Table 4.
Plasma Pharmacokinetic Parameters (Cycle 1) of MK-8353 and Selumetinib Following Oral Administration of the Combination
| Cmaxa, µmol/L |
tmaxb, h |
tlastb, h |
AUC0−12a, h∙µmol/L |
AUC0−lasta, h∙µmol/L |
|
|---|---|---|---|---|---|
| MK-8353 | |||||
| 50 mg | |||||
| Day 1 (n = 3) | 1.24 (138.4) | 2.05 (1.88−4.03) | 8.02 (7.83−8.07) | 14.3 (62.7)c | 6.76 (117.8) |
| Day 4 (n = 3) | 1.87 (149.4) | 2.00 (1.87−5.88) | 8.05 (7.97−8.08) | 16.7 (365.7)c | 10.7 (164.6) |
| 100 mg | |||||
| Day 1 (n = 12) | 1.65 (60.9) | 2.00 (0.98−3.90) | 8.00 (7.83−11.33) | 9.66 (50.7)d | 7.95 (63.1) |
| Day 4 (n = 10)e | 2.53 (51.5) | 1.97 (1.83−3.97) | 8.00 (7.83−8.33) | 19.0 (36.9)d | 14.0 (46.8) |
| 150 mg | |||||
| Day 1 (n = 15) | 2.95 (62.3) | 2.00 (1.85−7.95) | 8.00 (7.83−8.37) | 13.7 (32.8)f | 13.9 (61.0) |
| Day 4 (n = 13)g | 3.61 (80.9) | 2.00 (0.00−8.00)h | 8.00 (0.00−8.05)h | 20.9 (60.6)i | 23.4 (86.1)j |
| Selumetinib | |||||
| 25 mg | |||||
| Day 1 (n = 3) | 1.01 (29.7) | 1.03 (0.92−1.88) | 8.02 (7.83−8.07) | 2.99 (27.2) | 2.71 (29.0) |
| Day 4 (n = 3) | 1.04 (13.3) | 1.88 (0.87−2.00) | 8.05 (7.97−8.08) | 3.80 (24.6) | 3.42 (21.7) |
| 50 mg | |||||
| Day 1 (n = 12) | 1.96 (91.1) | 1.00 (0.88−2.00) | 8.00 (7.83−11.33) | 5.20 (63.2) | 4.92 (65.7) |
| Day 4 (n = 10)e | 1.44 (123.6) | 1.96 (0.95−3.97) | 8.00 (5.83−8.33) | 6.28 (75.3)k | 4.82 (80.5) |
| 75 mg | |||||
| Day 1 (n = 13) | 3.37 (57.1) | 1.85 (0.83−4.00) | 8.00 (7.83−8.37) | 10.9 (49.1)j | 10.2 (47.7) |
| Day 4 (n = 11)g | 2.37 (107.5) | 1.07 (0.00−5.92)h | 8.00 (0.00−8.05)h | 12.7 (31.5)k | 11.0 (27.7)f |
| Desmethyl selumetinib | |||||
| 25 mg | |||||
| Day 1 (n = 3) | 0.0437 (10.5) | 1.88 (0.92–2.05) | 8.02 (7.83–8.07) | 0.161 (52.4) | 0.144 (47.7) |
| Day 4 (n = 3) | 0.0563 (55.6) | 1.88 (1.87–2.00) | 8.05 (7.97–8.08) | 0.230 (63.5) | 0.202 (60.5) |
| 50 mg | |||||
| Day 1 (n = 12) | 0.0935 (124.8) | 1.02 (0.88–2.08) | 8.00 (3.92–11.33) | 0.344 (73.5)l | 0.261 (118.6) |
| Day 4 (n = 10)e | 0.0724 (142.8) | 1.96 (0.95–3.97) | 8.00 (5.83–8.33) | 0.386 (49.6)k | 0.267 (102.1) |
| 75 mg | |||||
| Day 1 (n = 13) | 0.158 (68.9) | 1.92 (0.83–4.00) | 8.00 (7.83–8.37) | 0.690 (56.3)j | 0.547 (61.3) |
| Day 4 (n = 11)g | 0.0977 (147.9) | 1.07 (0.00–5.92)h | 8.00 (0.00–8.05)h | 0.681 (35.7)k | 0.486 (87.7)f |
AUC, area under the plasma concentration−time curve; AUC0−12, AUC from time 0 to 12 h; AUC0−last, AUC from time 0 to time of last quantifiable measure; Cmax, maximum plasma concentration; tlast, time of last measurable plasma concentration; tmax, time of maximum plasma concentration
aGeometric mean (percent geometric coefficient of variation)
bMedian (range)
cn = 2
dn = 9
eFor 1 patient, the actual sample collection time deviated substantially from the intended time; this patient was excluded prior to analysis
fn = 10
gOne patient had only a predose sample available, which was below the limit of quantitation; this patient was excluded prior to analysis
hFor MK-8353, tmax was observed at predose for 1 patient because Cmax was observed at predose, and 1 patient had only a predose sample available with measureable concentration (tmax and tlast were therefore each observed at predose). For selumetinib and desmethyl selumetinib, 1 patient had only a predose sample available with measureable concentration (tmax and tlast were therefore each observed at predose)
in = 7
jn = 12
kn = 8
ln = 11