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. Modelling 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 treated with bosutinib 500 mg, QTcF increase >60 ms from baseline was observed in 9 (1.6%) of 570 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 (N=268) with a QTcF increase of >60 ms from baseline. In the Phase 3 clinical study in patients with newly-diagnosed Ph+ CP CML treated with bosutinib 500 mg, QTcF increase >60 ms from baseline was observed in 2 (0.8%) of 248 patients receiving bosutinib. In the Phase 4 clinical study in patients with Ph+ CML previously treated with 1 or more TKI(s) treated with bosutinib 500 mg (N=163), there were no patients with a QTcF increase >60 ms from baseline. A proarrhythmic potential of bosutinib cannot be ruled out.
Bosutinib pharmacokinetics were assessed following oral dosing with food in adult patients with CML and were presented as geometric mean (CV%), unless otherwise specified.
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 of AUC over the dose range of 100 to 600 mg. The bosutinib PK parameters for adults were derived from a population PK analysis using pooled data across studies. Bosutinib steady state Cmax was 127 ng/mL (31%), Ctrough was 68 ng/mL (39%) and AUC was 2 370 ng•h/mL (34%) following multiple oral doses of bosutinib 400 mg; Bosutinib steady state Cmax was 171 ng/mL (38%), Ctrough was 91 ng/mL (42%) and AUC was 3 150 ng•h/mL (38%) following multiple oral doses of bosutinib 500 mg.
No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet or intact hard capsule dosage forms of bosutinib at the same dose, under fed conditions. Bosutinib hard capsule contents mixed with applesauce or yogurt exhibited comparable PK to the bosutinib intact hard capsule under fed condition in healthy adult participants.
The solubility of bosutinib is pH-dependent and absorption is reduced when gastric pH is increased.
Bosutinib Cmax increased 1.8-fold and AUC increased 1.7-fold when bosutinib tablets were given with a high-fat meal to healthy subjects compared to administration under fasted condition. In a separate study, bosutinib hard capsule administration under the fed condition resulted in exposures approximately 1.5 – 1.6-fold higher than administration under fasted conditions.
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 and in healthy subjects indicate that there are no clinically relevant effects of age, gender or body weight. Population pharmacokinetic analyses revealed that Asians had a 18% lower clearance corresponding to an approximately 25% increase in bosutinib exposure (AUC).
The pharmacokinetics of bosutinib in 41 newly-diagnosed or resistant/intolerant paediatric patients 1 to <18 years of age were evaluated over the dose range of 300 mg/m² to 400 mg/m² administered orally once daily with food. In paediatric patients, median Tmax occurred at approximately 3 hours post-dose (range 1 to 8 hours post-dose). Exposures increased in a dose proportional manner between 100–600 mg. The geometric mean AUCtau in the 300 mg/m² to 400 mg/m² cohorts was within the range (+ / - 20%) of geometric mean AUCtau for the adult dose level in the respective newly-diagnosed and resistant or intolerant Ph+ CML indications, however Cmax and clearance were higher and Cmin was lower in paediatric patients than in adults.
Bosutinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, reproductive toxicity, and phototoxicity 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 comparison 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 38 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 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 and 6-month rasH2 mouse carcinogenicity studies.
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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