Alvespimycin

Alvespimycin Uses, Dosage, Side Effects, Food Interaction and all others data.

Alvespimycin is a derivative of geldanamycin and heat shock protein (HSP) 90 inhibitor. It has been used in trials studying the treatment of solid tumor in various cancer as an antitumor agent. In comparison to the first HSP90 inhibitor tanespimycin, it exhibits some pharmacologically desirable properties such as reduced metabolic liability, lower plasma protein binding, increased water solubility, higher oral bioavailability, reduced hepatotoxicity and superior antitumor activity .

Alvespimycin mediates an antitumor activity through HSP90 inhibition that targets client proteins for proteasomal destruction, including oncogenic kinases such as BRAF. The administration of the drug is shown to result in the depletion of client proteins that have oncogenic activity and potential induction of HSP70 (HSP72) . It is more selective for tumors over normal tissue. A study also reports that alvespimycin enhances the potency of telomerase inhibition by imetelstat in pre-clinical models of human osteosarcoma .

Trade Name Alvespimycin
Generic Alvespimycin
Alvespimycin Other Names 17-DMAG, Alvespimycin, DMAG
Type
Formula C32H48N4O8
Weight Average: 616.7455
Monoisotopic: 616.347214532
Protein binding

Reported to be minimal.

Groups Investigational
Therapeutic Class
Manufacturer
Available Country
Last Updated: September 19, 2023 at 7:00 am
Alvespimycin
Alvespimycin

Uses

Investigated for use as an antineoplastic agent for solid tumors, advanced solid tumours or acute myeloid leukaemia.

How Alvespimycin works

Alvespimycin inhibits HSP90 and its regulation of correct folding and function of many cellular signalling proteins, which are referred to as Hsp90 client proteins. These client proteins are also referred to as oncoproteins and include Her-2, EGFR, Akt, Raf-1, p53, Bcr-Abl, Cdk4, Cdk6 and steroid receptors that are involved in cellular signalling pathways that drive cellular proliferation and counteract apoptosis. They are often over-expressed or mutated in tumors, and contribute to cancer progression and therapy resistance . Alvespimycin promotes an anticancer activity by disrupting Hsp90's chaperone function and inducing the proteasomal degradation of oncoproteins. It is shown to reduce the levels of CDK4 and ERBB2 .

Toxicity

Alvespimycin exhibits a dose-limiting toxicity where most toxic effects were experienced at ≥ 80mg/m^2 in Phase I clinical trials. Common adverse effects include nausea, vomiting, fatigue, hematologic toxicity, liver enzyme disturbances and ocular disturbances including blurred vision and keratitis. They are reported to be generally reversible. The doses lower than 80mg/m^2 are well-tolerated. The dose-limiting

Volume of Distribution

At the maximum tolerated dose of 80mg/m^2, the mean Vd value is 385 L.

Elimination Route

Increasing concentration of the drug results in dose-proportional increase in the plasma concentration. At the maximum tolerated dose of 80mg/m^2, the plasma concentration exceeded 63nM (mean IC50 for 17-DMAG in the NCI 60 human tumor cell line panel) for less than 24 hours in all patients. The mean peak concentration (Cmax) reached 2680 nmol/L at this dose.

Half Life

The half-life across all dose levels ranged from 9.9 to 54.1 h (median, 18.2 h) .

Clearance

The mean clearance is 18.9 L/hr at the dose of 80mg/m^2.

Elimination Route

Mainly renal and biliary elimination pathways. In a mice study, the excreted urine 24 hours post-dose recovered 10.6–14.8% of delivered dose unchanged .

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