Table 4.
Key Plasma PK Parameters of Selumetinib and Selumetinib Metabolite (N-desmethyl Selumetinib)
Parameter (Units) |
Statistic | Single Dose (Cycle 1 day 1; N = 12) |
Steady State (Cycle 2 day 1; n = 11) |
||
---|---|---|---|---|---|
Selumetinib | N-desmethyl Selumetinib | Selumetinib | N-desmethyl Selumetinib | ||
Cmax (ng/mL) | Geometric mean | 783.1 | 55.5 | 869.4 | 40.9 |
gCV% | 52.7 | 49.1 | 53.5 | 53.1 | |
tmax (h) | Median | 1.5 | NA | 1.5 | NA |
Min–Max | 0.5–3.1 | NA | 0.4–2.9 | NA | |
AUC0–ta (ng·h/mL) | Geometric mean | 2224 | 169.7 | 2395 | 123.6 |
gCV% | 37.6 | 35.4 | 40.3 | 37.3 | |
AUC0–6 (ng·h/mL) | Geometric mean | 1926 | 140.8 | 2396 | 123.6 |
gCV% | 41.6 | 38.9 | 40.3 | 37.3 | |
AUC0–12 (ng·h/mL) | Geometric mean | 2523b | 188.7c | NA | NA |
gCV% | 24.2 | 24.3 | NA | NA | |
Ctrough (ng/mL) | Geometric mean | NA | NA | 92.7 | 6.7 |
gCV% | NA | NA | 63.2 | 57.1 | |
Rac Cmax | Geometric mean | NA | NA | 1.10 | 0.7 |
gCV% | NA | NA | 34.3 | 42.2 | |
Rac AUCd | Geometric mean | NA | NA | 1.27 | 0.9 |
gCV% | NA | NA | 17.3 | 43.1 | |
Metabolite:parent ratio Cmax | Geometric mean | NA | 0.07 | NA | 0.05 |
gCV% | NA | 18.3 | NA | 62.8 | |
Metabolite:parent ratio AUCe | Geometric mean | NA | 0.08 | NA | 0.05 |
gCV% | NA | 15.9 | NA | 55.5 |
aThe last sample was 10–12 hours post dose for cycle 1 day 1 and 6 hours post dose for cycle 2 day 1.
b n = 8.
c n = 7.
dRac AUC was calculated using AUC0–6 for cycle 1 day 1 and cycle 2 day 1.
eMetabolite: Parent ratio for AUC was calculated using AUC0–t for selumetinib and N-desmethyl selumetinib.
AUC, area under the concentration–time curve; AUC0–6, AUC from time 0 to 6 hours; AUC0–12, AUC from time 0 to 12 hours; AUC0–t, AUC from time 0 to last measurable concentration; Cmax, maximum plasma concentration; Ctrough, lowest concentration of selumetinib prior to next dose; gCV, geometric coefficient of variation; NA, not applicable; PK, pharmacokinetics; RAC, accumulation ratio; tmax, time to maximum plasma concentration.