Table 3 Pharmacokinetic and pharmacodynamic parameters of ARQ 087 after single and multiple oral doses of ARQ 087

From: A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours

 

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)

  1. 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.
  2. 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.
  3. aFor 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).
  4. bn=4, AUC0–24 not calculated for Subjects 69, 70, 72, 77, 78, 79, and 85 (Tlast ranged from 9.7 to 10.1 h).
  5. cThe 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.
  6. dMedian (Min, Max).
  7. eAUClast≈AUC0–24 since Tlast ranged between 22.0 and 29.3 h on Day 22.
  8. fn=4, AUC0–24 not calculated for Subject 28 (Tlast=11.8 h).
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