TABLE 3.
Pharmacokinetic (PK) properties of larotinib 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 (5.00–6.00) | 5.00 (3.00–6.00) | 5.00 (2.00–5.00) | 5.00 (2.00–5.00) | 5.00 (2.00–5.00) | 3.50 (2.00–5.00) | 5.00 (3.00–6.00) |
| Cmax, mean (min–max), ng/mL | 17.42 (15.96–18.70) | 64.08 (48.32–84.51) | 149.9 (128.4–174.9) | 278.0 (169.0–437.0) | 267.3 (106.8–401.0) | 299.8 (152.1–590.4) | 354.3 (76.53–678.8) |
| AUC0-24, mean (min–max), h*ng/mL | 244.7 (229.2–254.1) | 652.7 (506.0–822.1) | 1987 (1,507–2,705) | 3,104 (2,384–4,212) | 2,690 (1,153–4,397) | 3,236 (1741–5,416) | 3,973 (1,031–6,848) |
| AUC0-t, mean (min–max), h*ng/mL | 634.9 (561.0–691.4) | 1,243 (1,009–1,446) | 4,781 (3,586–6,799) | 6,359 (5,421–7977) | 4,885 (2,208–8,615) | 6,120 (3,871–9,164) | 7435 (2,119–11,572) |
| AUC0-∞, mean (min–max), h*ng/mL | 816.6 (701.3–923.0) | 1,390 (1,101–1,597) | 5,662 (3,938–8,198) | 8,093 (6,503–9,065) | 5,554 (2,576–9,951) | 6,832 (4,777–9,670) | 9,088 (2,747–13,379) |
| T1/2, mean (min–max), h | 56.71 (56.02–57.42) | 43.86 (35.81–52.38) | 39.29 (35.34–45.71) | 68.20 (44.62–99.19) | 46.20 (39.75–52.26) | 44.61 (32.56–56.39) | 68.60 (58.44–76.26) |
| Vz/F, mean (min–max), L | 5,071 (4,487–5,831) | 4,583 (3,919–5,138) | 1,651 (971.9–2040) | 2,715 (1,562–3,614) | 4,345 (1982–8,779) | 3,802 (1700–5,960) | 7408 (2,521–16,020) |
| CL/F, mean (min–max), L/h | 62.01 (54.17–71.3) | 73.81 (62.61–90.83) | 29.11 (18.30–38.09) | 27.79 (24.27–33.83) | 63.76 (30.15–116.4) | 55.78 (36.19–73.27) | 70.47 (29.90–145.6) |
| Multiple oral administration No | 3 | 3 | 3 | 3 | 5 | 3 | 3 |
| Tmax,ss, median (min–max), h | 5.00 (5.00–6.00) | 5.00 (5.00–5.00) | 5.00 (2.00–5.00) | 6.00 (2.00–12.00) | 5.00 (1.00–6.00) | 5.00 (4.00–6.00) | 6.00 (4.00–6.00) |
| Cmax,ss, mean (min–max), ng/mL | 67.50 (65.34–70.90) | 131.36 (85.19–185.4) | 371.37 (318.6–470.7) | 552.6 (405.4–804.4) | 437.9 (300.3–550.7) | 694.7 (476.3–840.3) | 844.8 (637.1–1,087) |
| AUCτ,ss, mean (min–max), h*ng/mL | 1,216 (1,029–1,334) | 1967 (1,183–2,756) | 6,502 (5,277–8,553) | 10,303 (8,707–13,353) | 7260 (5,889–8,237) | 13,155 (9,608–15,933) | 16,081 (12,503–19,042) |
| AUC0-t,ss, mean (min–max), h*ng/mL | 3,573 (3,009–4,374) | 4,479 (2,803–6,271) | 18,237 (15,139–23,862) | 30,159 (26,097–34,650) | 17,925 (13,660–21,285) | 35,937 (28,950–44,107) | 44,997 (32,935–54,565) |
| AUC0-∞,ss, mean (min–max), h*ng/mL | 4,922 (3,947–6,655) | 5,196 (3,387–7244) | 24,555 (19,828–33,984) | 43,641 (36,075–47,906) | 22,592 (16,340–28,368) | 47,327 (39,584–60,144) | 70,416 (50,669–96,144) |
| T1/2,ss, mean (min–max), h | 61.20 (50.41–72.73) | 44.79 (42.04–49.22) | 61.21 (55.71–68.70) | 75.66 (66.11–83.41) | 54.34 (47.58–67.58) | 58.60 (50.04–64.28) | 87.05 (66.36–102.4) |
| Vz/F,ss, mean (min–max), L | 921.4 (788.3–1,097) | 1,396 (837.2–2097) | 563.7 (437.5–646.3) | 552.9 (513.1–581.7) | 1,061 (904.9–1,260) | 640.7 (539.6–784.4) | 753.7 (594.3–1,052) |
| CL/F,ss, mean (min–max), L/h | 10.73 (7.513–12.58) | 21.17 (13.80–29.53) | 6.512 (4.414–7.565) | 5.126 (4.592–6.098) | 13.91 (10.58–18.36) | 7.648 (5.819–8.842) | 6.087 (4.160–7.894) |
| R1 (min-max) | 4.998 (4.048–5.817) | 3.231 (1.439–4.376) | 3.302 (3.162–3.502) | 3.360 (3.170–3.652) | 3.235 (1.713–5.108) | 4.639 (2.942–5.519) | 6.345 (2.781–12.12) |
| R2 (min-max) | 3.885 (3.711–4.152) | 2.308 (1.008–3.837) | 2.466 (2.177–2.691) | 2.068 (1.841–2.399) | 1.888 (1.114–2.813) | 2.757 (1.423–3.716) | 4.187 (1.602–8.325) |
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.