Chemical formula: C₂₆H₂₉Cl₂N₅O₃ Molecular mass: 530.446 g/mol PubChem compound: 5328940
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.
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.
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. 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 t½ 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 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.
Foetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental transfer study in gravid Sprague-Dawley rats. In a separate study, bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1, 3, and 10 mg/kg/day. This study did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes. 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) 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 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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