Tyrosine kinase inhibitor.
Bosutinib 100mg, 500mg; tablets.
Treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.
Bosutinib is a tyrosine kinase inhibitor. It inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells.
A single-arm, Phase 1/2 open-label, multicenter trial was conducted to evaluate the efficacy and safety of bosutinib 500mg once daily in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic, accelerated, and blast phase disease previously treated with one prior TKI (imatinib) or more than one TKI (imatinib followed by dasatinib and/or nilotinib). The trial enrolled 546 patients with CP, AP or BP CML.
The efficacy endpoints for patients with CP CML previously treated with imatinib were the rate of attaining MCyR at week 24 and the duration of MCyR. The efficacy endpoints for patients with CP CML previously treated with both imatinib and at least 1 additional TKI were the cumulative rate of attaining MCyR by week 24 and the duration of MCyR. In patients with CP CML with prior treatment with only imatinib, 33.8% achieved an MCyR at week 24 and, with a minimum follow-up of 23 months, 53.4% achieved an MCyR. In patients with CP CML with prior treatment with imatinib and dasatinib and/or nilotinib, 26.9% achieved an MCyR by week 24 and, with a minimum follow-up of 13 months, 32.4% achieved an MCyR.
The efficacy endpoints for patients with previously treated AP and BP CML were confirmed complete hematologic response (CHR) and overall hematologic response (OHR). By Week 48, 30.4% of patients with AP CML attained CHR; 55.1% attained OHR. Also, 15% of patients with BP CML attained CHR; 28.3% attained OHR.
500mg once daily with food. Continue until disease progression or patient intolerance. Consider dose escalation to 600mg once daily in patients who do not reach complete hematological response (CHR) by week 8 or a complete cytogenetic -response (CCyR) by week 12, who did not have Grade 3 or higher adverse reactions. Adjust dose for hematologic and non-hematologic toxicity: see literature. Hepatic impairment: 200mg daily.
<18 years: not established.
Monitor and manage GI toxicity, fluid retention; withhold, reduce dose, or discontinue as necessary. Perform CBC weekly for first month, then monthly; hepatic enzyme tests monthly for first three months (more frequently if transaminase elevations occur); withhold, reduce dose, or discontinue as necessary. Pregnancy (Category D), nursing mothers: not recommended.
Potentiated by concomitant strong or moderate CYP3A and/or P-gp inhibitors (eg, ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, conivaptan, fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprenavir, crizotinib, imatinib, verapamil, grapefruit products, ciprofloxacin); avoid. Antagonized by concomitant strong or moderate CYP3A inducers (eg, rifampin, phenytoin, carbamazepine, St. John’s Wort, rifabutin, phenobarbital, bosentan, nafcillin, efavirenz, modafinil etravirine); avoid. Antagonized by proton pump inhibitors (eg, lansoprazole); consider short-acting antacids or H2 blockers instead; separate dosing by more than 2 hours. May potentiate drugs that are P-gp substrates (eg, digoxin).
Diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, fatigue; fluid retention (monitor), hepatic toxicity.
Tabs 100mg—120; 500mg—30