TABLE 5.
Mean trough concentration unbound and ALK occupancy at steady state in plasma and CSF in ALK-positive NSCLC patients.
| Drug | Dosing regimen | Therapeutic target | ALK occupancy threshold (%) | Cetv (ng/mL) | Ki(nM) against ALK | Unbound Ctrough (nM, 90% CI) | Minimal ALK occupancy (%, 90% CI) | ||
|---|---|---|---|---|---|---|---|---|---|
| Plasma | Unbound CSF | Plasma | Intracranial | ||||||
| CRI | 250 mg BID | ALK (wild-type) | 75 | 235 | 10 | 78.2 (61.9, 94.5) | 1.56 (1.24, 1.89) | 88.7 (86.1, 90.4) | 13.5 (11.0, 15.9) |
| ALK (L1196M) | - | 446 | 14.9 (12.2, 17.5) | 0.3 (0.28, 0.42) | |||||
| ALK (G1269A) | - | 250 | 23.8 (19.8, 27.4) | 0.6 (0.49, 0.75) | |||||
| ALK (G1202R) | - | 191 | 29.0 (24.5, 33.1) | 0.8 (0.65, 0.98) | |||||
| ALE + M4 | 600 mg BID | ALK (WT) | 435 | 1.0 | 11.0 (8.8, 13.1) | 8.5 (6.8, 10.1) | 91.7 (89.8, 94.2) | 89.7 (87.2, 91.0) | |
| ALK (L1196M) | - | 0.8 | 93.2 (91.7, 80.9) | 91.6 (89.5, 92.7) | |||||
| ALK (G1269A) | - | 4.0 | 73.3 (68.8, 76.6) | 68.5 (63.0, 71.6) | |||||
| ALK (G1202R) | - | 29 | 27.5 (23.3, 31.1) | 23.0 (19.0, 25.8) | |||||
| LOR | 100 mg OD | ALK (WT) | 7.6 | 1.0 | 160 (140, 179) | 123 (108, 138) | 99.5 (99.5, 99.7) | 99.4 (99.3, 99.5) | |
| ALK (L1196M) | 62 | 17 | 93.8 (93.0, 94.5) | 92.1 (91.1, 92.9) | |||||
| ALK (G1269A) | - | 5.0 | 94.9 (94.3, 95.5) | 93.5 (92.7, 94.2) | |||||
| ALK (G1202R) | 150 | 25 | 83.1 (81.2, 84.6) | 79.1 (76.9, 80.9) | |||||
-, not reported data; Cetv, effective PK threshold values.