 | 8 | 6 | 8 | 6 |
Mean (SD) | 23.0 (8.9) | 49.4 (15.9) | 52.3 (14.2) | 20.1 (4.6) | 4.3 (1.6) | 120 (44.4) | 23.0 (8.8) | 52.3 (14.2) | ||
Median | 18.5 | 44.9 | 49.4 | 20.2 | 3.5 | 0.5 | 106 | 18.5 | 49.4 | |
Geometric mean | 21.7 | 47.4 | 50.9 | 19.6 | 4.1 | 115 | 21.7 | 50.9 | ||
3.0 | n | 8 | 8 | 7 | 7 | 7 | 8 | 7 | 8 | 7 |
Mean (SD) | 54.4 (9.6) | 154 (30.2) | 172 (30.6) | 17.9 (3.0) | 9.7 (2.1) | 257 (94.6) | 18.1 (3.2) | 57.2 (10.2) | ||
Median | 50.0 | 145.0 | 159.0 | 18.9 | 9.6 | 0.6 | 261 | 16.7 | 53.0 | |
Geometric mean | 53.7 | 152.0 | 169.0 | 17.7 | 9.5 | 242 | 17.9 | 56.5 |
Dose, mg | Statistic | Cmax, ng/mL | AUCτ, ng·h/mL | AUC∞, ng·h/mL | t½, h | tmax, h | Vd/Fss, L | AI | Cmax/dose, ng/mL/mg | AUCτ/dose, ng·h/mL/mg |
---|---|---|---|---|---|---|---|---|---|---|
1.0 | n | 8 | 8 | 5 | 5 | 8 | 5 | 5 | 8 | 8 |
Mean (SD) | 20.9 (6.2) | 52.9 (15.0) | 57.2 (21.3) | 7.1 (2.4) | 200 (72.3) | 1.1 (0.1) | 20.9 (6.17) | 52.9 (15.0) | ||
Median | 22.2 | 48.3 | 51.8 | 7.2 | 0.5 | 174 | 1.1 | 22.2 | 48.3 | |
Geometric mean | 20.1 | 51.2 | 54.3 | 6.7 | 191 | 1.1 | 20.1 | 51.2 | ||
3.0 | n | 8 | 8 | 6 | 6 | 8 | 6 | 6 | 8 | 8 |
Mean (SD) | 58.5 (13.6) | 177.0 (36.0) | 202.0 (37.5) | 12.6 (3.8) | 330 (111) | 1.4 (0.2) | 19.5 (4.52) | 59.1 (12.0) | ||
Median | 52.7 | 171.0 | 200.0 | 11.4 | 0.5 | 288 | 1.3 | 17.6 | 57.1 | |
Geometric mean | 57.2 | 174.0 | 199.0 | 12.3 | 316 | 1.4 | 19.1 | 58.1 |
Dosing day | Parameter | Slope (90% CI) | Critical lower/upper bound |
---|---|---|---|
A. Single-dose cohorts | |||
AUC∞ | 1.08 (1.01–1.16) | 0.943, 1.06 | |
Cmax | 0.953 (0.872–1.03) | ||
B. Multiple-dose cohorts | |||
1 | Cmax | 0.824 (0.609–1.04) | 0.797, 1.2 |
7 | Cmax, ss | 0.950 (0.738–1.16) | |
1 | AUC∞ | 1.09 (0.903–1.29) | |
1 | AUCτ | 1.03 (0.833–1.23) | |
7 | AUCτ, ss | 1.12 (0.928–1.30) |