Trabectedin

Uses

Trabectedin is an alkylating agent approved for the treatment of unresectable or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma).

Indicated for treatment of advanced soft tissue sarcoma in patients refractory to or unsuitable to receive anthracycline or ifosfamide chemotherapy in Europe, Russia and South Korea. Approved for orphan drug status by the U.S. FDA for treatment of soft tissue sarcomas and ovarian cancer. Investigated for use/treatment in cancer/tumors (unspecified), gastric cancer, ovarian cancer, pediatric indications, sarcoma, and solid tumors.

Trabectedin is also used to associated treatment for these conditions: Metastatic Leiomyosarcoma, Metastatic Liposarcoma, Relapsed platinum-sensitive Ovarian cancer, Unresectable Leiomyosarcoma, Unresectable Liposarcoma

How Trabectedin works

Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G2 phase, while cells at the G1 phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications.

Food Interaction

• Avoid alcohol. There may be an additive hepatotoxic effect if alcohol and trabectedin are coadministered.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of trabectedin.
• Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of trabectedin.

[Moderate] GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of trabectedin.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

GENERALLY AVOID: Coadministration of trabectedin with other agents known to induce hepatotoxicity such as alcohol may potentiate the risk of liver injury.

Reversible, acute increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have occurred frequently in patients treated with trabectedin alone or with pegylated liposomal doxorubicin in clinical trials.

In one U.S. trial with 378 patients, grade 3 or 4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) were reported in 35% of patients receiving trabectedin.

ALT or AST elevations greater than eight times the upper limit of normal (ULN) occurred in 18% of patients, and drug-induced liver injury (defined as concurrent elevations in ALT or AST more than three times ULN, alkaline phosphatase less than two times ULN, and total bilirubin at least two times ULN) occurred in 1.3% of patients.

MANAGEMENT: Consumption of grapefruit or grapefruit juice during treatment with trabectedin should be avoided.

Excessive use of alcohol is also not recommended.

Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

Monitoring of alkaline phosphatase, bilirubin, AST, and ALT should occur regularly during trabectedin treatment in accordance with the product labeling, or as often as necessary when clinical symptoms develop.

Trabectedin must not be used in patients with elevated bilirubin at the time of initiation of cycle.

Elevated liver function tests should be managed with treatment interruption, dosage reduction, or permanent discontinuation depending on the severity and duration of abnormality.

Trabectedin Drug Interaction

Moderate: paclitaxel protein-bound, celecoxib, sulfamethoxazole / trimethoprim, ethanolUnknown: doxorubicin, zolpidem, thyroid desiccated, aspirin, lorazepam, ubiquinone, prochlorperazine, copper gluconate, doxorubicin liposomal, apixaban, tamsulosin, glycerin, heparin, sodium chloride, arginine, tramadol

Trabectedin Disease Interaction

Moderate: cardiomyopathy, hepatotoxicity, neutropenic sepsis, rhabdomyolysis, Trabectedin – renal impairment

Elimination Route

Administered intravenously.

Half Life

33-50 hours

Innovators Monograph

You find simplified version here Trabectedin