Table 5. Pharmacokinetic parameters of plitidepsin and DTIC in cycle 1.
| Plitidepsin/DTIC dose level (mg m−2) | n | Cmax(ng ml−1) | AUC (h × ng ml−1) | t½ (h) | CL (l h−1) | Vss (l) |
|---|---|---|---|---|---|---|
|
Plitidepsin | ||||||
|
Phase I stage | ||||||
| 1.8/800 | 6 | 41.7 (25.6–50.4) | 540 (240–824) | 42.7 (32.2–56.5) | 7.1 (3.8–12.1) | 261 (175–401) |
| 2.4/800 (RD) | 6 | 42.4 (30.0–49.8) | 508 (262–727) | 39.5 (16.3–53.6) | 10.4 (7.6–17.0) | 408 (163–590) |
| 3.0/800 | 7 | 38.1 (24.6–49.0) | 323 (212–523) | 38.8 (15.4–69.1) | 19.0 (11.9–28.3) | 750 (316–1920) |
| 2.4/1000 (MTD) |
2 |
36.0 (35.5–36.4) |
277 (184–369) |
16.1 (15.1–17.0) |
16.7 (11.1–22.2) |
299 (245–353) |
|
Phase II stage | ||||||
| 3.2 | 17 | 38.3 (16.1–48.4) | 444 (205–848) | 45.1 (14.2–131) | 15.4 (7.5–24.5) | 652 (198–1380) |
| 2.4/800 |
29 |
40.3 (26.2–50.2) |
425 (215–1130) |
43.0 (13.7–85.5) |
12.0 (4.0–24.9) |
456 (158–826) |
|
DTIC | ||||||
|
Phase I stage | ||||||
| 1.8/800 | 5 | 19.9 (15.1–23.9) | 46.0 (30.3–69.8) | 1.3 (0.7–2.4) | 35.2 (22.4–47.8) | 50.6 (37.1–66.1) |
| 2.4/800 (RD) | 7 | 18.2 (5.0–24.4) | 42.3 (24.5–66.8) | 1.4 (0.5–1.9) | 41.8 (22.3–68.6) | 76.7 (28.4–185) |
| 3.0/800 | 4 | 16.1 (4.2–22.9) | 48.2 (14.8–84.9) | 2.5 (2.2–2.9) | 41.3 (18.9–86.6) | 94.8 (63.7–156) |
| 2.4/1000 (MTD) |
1 |
4.6 (−) |
15.7 (−) |
3.5 (−) |
114 (−) |
385 (−) |
|
Phase II stage | ||||||
| 2.4/800 | 32 | 15.4 (4.3–22.6) | 38.3 (13.6–60.8) | 2.6 (1.2–6.7) | 42.8 (22–124) | 96.2 (45.8–249) |
Abbreviations: AUC=area under the concentration–time curve from time zero to infinity; CL=total body clearance; Cmax=maximum plasma concentration; DTIC=dacarbazine; MTD=maximum tolerated dose; RD=recommended dose; t½=terminal half-life; Vss=volume of distribution at steady state.
Values are expressed as mean (range).