dosage
Experience with Bosulif overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse events associated with the overdoses. Patients who take an overdose of Bosulif should be observed and given appropriate supportive treatment.
Bosulif Description
Bosutinib is a kinase inhibitor. The chemical name for bosutinib monohydrate is 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl) propoxy]-, hydrate (1:1). Its chemical formula is C26H29Cl2N5O3•H2O (monohydrate); its molecular weight is 548.46 (monohydrate), equivalent to 530.46 (anhydrous). Bosutinib monohydrate has the following chemical structure:
Bosutinib monohydrate is a white to yellowish-tan powder. Bosutinib monohydrate has a pH dependent solubility across the physiological pH range. At or below pH 5, bosutinib monohydrate behaves as a highly soluble compound. Above pH 5, the solubility of bosutinib monohydrate reduces rapidly.
Bosulif® (bosutinib) tablets are supplied for oral administration in two strengths: a 100 mg yellow, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "100" on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "500" on the other.
Each 100 mg Bosulif tablet contains 103.40 mg of bosutinib monohydrate, equivalent to 100 mg of bosutinib; each 500 mg Bosulif tablet contains 516.98 mg of bosutinib monohydrate, equivalent to 500 mg of bosutinib. The following inactive ingredients are included in the tablets: microcrystalline cellulose, croscarmellose sodium, poloxamer, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow (for 100 mg tablet) and iron oxide red (for 500 mg tablet).
Bosulif - Clinical Pharmacology
Mechanism of Action
Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells. In mice, treatment with bosutinib reduced the size of CML tumors relative to controls and inhibited growth of murine myeloid tumors expressing several imatinib-resistant forms of Bcr-Abl.
Pharmacokinetics
Absorption
Following administration of a single dose of Bosulif (500 mg) with food in patients with cancer, the median time-to-peak concentration (tmax) was 4–6 hours. Bosutinib exhibits dose proportional increases in AUC and Cmax, over the dose range of 200 to 800 mg. After 15 daily doses of Bosulif (500 mg) with food in patients with CML, the mean (SD) Cmax value was 200 (12) ng/mL, and the mean (SD) AUC was 3650 (425) ng∙h/mL. When given with a high fat meal, the Cmax and AUC of bosutinib increased 1.8- and 1.7-fold, respectively.
Distribution
After administration of a single dose of Bosulif (500mg) with food in patients with CML, bosutinib had a mean apparent volume of distribution ± standard deviation of 6080 ± 1230 L.
Bosutinib was highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy subjects (96%), and binding was not concentration-dependent. Bosutinib is a P-gp substrate and inhibitor in vitro. No studies have been conducted with oth |
