TABLE 4.
Pharmacokinetic parameters of osimertinib, AZ5104, and AZ7550 for each hepatic function group (pharmacokinetic analysis set)
Comparisons are based on an analysis of variance model with a fixed effect for hepatic function group.
| Pharmacokinetic Parameter | Normal Hepatic Functiona (n = 10) | Mild Hepatic Impairment (n = 7) | Moderate Hepatic Impairment (n = 5) | Population PK (Based on n = 1367 Patients) |
|---|---|---|---|---|
| Osimertinib | ||||
| AUC (nM·h), geometric mean (%GCV) | 15,780 (38) | 9983 (36) | 10,790 (22) | 11,040b |
| Comparison: mild (n = 7) vs. normal (n = 9); ratio (90% CI) | 63.25 (47.34, 84.51) | |||
| Comparison: moderate (n = 5) vs. normal (n = 9); ratio (90% CI) | 68.36 (49.60, 94.21) | |||
| Cmax (nM), geometric mean (%GCV) | 291.8 (45) | 150.1 (37) | 177.1 (41) | 509b |
| Comparison: mild (n = 7) vs. normal (n = 10); ratio (90% CI) | 51.43 (36.58, 72.31) | |||
| Comparison: moderate (n = 5) vs. normal (n = 10); ratio (90% CI) | 60.67 (41.55, 88.60) | |||
| tmax (h), median (min, max) | 4.00 (1.50, 11.83) | 3.00 (1.98, 8.00) | 3.00 (1.50, 6.00) | NA |
| t1/2λz (h), mean (S.D.) | 69.05 (10.46) | 82.84 (19.33) | 71.88 (6.581) | 44 (3.0)c |
| CL/F (liters/h), mean (S.D.) | 10.76 (3.914) | 16.85 (5.538) | 15.12 (3.224) | 14.3 (1.4)d |
| Vz/F (liters), mean (S.D.) | 1038 (351.7) | 1937 (570.1) | 1560 (318.5) | 918 (3.3)d |
| CLR (liters/h), mean (S.D.) | 0.07879 (0.06086) | 0.1651 (0.09735) | 0.04419 (0.04575) | — |
| AZ5104 | ||||
| AUC (nM·h), geometric mean (%GCV) | 1387 (60) | 921.8 (47) | 705.2 (43) | — |
| Cmax (nM), geometric mean (%GCV) | 9.793 (47) | 6.489 (44) | 4.312 (50) | — |
| tmax (h), median (min, max) | 12.05 (4.00, 48.83) | 24.10 (3.00, 48.02) | 48.22 (12.00, 72.00) | — |
| t1/2λz (h), mean (S.D.) | 72.96 (10.72) | 82.34 (21.28) | 78.15 (10.88) | — |
| MRCmax, mean (S.D.) | 0.03586 (0.01386) | 0.04707 (0.02183) | 0.02687 (0.01481) | — |
| MRAUC, mean (S.D.) | 0.09184 (0.02926) | 0.09869 (0.04466) | 0.06873 (0.02476) | — |
| CLR (l/h), mean (S.D.) | 0.2859 (0.1632) | 0.9207 (0.4934) | 0.2983 (0.2240) | — |
| AZ7550 | ||||
| AUC (nM·h), geometric mean (%GCV) | 879.8 (41) | 588.7 (35) | 579.6 (37) | — |
| Cmax (nM), geometric mean (%GCV) | 4.929 (31) | 3.232 (42) | 3.005 (73) | — |
| tmax (h), median (min, max) | 9.95 (6.00, 72.02) | 12.00 (6.00, 47.58) | 23.92 (1.50, 48.22) | — |
| t1/2λz (h), mean (S.D.) | 104.0 (21.84) | 104.2 (16.99) | 98.66 (11.11) | — |
| MRCmax, mean (S.D.) | 0.01810 (0.006706) | 0.02508 (0.01502) | 0.01859 (0.008441) | — |
| MRAUC, mean (S.D.) | 0.05686 (0.01200) | 0.06694 (0.03260) | 0.05739 (0.02283) | — |
| CLR (l/h), mean (S.D.) | 0.6092 (0.4695) | 1.247 (0.3285) | 0.3681 (0.1514) | — |
AUC, area under the plasma-concentration time curve from zero to infinity; CL/F, apparent plasma clearance; CLR, renal clearance; Cmax, maximum plasma concentration; %GCV, percent geometric coefficient of variation; MR metabolite to parent ratio; t1/2λz, terminal half-life; tmax, time of maximum concentration; Vz/F, apparent volume of distribution.
Normal = normal hepatic function; Mild = mild hepatic impairment [Child-Pugh A]; moderate = moderate hepatic impairment [Child-Pugh B].
AUCss and Cssmax at steady state shown.
t1/2 shown.
Population typical value (% relative S.E.).