TABLE 4.
Pharmacokinetic (PK) properties of M5 after oral administration of single and multiple doses of 50-, 100-, 150-, 220-, 300-, 350- and 400-mg larotinib mesylate tablets.
| PK Variables | Dosage (mg) | ||||||
|---|---|---|---|---|---|---|---|
| 50 mg | 100 mg | 150 mg | 220 mg | 300 mg | 350 mg | 400 mg | |
| Single oral administration No | 3 | 3 | 3 | 3 | 6 | 3 | 3 |
| Tmax, median (min–max), h | 6.00 (1.00–6.00) | 6.00 (5.00–12.00) | 3.00 (2.00–9.00) | 3.00 (2.00–9.00) | 6.00 (2.00–12.00) | 3.00 (2.00–6.00) | 3.00 (2.00–12.00) |
| Cmax, mean (min–max), ng/mL | 11.826 (5.276–20.72) | 35.75 (5.310–72.28) | 49.09 (8.958–91.24) | 28.19 (19.05–42.48) | 114.7 (32.69–191.0) | 80.07 (67.58–94.76) | 120.3 (78.46–200.6) |
| AUC0-24, mean ((min-max)), h*ng/mL | 203.8 (113.5–356.8) | 474.5 (93.34–887.0) | 575.5 (167.6–1,039) | 425.5 (205.8–638.6) | 1,323 (386.9–2,681) | 978.2 (888.5–1,036) | 1,646 (1,043–2,450) |
| AUC0-t, mean ((min-max)), h*ng/mL | 515.4 (342.1–724.1) | 860.4 (223.7–1,612) | 1,195 (583.5–1842) | 803.7 (476.8–1,096) | 2,440 (674.1–4,640) | 1986 (1871–2091) | 3,612 (1774–4,733) |
| AUC0-∞, mean ((min-max)), h*ng/mL | 626.1 (367.5–765.6) | 920.8 (256.5–1714) | 1,347 (760.0–1916) | 949.6 (558.0–1,306) | 2,616 (705.5–5,111) | 2096 (1980–2,212) | 4,284 (1956–5,553) |
| T1/2, mean ((min-max)), h | 46.92 (24.98–88.00) | 37.21 (33.32–41.31) | 41.01 (26.43–59.33) | 64.24 (41.98–75.88) | 32.64 (23.25–44.17) | 28.57 (26.44–32.64) | 48.40 (40.13–53.58) |
| Vz/F, mean ((min-max)), L | 5,346 (2,617–8,519) | 9,654 (3,477–18,742) | 8,598 (2,986–16,894) | 22,148 (18,438–24,125) | 8,096 (2,580–15,907) | 6,925 (6,036–8,322) | 7660 (5,352–11,839) |
| CL/F, mean ((min-max)), L/h | 89.47 (65.30–136.0) | 191.5 (58.33–389.9) | 128.6 (78.30–197.4) | 262.0 (168.4–394.3) | 178.3 (58.70–425.2) | 167.3 (158.2–176.7) | 117.1 (72.04–204.5) |
| Multiple oral administration No | 3 | 3 | 3 | 3 | 5 | 3 | 3 |
| Tmax,ss, median (min–max), h | 9.00 (1.00–12.00) | 5.00 (5.00–24.00) | 5.00 (5.00–5.00) | 6.00 (6.00–12.00) | 6.00 (0.00–12.00) | 5.00 (2.00–6.00) | 5.00 (3.00–6.00) |
| Cmax,ss, mean ((min-max)), ng/mL | 44.94 (42.31–46.50) | 110.3 (46.48–187.0) | 242.4 (79.13–365.4) | 185.4 (123.2–291.1) | 230.9 (41.74–516.1) | 353.4 (159.3–503.1) | 752.0 (212.5–1,511) |
| AUCτ,ss, mean ((min-max)), h*ng/mL | 788.7 (681.9–874.4) | 1,356 (539.7–2,272) | 4,221 (1,269–6,440) | 3,128 (2,117–4,796) | 4,092 (701.6–8,440) | 5,852 (2,497–10,089) | 9,572 (3,610–16,790) |
| AUC0-t,ss, mean ((min-max)), h*ng/mL | 2,332 (1863–2,725) | 2,737 (1,320–4,450) | 12,043 (3,445–17,143 | 7998 (4,661–13,758) | 10,114 (2,229–22,840) | 14,576 (11,235–19,076) | 22,565 (12,430–32,554) |
| AUC0-∞,ss, mean ((min-max)), h*ng/mL | 3,057 (2,170–3,835) | 3,077 (1,643–4,952) | 13,510 (4,714–19,002) | 13,661 (6,569–27,809) | 15,385 (2,328–38,578) | 16,911 (14,280–20,484) | 40,022 (31,831–51,472) |
| T1/2,ss, mean ((min-max)), h | 53.79 (35.79–84.19) | 47.38 (35.09–65.09) | 38.79 (30.91–53.13) | 89.40 (49.83–124.7) | 70.75 (28.95–95.37) | 36.94 (31.47–44.32) | 151.3 (38.91–346.4) |
| Vz/F,ss, mean ((min-max)), L | 1,258 (815.5–1,584) | 3,011 (1,022–5,716) | 1,068 (368.2–2,439) | 2,777 (1,423–4,501) | 3,861 (1,070–8,728) | 1,150 (775.7–1,567) | 1912 (610.8–3,883) |
| CL/F,ss, mean ((min-max)), L/h | 17.29 (13.04–23.04) | 39.66 (20.19–60.87) | 16.21 (7.894–31.82) | 24.90 (7.911–33.49) | 48.76 (7.777–128.8) | 21.17 (17.09–24.51) | 10.41 (7.771–12.57) |
| R1 (min-max) | 5.08 (1.911–7.136) | 3.73 (2.561–5.782) | 7.77 (6.197–9.527) | 8.140 (4.899–12.01) | 3.882 (0.7928–6.478) | 5.94 (2.473–9.743) | 7.327 (2.499–16.09) |
| R2 (min-max) | 5.048 (2.221–8.020) | 4.874 (2.587–8.753) | 6.282 (4.005–8.833) | 6.549 (5.346–7.447) | 2.255 (0.7851–4.025) | 4.477 (2.358–5.762) | 8.171 (2.597–19.26) |
ss, steady state; SD, standard deviation; Tmax, time to peak plasma concentration; Cmax, peak plasma concentration; AUC, area under the plasma concentration curve; T1/2, terminal elimination halt-life; Vz/F, apparent volume of distribution; CL/F, apparent clearance; R1, AUCτ,cycle1/AUC0–24h,cycle0; R2, Cmax, cycle1/Cmax, cycle0.