Table 2. Pharmacological properties of Tyrosine Kinase Inhibitors.
| Imatinib 51 | Dasatinib 52 | Nilotinib 53 | Bosutinib 54 | Ponatinib 55 | |
|---|---|---|---|---|---|
|
Year of FDA/EMA
approval |
2001/2001 | 2006/2006 | 2007/2007 | 2012/2013 | 2012/2013 |
| Kinases inhibited | BCR-ABL, PDGF, SCF, c- kit |
BCR-ABL, SRC family kinases, c-kit, EPHA2, PDGFRβ |
BCR-ABL, c-kit, PDGFR, CSF-1R, DDR1 |
BCR-ABL, SRC family kinases, Minimal activity against c-kit or PDGFR |
Native/mutant BCR- ABL, including T315I, VEGFR, PDGFR, FGFR, EPH receptors, SRC family kinases, KIT,RET, TIE2, FLT3 |
|
Indications and
usage in CML |
First line | First or second line | First or second line | Resistance or intolerance to prior therapy |
T315I-positive or when no other TKI is indicated |
|
Absolute oral
bioavailability |
98% | 14-34% (animal studies) 56 |
50-82% | 23-64% (animal studies) |
Not determined |
|
Time to maximum
concentration (hours) |
2-4 | 0.5- 6 | 3 | 4-6 | 6 |
|
Volume of
distribution (liters) |
435 | 2505 | 273 57 | 6080 | 1223 |
| Half-life (hours) | 18 | 3- 5 | 17 | 22.5 | 24 |
| CNS penetration | 0.5-2% 58 | 5-28% 59 | 0.23-1.5% 60 | ~50% 61 | Not determined |
| Metabolism | Major: CYP3A4 Minor: CYP1A2, CYP2D6, CYP2C9, and CYP2C19 |
Major: CYP3A4 | Major: CYP3A4 | Major: CYP3A4 | Major: CYP3A4 Minor: CYP2C8, CYP2D6, CYP3A5 esterases and/or amidases |
| Mode of elimination | ~81% in feces, mostly as metabolites |
~85% in feces, mostly as metabolites |
~93% in feces, mostly as parent drug |
~91% in feces | ~ 87% in feces |
|
Recommended
dosage |
CP: 400-800 mg/day AP/BP: 600-800 mg/day |
CP: 100 mg OD AP/BP:140 mg OD With/without food |
First line in CP: 300 mg BID Second line in CP/AP: 400 mg BID Without food |
CP/AP/BP: 500-600 mg OD With food |
CP/AP/BP: 45 mg OD With food |
|
Dose adjustment:
Hepatic impairment Renal impairment |
Yes Yes |
No No |
Yes No |
Yes No |
Yes No |
|
Important drug
interactions |
CYP3A4 inducers CYP3A4 inhibitors Warfarin |
CYP3A4 inducers CYP3A4 inhibitors Proton pump inhibitors Antacids H2 Antagonists |
CYP3A4 inducers CYP3A4 inhibitors Proton pump inhibitors Anti-arrhythmics |
CYP3A4 inducers CYP3A4 inhibitors Proton pump inhibitors |
Strong CYP3A inhibitors Strong CYP3A inducers |
| Use in Pregnancy | Category D | Category D | Category D | Category D | Category D |
|
Use in breast
feeding mothers |
Not known | Not known | Not known | Not known | Not known |
| Contraindications | Hypokalemia Hypomagnesemia Long QT syndrome |
Hypersensitivity to Bosutinib* |
|||
|
Approximate cost
for one month supply |
$11053 | $12428 | $12433 | $13078 | $13536 |
| Other indications | Ph+ ALL; MDS/MPD; Aggressive systemic mastocytosis; Hypereosinophilic syndrome and/or chronic eosinophilic leukemia; Dermatofibrosarcoma protuberans; GIST |
Ph+ ALL GIST |
GIST | Ph+ ALL when no other TKI is indicated or T315I positive |
Abbreviations: FDA: US Food and Drug Administration; EMA: European Medicines Agency; CP: Chronic phase; AP: Accelerated phase; BP: Blast phase; OD: Once daily; BID: Twice daily;
In the BOSULIF clinical trials, anaphylactic shock occurred in less than 0.2% of treated patients.
Strong CYP3A inducers: rifampin, phenytoin, carbamazepine, St. John’s Wort, rifabutin and phenobarbital.
Moderate CYP3A inducers include bosentan, nafcillin, efavirenz, modafinil and etravirine
Strong CYP3A inhibitors include ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and conivaptan.
Moderate CYP3A inhibitors include fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin