Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors
ATC code: L01XE14
Bosutinib belongs to a pharmacological class of medicinal products known as kinase inhibitors. Bosutinib inhibits the abnormal BCR-ABL kinase that promotes CML. Modeling studies indicate that bosutinib binds the kinase domain of BCR-ABL. Bosutinib is also an inhibitor of Src family kinases including Src, Lyn and Hck. Bosutinib minimally inhibits platelet-derived growth factor (PDGF) receptor and c-Kit.
In in vitro studies, bosutinib inhibits proliferation and survival of established CML cell lines, Ph+ ALL cell lines, and patient-derived primary primitive CML cells. Bosutinib inhibited 16 of 18 imatinib-resistant forms of BCR-ABL expressed in murine myeloid cell lines. Bosutinib treatment reduced the size of CML tumours growing in nude mice and inhibited growth of murine myeloid tumours expressing imatinib-resistant forms of BCR-ABL. Bosutinib also inhibits receptor tyrosine kinases c-Fms, EphA and B receptors, Trk family kinases, Axl family kinases, Tec family kinases, some members of the ErbB family, the non-receptor tyrosine kinase Csk, serine/threonine kinases of the Ste20 family, and 2 calmodulin-dependent protein kinases.
The effect of bosutinib 500 mg administration on corrected QTc was evaluated in a randomised, single-dose, double-blind (with respect to bosutinib), crossover, placebo- and open-label moxifloxacin-controlled study in healthy subjects.
The data from this study indicate that bosutinib does not prolong the QTc in healthy subjects at the dose of 500 mg daily with food, and under conditions that give rise to supratherapeutic plasma concentrations. Following administration of a single oral dose of bosutinib 500 mg (therapeutic dose) and bosutinib 500 mg with ketoconazole 400 mg (to achieve supratherapeutic concentrations of bosutinib) in healthy subjects, the upper bound of the 1-sided 95% confidence interval (CI) around the mean change in QTc was less than 10 ms at all post-dose time points, and no adverse events suggestive of QTc prolongation were observed.
In a study in liver impaired subjects, an increasing frequency of QTc prolongation >450 ms with declining hepatic function was observed. In the Phase ½ clinical study in patients with previously treated Ph+ leukaemias, QTcF interval changes >60 ms from baseline were observed in 6 (1.1%) of 562 patients. In the Phase 3 clinical study in patients with newly-diagnosed CP CML treated with bosutinib 400 mg, there were no patients in the bosutinib treatment group with an increase of >60 ms from baseline when the QT interval was corrected using Fridericia’s formula (QTcF). In the Phase 3 clinical study in patients with newly diagnosed Ph+ CP CML treated with bosutinib 500 mg, QTcF interval changes >60 ms from baseline were observed in 2 (0.8%) of 248 patients receiving bosutinib. A proarrhythmic potential of bosutinib cannot be ruled out.
A 2-arm, Phase 3, open-label, multicentre superiority trial was conducted to investigate the efficacy and safety of bosutinib 400 mg once daily alone compared with imatinib 400 mg once daily alone in adult patients with newly-diagnosed Ph+ CP CML. The trial randomised 536 patients (268 in each treatment group) with Ph+ or Ph- newly-diagnosed CP CML (intent-to-treat population [ITT]) including 487 patients with Ph+ CML harbouring b2a2 and/or b3a2 transcripts and baseline BCR-ABL copies >0 (modified intent-to-treat [mITT] population).
The primary efficacy endpoint was the proportion demonstrating a major molecular response (MMR) at 12 months (48 weeks) in the bosutinib treatment group compared with that in the imatinib treatment group in the mITT population. MMR was defined as ≤0.1% BCR-ABL/ABL ratio by international scale (corresponding to ≥3 log reduction from standardised baseline) with a minimum of 3,000 ABL transcripts as assessed by the central laboratory. The secondary efficacy endpoints included MMR by 18 months, duration of MMR, CCyR by 12 months, duration of CCyR, event-free survival (EFS), and overall survival (OS). Complete cytogenetic response by Month 12, a secondary endpoint, was defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥20 metaphases derived from bone marrow aspirate or MMR if an adequate cytogenetic assessment was unavailable. The p-values for endpoints other than MMR at 12 months and CCyR by 12 months have not been adjusted for multiple comparisons.
Baseline characteristics for the mITT population were well balanced between the 2 treatment groups with respect to age (median age was 52 years for the bosutinib group and 53 years for the imatinib group with 19.5% and 17.4% of patients 65 years of age or older, respectively); gender (women 42.3% and 44.0%, respectively); and race (Caucasian 77.6% and 77.2%, Asian 12.2% and 12.4%, Black or African American 4.1% and 4.1%, and Other 5.7% and 5.8%, respectively, and 1 unknown in each group).
After a minimum of 12 months of follow-up in the mITT population, 77.6% of patients treated with bosutinib (N=241) and 72.4% of patients treated with imatinib (N=239) were still receiving first-line treatment.
After a minimum of 12 months of follow-up in the mITT population, discontinuations due to disease progression to AP or BP CML for bosutinib-treated patients were 0.4% compared to 1.7% for imatinib-treated patients. Five bosutinib patients and 7 imatinib patients transformed to AP CML or BP CML. Discontinuations due to suboptimal response or treatment failure as assessed by the investigator occurred for 2.0% of patients in the bosutinib-treated group compared to 6.3% of patients in the imatinib-treated group. One patient on bosutinib and 7 patients on imatinib died while on study.
The efficacy results are summarised in Table 3.
Table 3. Summary of MMR at Months 12 and 18 and CCyR by Month 12, by treatment group in the mITT population:
At Month 12, the MR4 rate (defined as ≤ 0.01% BCR-ABL [corresponding to ≥ 4 log reduction from standardised baseline] with a minimum of 9,800 ABL transcripts) was higher in the bosutinib treatment group compared to the imatinib treatment group in the mITT population (20.7% [95% CI: 15.7%, 25.8%] versus 12.0% [95% CI: 7.9%, 16.1%], respectively, 1-sided p-value=0.0052).
At Months 3, 6, and 9, the proportion of patients with MMR was higher in the bosutinib treatment group compared to the imatinib treatment group (Table 4).
Table 4. Comparison of MMR at Months 3, 6, and 9 by treatment in the mITT population:
| Time | Number (%) of subjects with MMR | 1-sided p-valuea | |
|---|---|---|---|
| Bosutinib (N=246) | Imatinib (N=241) | ||
| Month 3 (95% CI) | 10 (4.1) (1.6, 6.5) | 4 (1.7) (0.0, 3.3) | 0.0578 |
| Month 6 (95% CI) | 86 (35.0) (29.0, 40.9) | 44 (18.3) (13.4, 23.1) | <0.0001 |
| Month 9 (95% CI) | 104 (42.3) (36.1, 48.4) | 71 (29.5) (23.7, 35.2) | 0.0015 |
Note: Percentages were based on number of patients in each treatment group. MMR was defined as ≤0.1% BCR-ABL/ABL ratio on international scale (corresponding to ≥3 log reduction from standardised baseline) with a minimum of 3,000 ABL transcripts assessed by the central laboratory.
Abbreviations: BCR-ABL=breakpoint cluster region-Abelson; CI=confidence interval; CMH=Cochran-Mantel-Haenszel; CML=chronic myelogenous leukaemia; mITT=modified intent-to-treat; MMR=major molecular response; Ph+=Philadelphia chromosome-positive.
a p-value based on CMH test stratified by geographical region and Sokal score at randomisation.
The cumulative incidence of MMR adjusting for competing risk of treatment discontinuation without MMR was higher in the bosutinib treatment group compared to the imatinib treatment group in the mITT population (45.1% [95% CI: 38.8%, 51.2%] versus 33.7% [95% CI: 27.8%, 39.6%] at Week 48; hazard ratio [HR] from a stratified proportional subdistributional hazards model: 1.35 [95% CI: 1.07, 1.70], 1-sided p-value = 0.0086). The median time to MMR for responders was 24.7 weeks versus 36.3 weeks for the bosutinib treatment and imatinib treatment groups, respectively, in the mITT population.
The cumulative incidence of CCyR adjusted for the competing risk of treatment discontinuation without CCyR was higher in the bosutinib treatment group compared to the imatinib treatment group in the mITT population (79.1% [95% CI: 73.4%, 83.7%] versus 67.3% [95% CI: 60.9%, 72.8%] at Week 48; HR: 1.38, [95% CI: 1.13, 1.68]; 1-sided p-value=0.0003). The median time to CCyR (responders only) was 23.9 weeks in the bosutinib group compared to the 24.3 weeks imatinib group.
The Kaplan-Meier estimates of OS at 48 weeks for bosutinib and imatinib patients in the mITT population were 99.6% (95% CI: 97.1%, 99.9%) and 97.9% (95% CI: 95.0%, 99.1%), respectively.
No additional deaths or transformations occurred in the ITT population.
A single-arm, Phase ½ open-label, multicentre trial was conducted to evaluate the efficacy and safety of bosutinib 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 1 prior TKI (imatinib) or more than 1 TKI (imatinib followed by dasatinib and/or nilotinib).
There were 570 patients treated with bosutinib in this trial including CP CML patients previously treated with only 1 prior TKI (imatinib), CP CML patients previously treated with imatinib and at least 1 additional TKI (dasatinib and/or nilotinib), CML patients in accelerated or blast phase previously treated with at least 1 TKI (imatinib) and patients with Ph+ ALL previously treated with at least 1 TKI (imatinib).
The primary efficacy endpoint of the study was the major cytogenetic response (MCyR) rate at Week 24 in patients with imatinib-resistant CP CML previously treated with only 1 prior TKI (imatinib). Other efficacy endpoints include the cumulative MCyR rate, time to and duration of MCyR, and time to and duration of CHR, in patients with CP CML previously treated with only 1 prior TKI (imatinib). For patients previously treated with both imatinib and at least 1 additional TKI, the endpoints include the cumulative MCyR rate, time to and duration of MCyR, and time to and duration of CHR. For patients with AP and BP CML previously treated with at least 1 prior TKI (imatinib), the endpoints were cumulative overall haematological response (OHR) and time to and duration of OHR. Other efficacy endpoints include transformation to AP/BP, progression free survival and OS for all cohorts.
The efficacy results for Ph+ CP CML patients previously treated with imatinib and at least 1 additional TKI (minimum follow-up 48 months, median treatment duration of 9 months and 24.4% still on-treatment at 48 months) and the results for Ph+ CP CML patients previously treated with only imatinib (minimum follow-up 60 months, median treatment duration of 26 months and 40.5% still on-treatment at 60 months) are presented in Table 5.
The efficacy results for AP (minimum follow-up 48 months, median treatment duration of 10 months and 17.7% still on-treatment at 48 months) and BP (minimum follow-up 48 months, median treatment duration of 2.8 months and 3.1% still on-treatment at 48 months) Ph+ CML patients are present in Table 5.
Table 5. Efficacy results in previously treated patients with chronic and advanced phase CML*:
| Ph+ CP CML with prior imatinib treatment only | Ph+ CP CML with prior treatment with imatinib and dasatinib or nilotinib | Accelerated phase with prior treatment of at least imatinib | Blast phase with prior treatment of at least imatinib | |
|---|---|---|---|---|
| Cumulative cytogenetic responsea | N=262 | N=112 | N=72 | N=54 |
| MCyR, % (95% CI) | 59.5 (53.3, 65.5) | 40.2 (31.0, 49.9) | 40.3 (28.9, 52.5) | 37.0 (24.3, 51.3) |
| CCyR, % (95% CI) | 49.6 (43.4, 55.8) | 32.1 (23.6, 41.6) | 30.6 (20.2, 42.5) | 27.8 (16.5, 41.6) |
| Time to MCyR for responders onlyb, weeks (95% CI) | 12.3 (12.1, 12.7) | 12.3 (12.0, 14.1) | 12.0 (11.9, 12.1) | 8.2 (4.3, 12.0) |
| Duration of MCyRb | N=156 | N=45 | N=29 | N=20 |
| K-M at year 1/2, % (95% CI)c | 76.4 (68.5, 82.5) | 72.0 (55.1, 83.4) | 62.2 (41.1, 77.6) | 21.2 (5.2, 44.2) |
| K-M at year 4/5, % (95% CI)c | 71.1 (62.6, 78.0) | 69.3 (52.3, 81.3) | 46.7 (27.1, 64.1) | 21.2 (5.2, 44.2) |
| Median, weeks (95% CI) | N/R | N/R | 84.0 (24.0, N/E) | 29.1 (11.9, 38.3) |
| Cumulative haematological responsed | N=283 | N=117 | N=72 | N=60 |
| Overall, % (95% CI) | N/A | N/A | 56.9 (44.7, 68.6) | 28.3 (17.5, 41.4) |
| Major, % (95% CI) | N/A | N/A | 47.2 (35.3, 59.3) | 18.3 (9.5, 30.4) |
| Complete, % (95% CI) | 86.6 (82.0, 90.3) | 73.5 (64.5, 81.2) | 33.3 (22.7, 45.4) | 16.7 (8.3, 28.5) |
| Time to OHR for responders onlyb, weeks (95% CI) | N/A | N/A | 12.0 (11.1, 12.1) | 8.9 (4.1, 12.0) |
| Duration of CHR/OHRe | N=245 | N=86 | N=41 | N=17 |
| K-M at year 1/2, % (95% CI)c | 71.9 (65.1, 77.6) | 73.4 (61.7, 82.1) | 78.2 (59.4, 89.0) | 28.4 (7.8, 53.9) |
| K-M at year 4/5, % (95% CI)c | 66.0 (58.8, 72.3) | 62.9 (50.1, 73.3) | 52.0 (32.3, 68.5) | 19.0 (3.3, 44.5) |
| Median, weeks (95% CI) | N/R | N/R | 207.0 (63.1, N/E) | 32.0 (29.0, 54.6) |
| Transformation to AP/BPf | N=284 | N=119 | N=79 | N/A |
| On-treatment transformation, n | 15 | 5 | 3 | |
| Progression-free survivalf | N=284 | N=119 | N=79 | N=64 |
| K-M at year 1/2, % (95% CI)c | 80.0 (73.9, 84.8) | 75.1 (64.6, 82.9) | 66.8 (53.4, 77.1) | 16.1 (6.6, 29.3) |
| K-M at year 4/5, % (95% CI)c | 72.5 (65.6, 78.2) | 65.1 (53.1, 74.8) | 40.8 (26.6, 54.5) | 8.0 (1.7, 21.2) |
| Median, months (95% CI) | N/R | N/R | 22.1 (14.6, N/E) | 4.4 (3.2, 8.5) |
| Overall survivalf | N=284 | N=119 | N=79 | N=64 |
| K-M at year 1/2, % (95% CI)c | 91.2 (87.1, 94.0) | 91.3 (84.5, 95.2) | 78.1 (67.1, 85.8) | 42.1 (29.7, 53.9) |
| K-M at year 4/5, % (95% CI)c | 83.1 (77.5, 87.4) | 77.0 (66.9, 84.4) | 58.4 (45.6, 69.1) | 20.1 (6.2, 39.8) |
| Median, months (95% CI) | N/R | N/R | N/R | 10.9 (8.7, 19.7) |
* For efficacy results in the subgroup of patients corresponding to the approved indication, see text above.
Snapshot date: 02Oct2015
Cytogenetic Response criteria: Major Cytogenetic Response included Complete [0% Ph+ metaphases from bone marrow or <1% positive cells from fluorescent in situ hybridis ation (FISH)] or partial (1%-35%) cytogenetic responses. Cytogenetic responses were based on the percentage of Ph+ metaphases among ≥20 metaphase cells in each bone marrow sample. FISH analysis (≥200 cells) could be used for post-baseline cytogenetic assessments if ≥20 metaphases were not available.
Overall haematological response (OHR)=major haematological response (complete haematological response + no evidence of leukaemia) or return to chronic phase (RCP). All responses were confirmed after 4 weeks. Complete haematological response (CHR for AP and BP CML: WBC less than or equal to institutional upper limit of normal (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 b lood, and no extramedullary involvement. No evidence of leukaemia (NEL): Meets all other criteria for CHR except may have thrombocytopenia (platelets greater than or equal to 20,000/mm 3 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. Abbreviations: AP=accelerated phase; BP=blast phase; Ph+=Philadelphia chromosome-positive; CP=chronic phase; CML=chronic myelogenous leukaemia; K-M=Kaplan-Meier; N/n=number of patients; N/A=not applicable; N/R=not reached as of minimum follow-up; N/E=not estimable; CI=confidence interval; MCyR=major cytogenetic response; CCyR=complete cytogenetic response; OHR=overall haematological response; CHR=complete haematological response.
a Includes patients (N) with a valid baseline assessment. The analyses allow baseline responders who maintained response post-baseline to be responders. Minimum follow-up time (time from last patient first dose to data snapshot date) of 60 months for CP treated with imatinib only and, 48 months for CP treated with imatinib and at least 1 other TKI, AP and BP.
b Includes patients (N) who attained or maintained MCyR.
c Years 2 (Month 24) and 5 (60 months) for CP treated with imatinib only and Years 1 (Month 12) and 4 (48 months) for CP treated with imatinib and at least 1 other TKI, AP, and BP.
d Sample size (N) includes patients with a valid baseline haematological ass essment. These analyses allow baseline responders who maintained response post-baseline to be responders.
e Includes patients (N) who attained or maintained CHR for CP patients and OHR for AP and BP patients.
f Including patients (N) who received at least 1 dose of bosutinib.
Based on the limited clinical information from the Phase ½ study, some evidence of clinical activity was observed in patients with BCR-ABL mutations (see Table 6).
Table 6. Response by baseline BCR-ABL mutation status in CP CML evaluable population: prior imatinib and dasatinib and/or nilotinib (third-line):
| BCR-ABL mutation status at baseline | Incidence at baseline n (%)a | MCyR attained or maintained Resp/Evalb (%) N=112 |
|---|---|---|
| Mutation assessed | 96 (100.0) | 34/92 (37.0) |
| No mutation | 57 (59.4) | 21/55 (38.2) |
| At least 1 mutation | 39 (40.6) | 13/37 (35.1) |
| Dasatinib resistant mutations | 10 (10.4) | 1/9 (11.1) |
| E255K/V | 2 (2.0) | 0/2 |
| F317L | 8 (8.3) | 1/7 (14.3) |
| Nilotinib resistant mutationsc | 13 (13.5) | 8/13 (61.5) |
| Y253H | 6 (6.3) | 5/6 (83.3) |
| E255K/V | 2 (2.0) | 0/2 |
| F359C/I/V | 7 (7.3) | 5/7 (71.4) |
Snapshot date: 02Oct2015
Note: Baseline mutations were identified before the patient’s first dose of study drug.
Abbreviations: BCR-ABL=breakpoint cluster region-Abelson; CP=chronic phase; CML=chronic myelogenous leukaemia; MCyR=major cytogenetic response; N/n=number of patients; Resp=responders; Eval=evaluable.
a The percentage is based on number of patients with baseline mutation assessment.
b The evaluable population includes patients who had a valid baseline disease assessment.
c 2 patients had more than 1 mutation in this category.
One patient with the E255V mutation previously treated with nilotinib achieved CHR as best response.
In vitro testing indicated that bosutinib had limited activity against the T315I or the V299L mutation. Therefore, clinical activity in patients with these mutations is not expected.
The European Medicines Agency has deferred the obligation to submit the results of studies with Bosulif in one or more subsets of the paediatric population in CML (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called “conditional approval” scheme. This means that further evidence on this medicinal product is awaited.
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Following administration of a single dose of bosutinib (500 mg) with food in healthy subjects, the absolute bioavailability was 34%. Absorption was relatively slow, with a median time-to-peak concentration (tmax) reached after 6 hours. Bosutinib exhibits dose proportional increases in AUC and Cmax, over the dose range of 200 to 600 mg. Food increased bosutinib Cmax 1.8-fold and bosutinib AUC 1.7-fold compared to the fasting state. In CML patients at steady state, Cmax (geometric mean, coefficient of variation [CV]) was 145 (14) ng/mL, and AUCss (geometric mean, CV) was 2,700 (16) ng•h/mL after daily administration of bosutinib at 400 mg with food. After 500 mg bosutinib daily with food, Cmax was 200 (6) ng/mL and AUCss was 3,640 (12) ng•h/mL. The solubility of bosutinib is pH-dependent and absorption is reduced when gastric pH is increased (see section 4.5).
Following administration of a single intravenous dose of 120 mg bosutinib to healthy subjects, bosutinib had a mean (% coefficient of variation [CV]) volume of distribution of 2,331 (32) L, suggesting that bosutinib is extensively distributed to extra vascular tissue.
Bosutinib was highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy subjects (96%), and binding was not concentration-dependent.
In vitro and in vivo studies indicated that bosutinib (parent compound) undergoes predominantly hepatic metabolism in humans. Following administration of single or multiple doses of bosutinib (400 or 500 mg) to humans, the major circulating metabolites appeared to be oxydechlorinated (M2) and N-desmethylated (M5) bosutinib, with bosutinib N-oxide (M6) as a minor circulating metabolite. The systemic exposure of N-desmethylated metabolite was 25% of the parent compound, while the oxydechlorinated metabolite was 19% of the parent compound. All 3 metabolites exhibited activity that was ≤5% that of bosutinib in a Src-transformed fibroblast anchorage-independent proliferation assay. In faeces, bosutinib and N-desmethyl bosutinib were the major drug-related components. In vitro studies with human liver microsomes indicated that the major cytochrome P450 isozyme involved in the metabolism of bosutinib is CYP3A4 and drug interaction studies have shown that ketoconazole and rifampicin had marked effect on the pharmacokinetics of bosutinib (see section 4.5). No metabolism of bosutinib was observed with CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A5.
In healthy subjects given a single intravenous dose of 120 mg bosutinib, the mean (%CV) terminal elimination half-life was 35.5 (24) hours, and the mean (CV) clearance was 61.9 (26) L/h. In a mass-balance study with oral bosutinib, an average of 94.6 of the total dose was recovered in 9 days; faeces (91.3%) was the major route of excretion, with 3.29% of the dose recovered in urine. Seventy-five percent of the dose was recovered within 96 hours. Excretion of unchanged bosutinib in urine was low with approximately 1% of the dose in both healthy subjects and those with advanced malignant solid tumours.
A 200 mg dose of bosutinib administered with food was evaluated in a cohort of 18 hepatically impaired subjects (Child-Pugh classes A, B, and C) and 9 matched healthy subjects. Cmax of bosutinib in plasma increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C; and bosutinib AUC in plasma increased 2.3-fold, 2-fold, and 1.9-fold, respectively. The t1⁄2 of bosutinib increased in hepatic impaired patients as compared to the healthy subjects.
In a renal impairment study, a single dose of 200 mg bosutinib was administered with food to 26 subjects with mild, moderate, or severe renal impairment and to 8 matching healthy volunteers. Renal impairment was based on CLCr (calculated by the Cockcroft-Gault formula) of <30 mL/min (severe renal impairment), 30≤ CLCr ≤50 mL/min (moderate renal impairment), or 50< CLCr ≤80 mL/min (mild renal impairment). Subjects with moderate and severe renal impairment had an increase in AUC over healthy volunteers of 35% and 60%, respectively. Maximal exposure Cmax increased by 28% and 34% in the moderate and severe groups, respectively.
Bosutinib exposure was not increased in subjects with mild renal impairment. The elimination half-life of bosutinib in subjects with renal impairment was similar to that in healthy subjects.
Dose adjustments for renal impairment were based on the results of this study, and the known linear pharmacokinetics of bosutinib in the dose range of 200 to 600 mg.
No formal studies have been performed to assess the effects of these demographic factors. Population pharmacokinetic analyses in patients with Ph+ leukaemia or malignant solid tumour indicate that there are no clinically relevant effects of age, gender, body weight, race.
Bosulif has not yet been studied in children and adolescents less than 18 years of age.
Bosutinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, reproductive toxicity, and photoxicity studies.
