"The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).
CLL is a blood and bone ma"...
Mechanism of Action
Bosutinib is a tyrosine kinase inhibitor. Bosutinib 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. In mice, treatment with bosutinib reduced the size of CML tumors relative to controls and inhibited growth of murine myeloid tumors expressing several imatinib-resistant forms of Bcr-Abl.
The effect of a single dose of bosutinib 500 mg alone and with ketoconazole on the QTc interval was evaluated in a randomized, placebo-and active-controlled (moxifloxacin 400 mg) two or three-period crossover thorough QT study in 60 healthy subjects. No significant changes in placebo adjusted, baseline-corrected QTc were observed.
Following administration of a single dose of BOSULIF 500 mg with food in patients with cancer, the median time-to-peak concentration (tmax) was 4-6 hours. Bosutinib exhibits dose proportional increases in AUC and Cmax, over the dose range of 200 to 800 mg. After 15 daily doses of BOSULIF (500 mg) with food in patients with CML, the mean (SD) Cmax value was 200 (12) ng/mL, and the mean (SD) AUC was 3650 (425) ng•h/mL. When given with a high fat meal, the Cmax and AUC of bosutinib increased 1.8and 1.7-fold, respectively.
After administration of a single dose of BOSULIF 500 mg with food in patients with CML, bosutinib had a mean apparent volume of distribution ± standard deviation of 6080 ± 1230 L.
Bosutinib was highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy subjects (96%), and binding was not concentration-dependent. Bosutinib is a P-gp substrate and inhibitor in vitro. No studies have been conducted with other transporters.
Bosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite. All the metabolites were deemed inactive.
In patients with CML given single oral doses of BOSULIF 500 mg with food, the mean terminal phase elimination half-life (t½) was 22.5 (1.7) hours, and the mean (SD) clearance (Cl/F) was 189 (48) L/h. In six healthy male subjects given a single oral dose of [14C] radiolabeled bosutinib, 91.3% of the dose was recovered in feces and 3% of the dose recovered in urine.
In a dedicated hepatic impairment trial, a single dose of BOSULIF 200 mg was administered with food to 18 volunteers with hepatic impairment (Child-Pugh classes A, B, and C) and 9 matched healthy volunteers. Cmax of bosutinib increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C, and bosutinib AUC increased 2.3-fold, 2-fold, and 1.9-fold, respectively [see DOSAGE AND ADMINISTRATION, and Use in Special Populations].
In a dedicated renal impairment trial, a single dose of BOSULIF 200 mg was administered with food to 26 volunteers with mild (CLcr: 51 to 80 mL/min), moderate (CLcr: 30 to 50 mL/min) or severe renal impairment (CLcr less than 30 mL/min) and to 8 healthy volunteers with normal renal function. Creatinine Clearance for category classification was calculated by the Cockcroft-Gault formula. Subjects with moderate and severe renal impairment had a 35% and 60% increase in AUC compared to healthy volunteers with normal renal function, respectively. Bosutinib exposure was not changed in patients with mild renal impairment. The BOSULF dose should be reduced in patients with CLcr less than 30 mL/min and patients with CLcr between 30 to 50 mL/min should have their dose reduced if they are unable to tolerate a 500 mg dose [see DOSAGE AND ADMINISTRATION and Use in Special Populations].
In a cross-over trial of 24 healthy volunteers, a single dose of 100 mg of BOSULIF was either administered alone or in combination with five daily doses of 400 mg of ketoconazole under fasting conditions. Ketoconazole increased bosutinib Cmax and AUC 5.2-fold and 8.6-fold, respectively [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].
In a cross-over trial of 24 healthy volunteers, a single dose of 500 mg of BOSULIF was either administered alone or in combination with six daily doses of 600 mg of rifampin under fed conditions. Rifampin decreased bosutinib Cmax and AUC by 86% and 94%, respectively [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].
An in vitro study suggests that BOSULIF has the potential to increase the plasma concentrations of drugs that are P-gp substrates. The estimated I/IC50 was 0.19, when considering the Cmax at the 500 mg dose of BOSULIF.
pH Altering Medications
BOSULIF displays pH-dependent aqueous solubility, in vitro. In a cross-over trial in 24 healthy volunteers, a single oral dose of 400 mg of BOSULIF was either administered alone or in combination with multiple-oral doses of 60 mg of lansoprazole under fasting conditions. Lansoprazole decreased bosutinib Cmax and AUC by 46% and 26%, respectively.
Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP) and Blast Phase (BP) CML
A single-arm, Phase ½ open-label, multicenter trial was conducted to evaluate the efficacy and safety of BOSULIF 500 mg 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 definition of imatinib resistance included (1) failure to achieve or maintain any hematologic improvement within four weeks; (2) failure to achieve a complete hematologic response (CHR) by 3 months, cytogenetic response by 6 months or major cytogenetic response (MCyR) by 12 months; (3) progression of disease after a previous cytogenetic or hematologic response; or (4) presence of a genetic mutation in the BCR-Abl gene associated with imatinib resistance. Imatinib intolerance was defined as inability to tolerate imatinib due to toxicity, or progression on imatinib and inability to receive a higher dose due to toxicity. The definitions of resistance and intolerance to both dasatinib and nilotinib were similar to those for imatinib. The protocol was amended to exclude patients with a known history of the T315I mutation after 396 patients were enrolled in the trial.
The efficacy endpoints for patients with CP CML previously treated with one prior TKI (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. The efficacy endpoints for patients with previously treated AP and BP CML were confirmed complete hematologic response (CHR) and overall hematologic response (OHR).
The trial enrolled 546 patients with CP, AP or BP CML. Of the total patient population 73% were imatinib resistant and 27% were imatinib intolerant. In this trial, 53% of patients were males, 65% were Caucasian, and 20% were 65 years old or older. Of the 546 treated patients, 503 were considered evaluable for efficacy. Patients were evaluable for efficacy if they had received at least one dose of BOSULIF and had a valid baseline efficacy assessment. Among evaluable patients, there were 266 patients with CP CML previously treated with one prior TKI (imatinib), 108 patients with CP CML previously treated with both imatinib and at least 1 additional TKI, and 129 patients with advanced phase CML previously treated with at least one TKI.
Median duration of BOSULIF treatment was 22 months in patients with CP CML previously treated with one TKI (imatinib), 8 months in patients with CP CML previously treated with imatinib and at least 1 additional TKI, 10 months in patients with AP CML previously treated with at least imatinib, and 3 months in patients with BP CML previously treated with at least imatinib. The 24 week efficacy results are present in Table 6.
Table 6: Efficacy Results in Patients with Ph+ CP CML
with Resistance to or Intolerance to Imatinib
|Prior Treatment with Imatinib Only
at 24 Weeks
|Prior Treatment with Imatinib and Dasatinib or Nilotinib
n (%) by 24 Weeks
|MCyR (95% CI)||90 (33.8) (28.2, 39.9)||29 (26.9) (18.8, 36.2)|
|Abbreviations: CI = confidence interval, MCyR = major cytogenetic response|
The minimum follow-up was 23 months for patients with CP CML treated with one prior TKI (imatinib) and 13 months for patients with CP CML treated with imatinib and at least one additional TKI. For the 53.4% of patients with CP CML treated with one prior TKI (imatinib) who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 52.8% had a MCyR lasting at least 18 months. For the 32.4% of patients with CP CML treated with imatinib and at least one additional TKI who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 51.4% had a MCyR lasting at least 9 months. Of the 374 evaluable patients with CP CML, 16 patients had confirmed disease transformation to AP or BP while on treatment with BOSULIF.
The 48 week efficacy results in patients with accelerated and blast phases CML previously treated with at least imatinib are summarized in Table 7.
Table 7: Efficacy Results in
Patients with Accelerated Phase and Blast Phase CML Previously Treated with at
|CHRa by Week 48 (95% CI)||21 (30.4) (19.9, 42.7)||9 (15) (7.1, 26.6)|
|OHRa by Week 48 (95% CI)||38 (55.1) (42.6, 67.1)||17 (28.3) (17.5, 41.4)|
|Abbreviations: CI = confidence
interval, OHR = overall hematologic response, CHR = complete hematologic
aOverall hematologic response (OHR) = major hematologic response (complete hematologic response + no evidence of leukemia) or return to chronic phase (RCP). All responses were confirmed after 4 weeks. Complete hematologic response (CHR) for AP and BP CML: WBC less than or equal to institutional ULN, platelets greater than or equal to 100,000/mm³ and less than 450,000/mm³, absolute neutrophil count (ANC) greater than or equal to 1.0×109 /L, no blasts or promyelocytes in peripheral blood, less than 5% myelocytes + metamyelocytes in bone marrow, less than 20% basophils in peripheral blood, and no extramedullary involvement. No evidence of leukemia (NEL): Meets all other criteria for CHR except may have thrombocytopenia (platelets greater than or equal to 20,000/mm³ and less than 100,000/mm³) and/or neutropenia (ANC greater than or equal to 0.5×109 /L and less than 1.0×109 /L). Return to chronic phase (RCP) =disappearance of features defining accelerated or blast phases but still in chronic phase.
The CHR and OHR rates were based on a minimum follow-up of 12 months for patients with AP CML and 18 months for patients with BP CML. Of the 69 evaluable patients with AP CML, 4 patients had confirmed disease transformation to BP while on BOSULIF treatment.
Last reviewed on RxList: 10/17/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Bosulif Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.