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Tirbanibulin API Manufacturers & Suppliers

General Description:

Tirbanibulin, identified by CAS number 897016-82-9, is a notable compound with significant therapeutic applications. Tirbanibulin (KX-O1 or KX2–391) is a dual inhibitor of Src Kinase and tubulin. On December 14, 2020, tirbanibulin was approved by the FDA for the topical treatment of actinic keratosis on the face or scalp. It is marketed under the brand name Klisyri. Actinic keratosis is a chronic condition characterized by lesions, which can potentially transform into invasive squamous cell carcinoma with a risk of 1% over 10 years. Tirbanibulin blocks the molecular pathways that promote the proliferation, survival, and metastasis of malignant cells. Tirbanibulin exhibits antitumour effects in vitro and in vivo and has been investigated for its antitumor efficacy in the management of various cancers, such as prostate cancer and breast cancer.

Indications:

This drug is primarily indicated for: Tirbanibulin is indicated for the topical treatment of actinic keratosis on the face or scalp. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tirbanibulin undergoes metabolic processing primarily in: _In vitro_, tirbanibulin is mainly metabolized by CYP3A4, and to a lesser extent, CYP2C8. In adult subjects with actinic keratosis, detected metabolites were KX2-5036 and KX2-5163, which were pharmacologically inactive metabolites with the highest plasma concentrations of 0.09 ng/mL and 0.12 ng/mL, respectively. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Tirbanibulin are crucial for its therapeutic efficacy: Tirbanibulin demonstrates good oral bioavailability. Following topical administration of doses ranging from 54 to 295 mg on the face or scalp, the steady-state concentration of tirbanibulin was achieved by 72 hours. At five days following initial administration, the mean C_max was 0.34±0.30 ng/mL in subjects who received topical treatment on the face and 0.18±0.10 ng/mL in subjects who received topical treatment on the scalp. The mean AUC₂₄ was 5.0±3.9 h x ng/mL in subjects who received topical treatment on the face and 3.2±1.9 h x ng/mL in subjects who received topical treatment on the scalp. The median T_max was about seven hours. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tirbanibulin is an important consideration for its dosing schedule: The half-life is about 4 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Tirbanibulin exhibits a strong affinity for binding with plasma proteins: Tirbanibulin is 88% bound to plasma proteins and the extent of plasma protein binding is independent of drug concentrations in the range of 0.01 to 10 µg/mL. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Tirbanibulin from the body primarily occurs through: There is limited information on the route of elimination of tirbanibulin. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Tirbanibulin is distributed throughout the body with a volume of distribution of: There is limited information on the volume of distribution of tirbanibulin. In mouse HT29 xenograft studies, the tissue to plasma ration of tirbanibulin was 1.52. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tirbanibulin is a critical factor in determining its safe and effective dosage: There is limited information on the clearance rate of tirbanibulin. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tirbanibulin exerts its therapeutic effects through: In clinical trials composed comprising patients with actinic keratosis of the face or scalp, tirbanibulin promoted complete clearance of actinic keratosis lesions at day 57 in treated areas in 44-54% of patients compared to 5-13% of patients who received the placebo. Actinic keratosis is a chronic, pre-malignant condition characterized by lesions and proliferation of neoplastic keratinocytes. Tirbanibulin mediates an anti-proliferative effect by inhibiting tubulin polymerization and Src kinase signalling. Tirbanibulin inhibited primary tumour growth and metastasis in many preclinical animal models of cancer. In human triple-negative breast cancer, or estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2)-negative tumour, xenografts, tirbanibulin suppressed tumour growth and metastasis. Tirbanibulin was also shown to restore functional ERα expression in ERα-negative breast tumours. Tirbanibulin promoted synergistic tumour growth inhibition of breast cancer cell lines when used in combination with tamoxifen and paclitaxel. In a clinical trial comprising patients with advanced solid tumours, dose-limiting toxicities of tirbanibulin included elevated liver transaminases, neutropenia and fatigue. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tirbanibulin functions by: Src tyrosine kinases regulate normal cell growth: the expression of Src kinase is upregulated during the normal hair cycle during the proliferative anagen phase. Additionally, Src tyrosine kinases act as key modulators of cancer cell proliferation, survival, angiogenesis, migration, invasion and metastasis. Src is frequently upregulated in various epithelial tumours including colon, breast and pancreas compared with the adjacent normal tissues. The expression and activity of Src are also enhanced in human actinic keratosis, which is characterized by hyperproliferative premalignant skin lesions. The pathogenesis of actinic keratosis commonly involves skin inflammation, oxidative stress, immunosuppression, impaired apoptosis, mutagenesis, dysregulation of keratinocyte growth and proliferation, and tissue remodelling. _In vitro_ studies suggest that Src plays a predominant role in the early stages of human skin tumour development, rather than at later stages of tumour progression. The exact mechanism of tirbanibulin as a topical treatment of actinic keratosis has not been fully elucidated; however, it mainly works by inhibiting fast proliferating cells. Tirbanibulin is a non-ATP competitive Src kinase inhibitor and tubulin polymerization inhibitor. It binds to the peptide substrate binding site of Src, a primary target of tirbanibulin, and blocking its downstream signalling pathways that promote cancer cell migration, proliferation, and survival. Tublin is responsible for cell migration, protein transport, and mitosis: tibranibulin directly binds to the colchicine-binding site of beta-tubulin and causes induces tubulin depolymerization. It is also hypothesized that inhibition of Src can also contribute to the inhibitory effects on microtubule polymerization. At low nanomolar concentrations, tirbanibulin induces G2/M phase cell cycle arrest in a reversible and dose-dependent manner. By inhibiting microtubule polymerization, tirbanibulin also induces mitotic catastrophe. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Tirbanibulin is categorized under the following therapeutic classes: Acetates, Acids, Acyclic, Amides, Antineoplastic Agents, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (weak), Cytochrome P-450 CYP2B6 Inhibitors, Cytochrome P-450 CYP2B6 Inhibitors (weak), Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 Inhibitors (weak), Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (weak), Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP2C9 Inhibitors, Cytochrome P-450 CYP2C9 Inhibitors (weak), Cytochrome P-450 CYP2D6 Inhibitors, Cytochrome P-450 CYP2D6 Inhibitors (weak), Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (weak), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Dermatologicals, Enzyme Inhibitors, Fatty Acids, Fatty Acids, Volatile, Keratosis, Actinic, drug therapy, Kinase Inhibitor, Lipids, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE inhibitors, Microtubule Inhibitors, OATP1B1/SLCO1B1 Inhibitors, OATP1B3 inhibitors, OCT1 inhibitors, OCT2 Inhibitors, Oxazines, Tubulin Inhibiting Agent, Tyrosine Kinase Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.