Table 1.
Metabolism Profiles of Lung Cancer TKIs
| TKIs | % of Dose Recovered (% Recovered Unchanged) |
Metabolism |
||||
|---|---|---|---|---|---|---|
| Feces | Urine | Major Substrate | Minor Substrate | Induces | Inhibits | |
| EGFR inhibitors | ||||||
| Gefitinib6 | 86 | <4 | CYP3A4 | CYP2D6 | CYP2C19, CYP2D6 | |
| Erlotinib8 | 83 (1) | 8 (0.3) | CYP3A4 | CYP1A2, CYP1A1 | ||
| Afatinib5 | 85 (74.8) | 4 (3.52) | <2% Metabolized by FMO3, otherwise negligible | |||
| Osimertinib7 | 68 | 14 | CYP3A4 | CYP3A4 (pregnane X dependent), CYP1A2 | CYP3A4 | |
| Aumolertinib | Unknown | Unknown | CYP3A4 | |||
| Furmonertinib55 | 71.2 | 6.63 | CYP3A4 | CYP3A4 | ||
| Icotinib56,57 | CYP3A4 CYP2C19 |
CYP3A5 CYP1A2 |
||||
| Dacomitinib9 | 79 (20) | 3 (<1) | CYP2D6 | CYP3A4 | ||
| Lazertinib58 | 24 (unknown) | 4.4 (unknown) | CYP3A4 | CYP3A4 | ||
| EGFR exon 20 insertion | ||||||
| Mobocertinib10 | 76 (6) | 4 (1) | CYP3A | CYP3A | ||
| Sunvozertinib59 (DZD9008) | Unspecified but largely feces and biliary route | CYP3A4 CYP3A5 |
CYP3A4 | |||
| ALK inhibitors | ||||||
| Alectinib60 | 98 (84) | <0.5 | CYP3A4 | |||
| Brigatinib12 | 65 (26.65) | 25 (21.5) | CYP3A4 CYP2C8 |
CYP3A4 | ||
| Lorlatinib13 | 41 (9) | 48 (<1) | CYP3A4 | CYP2C8, CYP2C19, CYP3A5 | CYP3A CYP2B6 CYP2C9 |
|
| ROS1 inhibitors | ||||||
| Crizotinib15 | 63 (53) | 22 (2.3) | CYP3A | CYP3A, CYP2B6 | ||
| Entrectinib14 | 83 (36) | 3 | CYP3A4 | CYP3A4 | ||
| Repotrectinib61 | Unknown | Unknown | CYP3A4 | CYP3A4 CYP2B6 |
CYP2C8/9 CYP2C19 CYP3A4 |
|
| Taletrectinib62 | Unknown | Unknown | CYP3A4 CYP3A5 |
|||
| MET inhibitors | ||||||
| Capmatinib16 | 78 (42) | 22 (negligible) | CYP3A4 | CYP1A2 | ||
| Tepotinib63 | 85 (45) | 13.6 (7) | CYP3A4 CYP2C8 |
|||
| RET inhibitors | ||||||
| Selpercatinib18 | 69 (14) | 24 (12) | CYP3A4 | CYP3A, CYP2C8 | ||
| Pralsetinib17 | 73 (66) | 6 (4.8) | CYP3A4 | CYP2D6, CYP1A2 | CYP3A4, CYP3A5, CYP2C8, CYP2C9 |
CYP3A4, CYP3A5, CYP2C8, CYP2C9 |
| KRAS p.G12C mutations | ||||||
| Sotorasib64 | 74 (53) | 6 (1) | CYP3A | CYP2C8, CYP2C9, CYP2B6 |
||
| Adagrasib | 40.3 (predominately unchanged) | 0.036 (predominately unchanged) | CYP3A4 | CYP3A4 | CYP2B6, CYP2C9, CYP3A4, CYP2D6 |
|
| HER2 ± HER4 inhibitors | ||||||
| Tucatinib11 | 86 (16) | 4.1 (NA) | CYP2C8 | CYP3A | CYP3A, CYP2C8 | |
| Neratinib65 | 91.1 | 1.13 | CYP3A4 | |||
| NTRK inhibitor | ||||||
| Larotrectinib20 | 58 (5) | 39 (20) | CYP3A4 | CYP3A4 | ||
| MEK/BRAF inhibitors | ||||||
| Dabrafenib19 | 71 (NA) | 23 (NA) | CYP2C8 CYP3A4 |
CYP3A4, CYP2C9, CYP1A2, CYP2B |
||
| Trametinib66 | 80 (<0.1) | 20 (0.1) | CYP2C8 | |||
| Cobimetinib67 | 76 (6.6) | 17.8 (1.6) | CYP3A | CYP3A, CYP2D6 | ||
| Vemurafenib68 | 94 (NA) | 1 (NA) | CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 | |||
| Encorafenib69 | 47 (5) | 47 (2) | CYP3A4 | CYP2C19 | CYP2B6 CYP2C9 CYP3A4 |
CYP2B6, CYP2C8/9, CYP2D6 CYP3A4 |
| Binimetinib70 | 62 (32) | 31 (6.5) | CYP1A2 CYP2C19 |
|||
| Multiple-target TKIs | ||||||
| Cabozantinib71 | 54 (43) | 27 (not detectable) | CYP3A4 | CYP1A1 | CYP2C8 | |
| Anlotinib72,73 | 2.2 (NA) | 0.9 (NA) | CYP3A4 CYP3A5 |
CYP3A4 CYP2C9 |
||
NA, not applicable; TKI, tyrosine kinase inhibitor.