Nilotinib Hydrochloride Monohydrate (CAS NO: 923288-90-8) is the monohydrate monohydrochloride form of nilotinib, an orally bioavailable aminopyrimidine-derivative Bcr-Abl tyrosine kinase inhibitor with antineoplastic activity[1].

Mechanism of action

Designed to overcome imatinib resistance resulting from Bcr-Abl kinase mutations, upon administration, nilotinib binds to and stabilizes the inactive conformation of the kinase domain of the Abl portion of the Bcr-Abl fusion protein, resulting in the inhibition of the constitutive kinase activity of Bcr-Abl protein. This inhibits the Bcr-Abl-mediated proliferation of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) cells. Nilotinib also inhibits the receptor tyrosine kinases platelet-derived growth factor receptor (PDGF-R; PDGFR), mast/stem cell growth factor receptor Kit (c-Kit), and, to a lesser extent, colony-stimulating factor 1 receptor (CSF-1R; CSF1R), and discoidin domain-containing receptor 1 (DDR1).

Chemical Property

Nilotinib hydrochloride monohydrate (NHM) lacks a chiral center, making it incapable of tautomerism. NHM is a chemical compound with the following name: 4-methyl-N-[3-(4-methyl-1H-imidazol1-yl)-5-(trifluoromethyl) phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl) amino] benzamide hydrochloride monohydrate. It is a white powder with a slight yellowish or greenish-yellowish shade. At 25 °C, the aqueous solubility of NHM markedly decreases with pH. Moreover, it is almost insoluble in buffer solutions with pH values higher than 4.5[2]. NHM shows slight solubility in ethanol and methanol. The solubility rate is a critical factor affecting the bioavailability of the active components in orally administered drugs. The poor bioavailability of NHM can be due to its low water solubility, which influences its efficiency in the body.

Metabolism

Unchanged nilotinib is the main circulating form of the drug in serum. Nilotinib has a half-life of approximately 17 hours, greater than 90% eliminated in feces. Its mean clearance in patients with newly diagnosed Ph+ CML in the chronic phase was 20.2l/h[3].

Nilotinib is metabolized by oxidation and hydroxylation, mainly by CYP3A4. Some papers suggest that CYP2C8 plays a minor role, although primary data was not shown. In studies of healthy volunteers given nilotinib alone or in combination with rifampicin (a CYP3A4 inducer) and ketoconazole (a CYP3A4 inhibitor), rifampicin increased clearance of nilotinib around 5-fold and ketoconazole increased exposure of nilotinib and increased the occurrence of side effects. No nilotinib metabolites contribute to its pharmacological activity. Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1.

Nilotinib can be transported by both ABCB1 and ABCG2. In one in vitro system, overexpression of ABCG2 protected cells from nilotinib toxicity, whereas overexpression of ABCB1 only slightly decreased nilotinib toxicity. However, in a different in vitro system using transporter-specific inhibitors and different concentrations of nilotinib, ABCB1 was considered the main transporter, with ABCG2 having a lesser role.

References

[1] Xianbin Tian PhD, Hefei Zhang MD and PhD. “Clinical Pharmacokinetic and Pharmacodynamic Overview of Nilotinib, a Selective Tyrosine Kinase Inhibitor.” The Journal of Clinical Pharmacology 58 12 (2018): 1533–1540.

[2] Hassan Nateghi. “A machine learning approach for thermodynamic modeling of the statically measured solubility of nilotinib hydrochloride monohydrate (anti-cancer drug) in supercritical CO2.” Scientific Reports 13 1 (2023): 12906.

[3] Jonathan Trent , Mathieu Molimard. “Pharmacokinetics and Pharmacodynamics of Nilotinib in Gastrointestinal Stromal Tumors.” Seminars in oncology 38 (2011): Pages S28-S33.