Table 1.
Pharmacokinetics of commonly used targeted cancer therapies
| Tyrosine Kinase Inhibitors | Molecular Target(s) | FDA-Approved Indications | Clinically Significant Drug Metabolism/Elimination | Clinically Significant Adverse Effects |
|---|---|---|---|---|
| Afatinib | ErbB family (EGFR, HER-2,-4) | NSCLC | P-gp substrate | |
| Axitinib | VEGFR-1,-2,-3 | RCC | CYP3A4 substrate | |
| Bosutinib | BCR-ABL, SRC family (SRC, LYN, HCK), c-KIT, PDGFR | CML | CYP3A4 substrate; P-gp inhibitor | QT prolongation |
| Cabozantinib | HGFR, RET, VEGFR-1, −2, −3, KIT, FLT3, TIE-2, TRKB, AXL | Medullary thyroid cancer | CYP3A4 substrate | |
| Ceritinib | ALK, IGF-1R, InsR, ROS1 | NSCLC | CYP3A4 substrate & strong inhibitor; P-gp substrate |
QT prolongation Bradycardia |
| Crizotinib | ALK, HGFR, RON | NSCLC | CYP3A4 substrate & moderate inhibitor; CYP2B6 moderate inhibitor; P-gp substrate and inhibitor |
QT prolongation Bradycardia |
| Dasatinib | SRC family (SRC, LCK, YES, FYN), BCR-ABL, c-KIT, EPH-A2, PDGFR-β | ALL, CML | CYP3A4 substrate & weak inhibitor | QT prolongation |
| Erlotinib | EGFR | NSCLC, Pancreatic cancer | CYP3A4 substrate | |
| Gefitinib | EGFR | NSCLC | CYP3A4 substrate; CYP2D6 substrate | |
| Ibrutinib | BTK | CLL, MCL, WM | CYP3A4 substrate; P-gp inhibitor | |
| Imatinib | BCR-ABL, c-KIT, PDGFR, SCF | ALL, CEL, CML, GIST, ASM, DFSP, MDS/MPD | CYP3A4 substrate & moderate inhibitor; P-gp substrate | |
| Lapatinib | EGFR, HER2 | Breast cancer | CYP3A4 substrate; CYP2C8 moderate inhibitor; P-gp substrate & inhibitor | QT prolongation |
| Lenvatinib | VEGFR-1,-2,-3, FGFR-1,-2,-3,-4, PDGF-α, KIT, RET | Thyroid cancer | QT prolongation | |
| Nilotinib | BCR-ABL, PDGFR, c-KIT | CML | CYP3A4 substrate & moderate inhibitor; CYP2D6 moderate inhibitor; CYP2C8 moderate inhibitor; P-gp inhibitor | QT prolongation |
| Osimertinib | EGFR | NSCLC | CYP3A4 substrate; BRCP inhibitor | QT prolongation |
| Pazopanib | VEGFR-1,-2,-3, PDGFR-α,-β, FGFR-1,-3, c-KIT, IL-2 inducible TcK, Lck, c-Fms | RCC, STS | CYP3A4 substrate; P-gp substrate | QT prolongation |
| Ponatinib | BCR-ABL, VEGFR, FGFR, PDGFR, EPH, SRC, KIT, RET, TIE2, FLT3 | ALL, CML | CYP3A4 substrate | |
| Regorafenib | VEGFR-1,-2,-3, KIT, PDGFR-α,-β, RET, FGFR-1,-2, TIES2, DDR2, TrkA, EPH-A2, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, ABL | Colorectal cancer, GIST | CYP3A4 substrate | Bradycardia |
| Ruxolitinib | JAK-1,-2 | Myelofibrosis, Polycythemia vera | CYP3A4 substrate | Bradycardia |
| Sorafenib | RAF, VEGFR-1,-2,-3, PDGFR-β, c-KIT, FLT-3, RET, RET/PTC | RCC, HCC, Thyroid carcinoma | CYP2C9 moderate inhibitor; CYP2B6 moderate inhibitor | QT prolongation |
| Sunitinib | PDGFR-α,-β, VEGFR-1,-2,-3, FLT3, CSF-1R, RET | RCC, GIST, PNET | CYP3A4 substrate; P-gp inhibitor | QT prolongation |
| Vandetanib | EGFR, VEGFR, RET, BRK, TIES2, EPH, SRC | Medullary thyroid cancer | P-gp inhibitor | QT prolongation |
ALK anaplastic lymphoma kinase, BCR-ABL fusion gene, BRAF B-Raf Proto-Oncogene, Serine/Threonine Kinase, BRK protein tyrosine kinase 6, BTK Bruton’s Tyrosine Kinase, c-Fms transmembrane glycoprotein receptor tyrosine kinase, c-KIT cytokine receptor, CSF-1R colony-stimulating factor type 1, DDR2 discoidin domain receptor 2, EGFR epidermal growth factor receptor, EPH Ephrin Receptor, ErbB family of tyrosine kinase inhibitors, FGFR fibroblast growth factor receptor, FLT FMS-like Tyrosine Kinase, HCK Hemopoietic cell kinase, HER human epidermal growth factor receptor, HGFR hepatocyte growth factor receptor, IGF-1R insulin-like growth factor 1 receptor. IL-2 inducable, TCK interleukin-2 receptor inducible T-cell Kinase, InsR insulin receptor, JAK Janus Associated Kinases, Lck Leukocyte-specific Protein Tyrosine Kinase, PDGFR platelet-derived growth factor receptor, PTK protein tyrosine kinase 2 beta, RET “Rearranged During Transfection”, RON Recepteur d’Origine Nantais, SCF stem cell factor, TIE Tyrosine Kinase with Immunoglobulin-like and EGF-like Domains, VEGFR vascular endothelial growth receptor, ALL acute lymphoblastic leukemia, ASM aggressive systemic mastocytosis, CEL chronic eosinophilic leukemia, CML chronic myeloid leukemia, DFSP Dermatofibrosarcoma Protuberans, GIST gastrointestinal stromal tumor, HCC hepatocellular carcinoma, MCL mantle cell lymphoma, MDS/MPD myelodysplastic syndrome/myeloproliferative disease, NSCLC non-small cell lung cancer, PNET pancreatic neuroendocrine tumor, RCC renal cell carcinoma, STS soft tissue sarcoma, WM Waldenstrom’s Macroglobulinemia, BRCP breast cancer resistance protein, P-gp P-glycoprotein