Klisyri
Klisyri Uses, Dosage, Side Effects, Food Interaction and all others data.
Klisyri (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. Klisyri blocks the molecular pathways that promote the proliferation, survival, and metastasis of malignant cells. Klisyri 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.
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. Klisyri mediates an anti-proliferative effect by inhibiting tubulin polymerization and Src kinase signalling.
Klisyri 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. Klisyri was also shown to restore functional ERα expression in ERα-negative breast tumours. Klisyri promoted synergistic tumour growth inhibition of breast cancer cell lines when used in combination with tamoxifen and paclitaxel.
| Trade Name | Klisyri |
| Availability | Prescription only |
| Generic | Tirbanibulin |
| Tirbanibulin Other Names | Tirbanibulin |
| Related Drugs | fluorouracil topical, Efudex, Klisyri, Tolak, Carac |
| Weight | 1%, |
| Type | Topical Ointment, Ointment |
| Formula | C26H29N3O3 |
| Weight | Average: 431.536 Monoisotopic: 431.220891806 |
| Protein binding | 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. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States, |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Klisyri is a tyrosine kinase and tubulin inhibitor used to treat actinic keratosis on the face or scalp.
Klisyri is indicated for the topical treatment of actinic keratosis on the face or scalp.
Klisyri is also used to associated treatment for these conditions: Actinic Keratoses of the face, Actinic Keratoses of the scalp
How Klisyri works
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. Klisyri 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.
Toxicity
The LD50 value of tirbanibulin has not been determined. While there is limited information on overdose from tirbanibulin, it may lead to an increase in the incidence and severity of local skin reactions.
Food Interaction
No interactions found.Volume of Distribution
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.
Elimination Route
Klisyri 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 Cmax 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 Tmax was about seven hours.
Half Life
The half-life is about 4 hours.
Clearance
There is limited information on the clearance rate of tirbanibulin.
Elimination Route
There is limited information on the route of elimination of tirbanibulin.
Innovators Monograph
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