Bosutinib BOSUTRIS Bosulif

[Drug Name] Bosutinib Tablets

[Other Chinese Names] Bosutinib, Boshutini, Poshutini

[English Name] Bosutinib Tablets

[Specification] 100 mg × 120 tablets/box; 500 mg × 30 tablets/box

[Manufacturer] Mylan Pharmaceuticals Pvt Ltd

[Indications]

Bosutinib is a tyrosine kinase inhibitor primarily indicated for the following conditions:

Chronic Myeloid Leukemia (CML)

Newly Diagnosed Chronic-Phase CML: It is indicated for adult patients with newly diagnosed chronic-phase Philadelphia chromosome-positive (Ph+) CML. By inhibiting BCR-ABL tyrosine kinase activity and blocking associated signaling pathways, it suppresses the proliferation and survival of leukemia cells, thereby achieving therapeutic objectives.

CML in Various Phases Resistant or Intolerant to Prior Therapy: For patients with Ph+ CML in the chronic, accelerated, or blast phase who are resistant or intolerant to prior therapies—including imatinib—bosutinib serves as an effective treatment option, helping patients control the disease, alleviate symptoms, and prolong survival.

The use of bosutinib must strictly adhere to a physician's advice, with the treatment regimen determined based on the patient's specific medical condition and physical status.

[Recommended Dosage and Administration]

(1) 500 mg once daily, taken with food.

(2) If a patient has not achieved a complete hematologic response by Week 8, or if they have achieved a complete hematologic response by Week 12 without experiencing Grade 3 adverse reactions, a dose increase to 600 mg may be considered.

(3) In the event of hematologic or non-hematologic toxicities, dose adjustment should be considered.

[Adverse Reactions]

Common adverse reactions (≥20%) include diarrhea, nausea/vomiting, thrombocytopenia, rash, abdominal pain, respiratory tract infection, anemia, fever, abnormal liver function, fatigue, cough, and headache. [Warnings and Precautions]

(1) Gastrointestinal Toxicity: Monitor patients for symptoms; treat as necessary, and consider dose adjustment or discontinuation of the drug.

(2) Myelosuppression: Monitor complete blood cell counts; provide symptomatic treatment as necessary.

(3) Hepatotoxicity: Monitor liver enzyme levels at least once monthly during the first three months of treatment; adjust the dose or discontinue the drug as necessary.

(4) Fluid Retention: Monitor patients; provide symptomatic treatment, adjust the dose, or discontinue the drug as necessary.

(5) Nephrotoxicity: Monitor patients' renal function levels during treatment.

(6) Embryo-Fetal Toxicity: May cause fetal harm; women of reproductive potential should avoid pregnancy while taking this medication.

[Contraindications]

Contraindicated in patients with a known hypersensitivity to bosutinib.

[Drug Overview and Mechanism of Action]

(1) Bosutinib is a tyrosine kinase inhibitor that inhibits the Bcr-Abl kinase associated with Chronic Myeloid Leukemia (CML). Additionally, it inhibits Src-family kinases—including Src, Lyn, and Hck—and inhibits Bcr-Abl expressed in imatinib-resistant myeloid cell lines (16/18). However, Bosulif does not inhibit cells harboring the T315I or V299L mutations.

(2) Animal studies have demonstrated that Bosulif can reduce tumor burden and inhibit the growth of myeloid tumors that express the Bcr-Abl gene and are resistant to imatinib.

[Pharmacology and Toxicology]

Pharmacodynamic Properties

Pharmacotherapeutic Group: Protein kinase inhibitors; ATC Code: L01XE06

Bosutinib inhibits the BCR-ABL kinase and Src-family kinases, as well as numerous other selective oncogenic kinases, including c-KIT, ephrin (EPH) receptor kinases, and the PDGFβ receptor. Bosutinib is a potent, subnanomolar inhibitor of the BCR-ABL kinase, demonstrating strong activity at concentrations of 0.6–0.8 nM. It binds to both the inactive and active conformations of the BCR-ABL enzyme. In *in vitro* studies, bosutinib demonstrated activity in leukemia cell lines expressing various imatinib-sensitive and imatinib-resistant disease states. Results from these non-clinical studies indicate that bosutinib can overcome imatinib resistance resulting from: BCR-ABL overexpression, mutations in the BCR-ABL kinase domain, activation of alternative signaling pathways—including SRC family kinases (LYN, HCK)—and overexpression of multi-drug resistance genes. Furthermore, bosutinib inhibits SRC family kinases at sub-nanomolar concentrations.

In separate *in vivo* studies utilizing murine CML models, bosutinib prevented the progression of chronic-phase CML to the blast phase and prolonged the survival of tumor-bearing mice (inoculated with patient-derived CML cell lines growing in various sites, including the central nervous system).

Pre-clinical Safety Data

The non-clinical safety profile of bosutinib was evaluated in a series of *in vitro* and *in vivo* studies conducted in mice, rats, monkeys, and rabbits.