Bosutinib did not have effects on respiratory functions. In a study of the central nervous system (CNS), bosutinib treated rats displayed decreased pupil size and impaired gait. A no observed effect level (NOEL) for pupil size was not established, but the NOEL for impaired gait occurred at exposures approximately 11-times the human exposure resulting from the clinical dose of 400 mg and 8-times the human exposure resulting from the clinical dose of 500 mg (based on unbound Cmax in the respective species). Bosutinib activity in vitro in hERG assays suggested a potential for prolongation of cardiac ventricular repolarisation (QTc). In an oral study of bosutinib in dogs, bosutinib did not produce changes in blood pressure, abnormal atrial or ventricular arrhythmias, or prolongation of the PR, QRS, or QTc of the ECG at exposures up to 3-times the human exposure resulting from the clinical dose of 400 mg and 2-times the human exposure resulting from the clinical dose of 500 mg (based on unbound Cmax in the respective species). A delayed increase in heart rate was observed. In an intravenous study in dogs, transient increases in heart rate and decreases in blood pressure and minimal prolongation of the QTc (<10 msec) were observed at exposures ranging from approximately 6-times to 20-times the human exposure resulting from the clinical dose of 400 mg and 4-times to 15-times the human exposure resulting from the clinical dose of 500 mg (based on unbound Cmax in the respective species). The relationship between the observed effects and medicinal product treatment were inconclusive.
Repeated-dose toxicity studies in rats of up to 6 months in duration and in dogs up to 9 months in duration revealed the gastrointestinal system to be the primary target organ of toxicity of bosutinib. Clinical signs of toxicity included foecal changes and were associated with decreased food consumption and body weight loss which occasionally led to death or elective euthanasia.
Histopathologically, luminal dilation, goblet cell hyperplasia, haemorrhage, erosion, and oedema of the intestinal tract, and sinus erythrocytosis and haemorrhage in the mesenteric lymph nodes, were observed. The liver was also identified as a target organ in rats. Toxicities were characterised by an increase in liver weights in correlation with hepatocellular hypertrophy which occurred in the absence of elevated liver enzymes or microscopic signs of hepatocellular cytotoxicity, and is of unknown relevance to humans. The exposure camparison across species indicates that exposures that did not elicit adverse events in the 6- and 9-month toxicity studies in rats and dogs, respectively, were similar to the human exposure resulting from a clinical dose of 400 mg or 500 mg (based on unbound AUC in the respective species).
Genotoxicity studies in bacterial in vitro systems and in mammalian in vitro and in vivo systems with and without metabolic activation did not reveal any evidence for a mutagenic potential of bosutinib.
In a rat fertility study, fertility was slightly decreased in males. Females were observed with increased embryonic resorptions, and decreases in implantations and viable embryos. The dose at which no adverse reproductive effects were observed in males (30 mg/kg/day) and females (3 mg/kg/day) resulted in exposures equal to 0.6-times and 0.3-times, respectively, the human exposure resulting from the clinical dose of 400 mg, and 0.5-times and 0.2-times, respectively, the human exposure resulting from the clinical dose of 500 mg (based on unbound AUC in the respective species). An effect on male fertility cannot be excluded (see section 4.6).
Foetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental transfer study in gravid Sprague-Dawley rats. In a rat pre- and postnatal development study, there were reduced number of pups born at ≥30 mg/kg/day, and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day. The dose at which no adverse development effects were observed (10 mg/kg/day) resulted in exposures equal to 1.3-times and 1.0-times human exposure resulting from the clinical dose of 400 mg and 500 mg, respectively (based on unbound AUC in the respective species). In a rabbit developmental toxicity study at the maternally toxic dose, there were foetal anomalies observed (fused sternebrae, and 2 foetuses had various visceral observations), and a slight decrease in foetal body weight. The exposure at the highest dose tested in rabbits (10 mg/kg/day) that did not result in adverse foetal effects was 0.9-times and 0.7-times the human exposure resulting from the clinical dose of 400 mg or 500 mg, respectively (based on unbound AUC in the respective species).
Following a single oral (10 mg/kg) administration of [14C] radiolabelled bosutinib to lactating Sprague-Dawley rats, radioactivity was readily excreted into breast milk as early as 0.5 hr after dosing. Concentration of radioactivity in milk was up to 8-fold higher than in plasma. This allowed measurable concentrations of radioactivity to appear in the plasma of nursing pups.
Bosutinib was not carcinogenic in the 2-year rat carcinogenicity study.
Bosutinib has demonstrated the ability to absorb light in the UV-B and UV-A range and is distributed into the skin and uveal tract of pigmented rats. However, bosutinib did not demonstrate a potential for phototoxicity of the skin or eyes in pigmented rats exposed to bosutinib in the presence of UV radiation at bosutinib exposures up to 3-times and 2-times the human exposure resulting from the clinical dose of 400 or 500 mg, respectively (based on unbound Cmax in the respective species).
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