Bosutinib (SKI-606), with IC50 values in the low nanomolar range, is an effective inhibitor of Bcr-Abl in a number of chronic myelogenous leukemia cell lines[2].

In nude mice, busutinib (oral gavage; 75 mg/kg twice daily or 150 mg/kg once daily) has anti-human KU812 xenograft action. Against syngeneic Bcr-Abl WT and mutant Ba/F3 xenografts, bosutinib (150 mg/kg; once day, five days weekly) has activity[2].

Cell Proliferation Assay[2]
Cell Types: The leukemic Bcr-Abl+ cell lines (KCL22, K562, KU812, and Lama84)
Tested Concentrations: 0.1 μmol/L
Incubation Duration: 72 h
Experimental Results: Inhibited several human CML derived cell lines with IC50 values ranging from 1 to 20 nmol/L

Animal/Disease Models: KU812CM L xenograft model[2]
Doses: 75 mg/kg twice (two times) daily or 150 mg/kg one time/day
Route of Administration: Bosutinib (po (oral gavage); 75 mg/kg twice (two times) daily or 150 mg/kg one time/day)
Experimental Results: Had the therapeutic activity and produced a dose- and schedule-dependent weight loss.

---

Animal/Disease Models: Syngeneic Bcr-Abl WT and mutant Ba/F3 xenografts[2]
Doses: 150 mg/kg
Route of Administration: Bosutinib (150 mg/kg; one time/day, 5 days weekly)
Experimental Results: diminished the rate of tumor growth and prolonged event-free survival of mice.

Absorption, Distribution and Excretion
Bosutinib exhibits dose-proportional increases in Cmax and AUC over the oral dose range of 200 to 800 mg (0.33 to 1.3 times the maximum approved recommended dosage of 600 mg). Bosutinib steady-state Cmax was 127 ng/mL (31%), Ctrough was 68 ng/mL (39%) and AUC was 2370 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 3150 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 capsule dosage forms of bosutinib at the same dose, under fed conditions. The median bosutinib (minimum, maximum) tmax was 6.0 (6.0, 6.0) hours following oral administration of a single oral dose of bosutinib 500 mg with food. The absolute bioavailability was 34% in healthy subjects. 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 conditions. Bosutinib Cmax increased 1.6-fold and AUC increased 1.5-fold when bosutinib capsules were given with a high-fat meal to healthy subjects compared to administration under fasted conditions. The high-fat meal (800-1000 total calories) consisted of approximately 150 protein calories, 250 carbohydrate calories, and 500-600 fat calories.
Following a single oral dose of [¹⁴C] radiolabeled bosutinib without food, 91.3% of the dose was recovered in feces and 3.3% of the dose was recovered in urine.
The mean (SD) apparent bosutinib volume of distribution is 6080 ± 1230 L after an oral dose of 500 mg of bosutinib.
The mean (SD) apparent clearance was 189 ± 48 L/h following a single oral dose of bosutinib.

---

Metabolism / Metabolites
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.

---

Biological Half-Life
The mean (SD) bosutinib terminal phase elimination half-life (t^1/2) was 22.5 ± 1.7 hours following a single oral dose of bosutinib.

Hepatotoxicity
In large clinical trials of bosutinib, elevations in serum aminotransferase levels were common, occurring in up to 58% of bosutinib treated patients. Values greater than 5 times the upper limit of normal (ULN) occurred in 4% to 19% of bosutinib recipients (and 3% of imatinib treated subjects). These abnormalities were usually asymptomatic, but led to discontinuation of therapy in up to 2% of treated patients. In addition, there have been isolated reports of clinically apparent liver injury attributed to bosutinib therapy, although the frequency of this outcome and the clinical features of the injury have not been well defined. The time to onset has generally been within 3 months and the pattern of serum enzyme elevations was usually hepatocellular.
Certainly other tyrosine kinase receptor inhibitors used in the therapy of CML such as imatinib, nilotinib and ponatinib have been associated with cases of acute liver injury with jaundice. With these agents, the liver injury typically arises after several months of therapy and the pattern of serum enzyme elevations is typically hepatocellular. Immunoallergic features (rash, fever and eosinophilia) and autoantibody formation are usually not present.
Reactivation of hepatitis B has been reported with imatinib and nilotinib therapy, but not with bosutinib. Reactivation typically occurs in an HBsAg positive person treated with the tyrosine kinase inhibitor for 3 to 6 months, presenting with jaundice, marked serum aminotransferase elevations and an increase in HBV DNA levels. Reactivation of hepatitis B can be severe and fatal instances have been reported after imatinib and nilotinib therapy. Screening of patients for HBsAg and anti-HBc is sometimes recommended before starting cancer chemotherapy and those with HBsAg offered prophylaxis with oral antiviral agents, such as lamivudine, tenofovir or entecavir. Whether reactivation occurs with bosutinib therapy is unclear.
Likelihood score: D (possible uncommon cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of bosutinib during breastfeeding. Because bosutinib is 96% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 22 hours and it might accumulate in the infant. National Comprehensive Cancer Network guidelines recommend avoiding breastfeeding during bosutinib therapy and the manufacturer recommends withholding breastfeeding until 2 weeks following the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
Bosutinib protein binding is 94% in vitro and 96% ex vivo and is independent of concentration.

[1]. Jorge E Cortes, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012 Oct 1;30(28):3486-92.
[2]. Miriam Puttini, et al. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res. 2006 Dec 1;66(23):11314-22.

Pharmacodynamics
A greater likelihood of response and a greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies. The time course of bosutinib pharmacodynamic response has not been fully characterized. At a single oral dose of 500 mg bosutinib with ketoconazole (a strong CYP3A inhibitor), bosutinib does not prolong the QT interval to any clinically relevant extent.

C26H29CL2N5O3

530.45

529.164

380843-75-4

Bosutinib hydrate;918639-08-4;Bosutinib-d8;Bosutinib isomer;1391063-17-4

5328940

Typically exists as solid at room temperature

1.4±0.1 g/cm3

649.7±55.0 °C at 760 mmHg

116-120ºC

346.7±31.5 °C

0.0±1.9 mmHg at 25°C

1.652

5.48

1

8

9

36

734

0

ClC1=C([H])C(=C(C([H])=C1N([H])C1=C(C#N)C([H])=NC2=C([H])C(=C(C([H])=C21)OC([H])([H])[H])OC([H])([H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])OC([H])([H])[H])Cl

UBPYILGKFZZVDX-UHFFFAOYSA-N

InChI=1S/C26H29Cl2N5O3/c1-32-6-8-33(9-7-32)5-4-10-36-25-13-21-18(11-24(25)35-3)26(17(15-29)16-30-21)31-22-14-23(34-2)20(28)12-19(22)27/h11-14,16H,4-10H2,1-3H3,(H,30,31)

4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carbonitrile

Bosutinib; SKI606; SKI 606; SK-I606; trade name: Bosulif.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (3.92 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

Solubility in Formulation 4: 2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 10 mg/mL

---

 (Please use freshly prepared in vivo formulations for optimal results.)