The primary toxicities occurred in the gastrointestinal tract, hematopoietic system, and lymphatic system. In rats and monkeys, gastrointestinal toxicity was dose-limiting, as the intestine consistently served as a target organ. In rats, minimal to mild reductions in erythrocyte parameters were observed, accompanied by changes in the bone marrow; similar changes were noted in monkeys, albeit with a lower incidence. Lymphatic toxicity observed in rats included lymphoid depletion in the lymph nodes, spleen, and thymus, as well as reductions in the weights of lymphoid organs. Changes observed in the gastrointestinal, hematopoietic, and lymphatic systems were reversible following the cessation of treatment.

Renal changes observed in monkeys treated for up to 9 months were limited to an increase in background renal mineralization. Dermal hemorrhage was observed in an acute, single-oral-dose study in monkeys, but was not observed in repeat-dose studies conducted in either monkeys or rats. In rats, bosutinib inhibited platelet aggregation *in vitro* and prolonged epidermal bleeding time *in vivo*, yet it did not induce spontaneous hemorrhage. In vitro analyses of bosutinib activity, utilizing hERG and Purkinje fiber assays, suggest that the drug may prolong ventricular repolarization (QT interval). However, in a single-dose study conducted in monkeys (monitored via telemetry while awake), no changes were observed in the QT interval or ECG waveforms.

Bosutinib was not mutagenic in an in vitro bacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study. In vitro, bosutinib was clastogenic in proliferating Chinese Hamster Ovary (CHO) cells.

The effects of bosutinib on male and female fertility have not been studied. However, findings from repeated-dose toxicity studies conducted across multiple species suggest that bosutinib may potentially impair reproductive function and fertility. Evidence of effects observed in male animals included reduced seminal vesicle volume and secretion, as well as immaturity of the prostate, seminal vesicles, and testes. Administration of bosutinib resulted in uterine inflammation and mineralization in monkeys, as well as ovarian cysts and ovarian enlargement in rodents.

In a standard study of fertility and early embryonic development in rats, bosutinib did not affect the fertility of male or female rats; however, it caused embryonic death at dose levels approximating human clinical exposure. In embryo-fetal development studies, bosutinib similarly caused embryonic death, accompanied by a reduction in litter size in rats and skeletal alterations in the fetuses of both rats and rabbits. These effects occurred at dose levels that did not induce maternal toxicity, indicating that bosutinib acts as a selective reproductive toxicant during the period from implantation through organogenesis.

In mice, bosutinib can induce immunosuppression; this effect is dose-dependent and can be effectively managed through dose reduction and/or modification of the dosing regimen. In an in vitro neutral red uptake phototoxicity assay using mouse fibroblasts, bosutinib demonstrated potential phototoxic activity. A single oral dose of bosutinib administered to female hairless mice, resulting in an exposure level up to 3 times that observed in humans receiving the recommended therapeutic dose (based on AUC), was considered to be devoid of phototoxicity *in vivo*.

[Use in Specific Populations: Pregnancy and Lactation]

Pregnancy

There are currently no adequate data regarding the use of bosutinib in pregnant women. Animal studies have demonstrated reproductive toxicity (see [Pharmacology and Toxicology]). The potential risk to humans is unknown. Bosutinib should not be used in pregnant women unless the potential benefit justifies the potential risk to the fetus. If the drug is used during pregnancy, the patient must be informed of the potential risk to the fetus.

In non-clinical studies, embryo-fetal toxicity was observed in rats and rabbits at plasma concentrations lower than those observed in humans undergoing bosutinib treatment. Fetal death was observed in rats. Embryo-fetal toxicity was induced in rats and rabbits at the lowest tested doses of bosutinib (rats: 2.5 mg/kg/day [15 mg/m²/day]; rabbits: 0.5 mg/kg/day [6 mg/m²/day]). These doses produced maternal AUC values of 105 ng·hr/mL in rats (0.3 times the AUC observed in human females receiving 70 mg twice daily) and 44 ng·hr/mL in rabbits (0.1 times the human AUC). Embryo-fetal toxicity included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; anterior phalanges; pelvis; and body of the hyoid bone), edema, and small liver.

Lactation

There is currently insufficient and limited information regarding the excretion of bosutinib in human or animal milk. Physicochemical data and available pharmacodynamic/toxicological data regarding bosutinib suggest that the drug may be excreted into milk, and a risk to the nursing infant cannot be excluded. Breastfeeding should be discontinued during treatment with this product. [Overdosage]

In clinical studies, overdose with this product was limited to isolated cases. Two patients reported an overdose (280 mg/day for 1 week); in both cases, a significant decrease in platelet count was observed. Since bosutinib is associated with Grade 3 or 4 myelosuppression (see [Precautions]), patients who have ingested a dose exceeding the recommended dosage should be closely monitored for myelosuppression and receive appropriate supportive care. Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular myocardial necrosis and valvular/ventricular/atrial hemorrhage observed in rodents following a single dose of ≥100 mg/kg (600 mg/m²). In monkeys, a trend toward increased systolic and diastolic blood pressure was observed following a single dose of ≥10 mg/kg (120 mg/m²).

[Drug Interactions]

(1) CYP3A Inhibitors and Inducers: Avoid concomitant use with moderate to strong CYP3A inhibitors and inducers.

(2) Proton Pump Inhibitors (PPIs): May reduce Bosulif concentrations; consider using short-acting antacids as an alternative to PPIs.

[Use in Specific Populations]

Nursing Mothers: Breastfeeding should be discontinued.