Table 3. Pharmacokinetic and pharmacodynamic parameters of ARQ 087 after single and multiple oral doses of ARQ 087.
|
ARQ 087 treatment |
||||
|---|---|---|---|---|
| 100 mg QD | 200 mg QD | 300 mg QD | 400 mg QD | |
| Mean (CV%) |
Plasma ARQ 087 |
|||
|
PK Day 1 | ||||
| N | 4 | 5 | 11 | 5 |
| Cmax (ng ml−1) | 61.65 (34.2) | 106.4 (46.3) | 164.2 (74.7) | 176.4 (24.3) |
| AUC0–24a (ng.h ml−1) | 1099.72 (36.8) | 1820.51 (43.4) | 3681.63 (53.2)b | 2949.84 (31.2) |
| AUClastc (ng.h ml−1) | 3274.13 (39.7) | 1820.51 (43.4) | 1940.87 (97.4) | 2949.84 (31.2) |
| Tmaxd (h) | 17.18 (5.97, 46.82) | 11.78 (8.00, 23.68) | 7.95 (4.00, 24.05) | 6.08 (5.93, 22.78) |
|
PK Day 22 | ||||
| N | 3 | 5 | 8 | 5 |
| Cmax (ng ml−1) | 330.0 (66.0) | 630.0 (12.1) | 963.1 (44.6) | 913.0 (37.9) |
| AUC0–24e (ng.h ml−1) | 6689.65 (64.3) | 13 584.53 (15.4)f | 20 339.47 (43.7) | 19 887.28 (44.9) |
| AUClast (ng.h ml−1) | 6689.65 (64.3) | 12 109.14 (31.1) | 20 339.47 (43.7) | 19 887.28 (44.9) |
| Cmin (ng ml−1) | 248.7 (66.8) | 506.0 (16.4) | 776.3 (43.5) | 744.4 (48.1) |
| Tmaxd (h) | 11.77 (3.92, 23.17) | 6.00 (4.00, 9.82) | 5.99 (3.83, 22.12) | 6.08 (4.00, 22.02) |
| Tmind (h) | 0.92 (0.00, 9.77) | 1.00 (0.00, 23.87) | 1.06 (0.00, 10.00) | 1.00 (0.00, 12.13) |
| RA Cmax | 4.93 (32.4) | 6.66 (30.5) | 9.69 (75.5) | 5.24 (32.4) |
| RA AUC0–24 | 5.45 (31.5) | 9.21 (9.3) | 8.42 (51.7) | 6.9 (41.6) |
| Mean (CV%) |
Serum phosphate and plasma FGF19 |
|||
|
PD Cycle 1 | ||||
| N (serum phosphate/FGF19) | 4/4 | 5/5 | 19/13 | 5/5 |
| Phosphate BRmax (mg dl−1) | 0.73 (90.0) | 0.95 (78.9) | 1.25 (53.8) | 1.57 (57.2) |
| FGF19 BRmax (pg ml−1) | 186.1 (93.2) | 255.4 (127.6) | 220.3 (87.7) | 371.5 (319.7) |
Abbreviations: AUC=area under the plasma concentration–time curve; BR=maximum change from baseline response value; calculated as Rmax—B, where R=maximum response and B=baseline; PD=pharmacodynamics; PK=pharmacokinetics; RA=accumulation ratio; RP2D=recommended phase 2 dose.
Note: on Day 22, the profiles of Subjects 51, 61, 63, and 64 were excluded because of dose reduction after Day 1 or less than 90% compliance to scheduled dosing; 300 mg QD is the RP2D/Expanded cohort.
For ARQ 087 dose of 150–425 mg, AUClast≈AUC0–24 since Tlast ranged between 21.9 and 25.3 h on Day 1 (except for Subjects 20 and 21 in the 150 mg cohort).
n=4, AUC0–24 not calculated for Subjects 69, 70, 72, 77, 78, 79, and 85 (Tlast ranged from 9.7 to 10.1 h).
The last blood draw for ARQ 087 25–100 mg was taken 72 h post-dose, whereas the last blood draw was taken 24 h post-dose for ARQ 087 150–425 mg.
Median (Min, Max).
AUClast≈AUC0–24 since Tlast ranged between 22.0 and 29.3 h on Day 22.
n=4, AUC0–24 not calculated for Subject 28 (Tlast=11.8 h).