Innotubilin

Uses

Innotubilin is used for Breast, Non-Small Cell Lung, Gastric and Head and Neck Cancers, Prostate Cancer, Breast Cancer, Patients with Locally Advanced or Metastatic Breast Cancer, Non-Small Cell Lung Cancer (NSCLC), Prostate Cancer, Gastric Adenocarcinoma, Head and Neck Cancer, Induction Treatment of Inoperable, Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN), Ovarian Cance,

Innotubilin is also used to associated treatment for these conditions: Esophageal Cancers, Ewing's Sarcoma, Locally Advanced Breast Cancer (LABC), Metastatic Bladder Cancer, Metastatic Breast Cancer, Metastatic Hormone Refractory Prostate Cancer, Node Positive Breast Cancer, Ovarian Cancer Metastatic, Small Cell Lung Cancer (SCLC), Soft Tissue Sarcoma (STS), Advanced untreated gastric adenocarcinoma, Locally advanced Squamous cell carcinoma of head and neck, Locally advanced untreated non small cell lung cancer, Metastatic Squamous cell carcinoma of head and neck, Metastatic untreated non small cell lung cancer, Refractory, locally advanced Non small cell lung cancer, Refractory, metastatic Non small cell lung cancer

How Innotubilin works

Innotubilin interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, docetaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, docetaxel binds to the β-subunit of tubulin. Tubulin is the "building block" of microtubules, and the binding of docetaxel locks these building blocks in place. The resulting microtubule/docetaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that docetaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function.

Dosage

Innotubilin dosage

Breast, non-small cell lung, gastric, head & neck cancers: Premedication consisting of an oral corticosteroid eg dexamethasone 16 mg/day (8 mg twice daily) for 3 days starting 1 day prior to docetaxel administration.

Prostate cancer: Given the concurrent use of prednisone or prednisolone, the recommended premedication regimen: Oral dexamethasone 8 mg 12 hr, 3 hr & 1 hr before docetaxel infusion. Administered as 1-hr infusion every 3 wk.

Breast cancer:

• In the adjuvant treatment of operable node +ve: 75 mg/m2 administered 1 hr after doxorubicin 50 mg/m2& cyclophosphamide 500 mg/m2 every 3 wk for 6 cycles.
• For the treatment of patients with locally advanced or metastatic breast cancer: 100 mg/m2 in monotherapy.
• In the 1st-line treatment combination therapy: 75 mg/m2 with doxorubicin (50 mg/m2).
• In combination with trastuzumab: 100 mg/m2 every 3 wk, administered wkly.
• In combination with capecitabine: 75 mg/m2 every 3 wk, combined with capecitabine at 1250 mg/m2 twice daily (within 30 min after a meal) for 2 wk followed by a 1-wk rest period.

Non-small cell lung cancer:

• In chemotherapy-naive patients treated for non-small cell lung cancer: 75 mg/m2 immediately followed by cisplatin 75 mg/m2 over 30-60 min.
• For treatment after failure of prior platinum-based chemotherapy: 75 mg/m2 as a single agent.

Prostate cancer: 75 mg/m2. Prednisone or prednisolone 5 mg orally twice daily is administered continuously

Gastric adenocarcinoma: 75 mg/m2 as 1-hr infusion, followed by cisplatin 75 mg/m2, as 1-3-hr infusion (both on day 1 only), followed by 5-fluorouracil 750 mg/m2/day given as 24-hr continuous infusion for 5 days, starting at the end of the cisplatin infusion.

Head & neck cancer: For the induction treatment of inoperable locally advanced squamous cell carcinoma of the head & neck: 75 mg/m2 as 1-hr infusion followed by cisplatin 75 mg/m2 over 1 hr on day 1, followed by 5-fluorouracil as a continuous infusion at 750 mg/m2 per day for 5 days. Administered every 3 wk for 4 cycles. Following chemotherapy, patients should receive radiotherapy.

Ovarian cancer: 75-100 mg/m2 administered as 1-hr infusion every 3 wk.

Side Effects

Neutropenia, anaemia, alopecia, nausea, asthenia, hypersensitivity, anorexia, neurologic effects, neuropathy, dizziness, dyspnoea, epitaxis, GI effects, skin & cutaneous reactions, myalgia, fluid retention, pain, lacrimation increased, conjunctivitis, lymphoedema, pharyngolaryngeal pain, oedema peripheral, fatigue, vasodilation, amenorrhoea, pyrexia, lethargy, fever, arrhythmia, hypotension, dehydration.

Toxicity

Oral LD₅₀ in rat is >2000 mg/kg. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. In two reports of overdose, one patient received 150 mg/m² and the other received 200 mg/m² as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.

Precaution

Monitor blood counts. Reduce dose in case of severe neutropenia (2 to 75 mg/m2, &/or from 75 mg/m2 to 60 mg/m2. Monitor patient for hypersensitivity, fluid retention, liver impairment, cardiac toxicity. Contraceptive measures must be taken by both men & women during treatment & for men at least 6 mth after cessation of therapy. Elderly.

Interaction

CYP P450-3A inhibitor eg, ciclosporine, terfenadine, ketoconazole, erythromycin & troleandomycin. Increased clearance of carboplatin. Potent CYP3A4 inhibitors eg, protease inhibitors eg, ritonavir, azole antifungals eg, ketoconazole or itraconazole.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of docetaxel.
• Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of docetaxel.

[Major] GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4, such as grapefruit juice, may significantly increase the plasma concentrations of docetaxel, which is a substrate of the isoenzyme.

Current data suggest that consumption of large quantities of grapefruit juice inhibit both intestinal and hepatic CYP450 3A4 due to certain compounds present in grapefruit.

In a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel systemic exposure (AUC) increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 mg

In addition, a case report of a 52-year-old woman with esophageal squamous cell carcinoma receiving a twice weekly chemotherapy regimen including intravenous docetaxel (40 mg

In the absence of other CYP450 3A4 inhibitors, these effects were attributed to daily consumption of 250 mL of grapefruit juice, which the patient had been consuming for at least 3 months.

Two weeks after the patient ceased the grapefruit juice, the docetaxel AUC was closer to the target value and the neutrophil count reduction was less than 35%.

MANAGEMENT: The use of docetaxel in combination with grapefruit and grapefruit juice should generally be avoided.

If concomitant use is required, a reduced dosage of docetaxel should be considered, particularly if used with large amounts of grapefruit juice, and therapeutic drug monitoring of docetaxel considered per local treatment protocols.

Patients should be closely monitored for the development of docetaxel toxicity such as myelosuppression, stomatitis, neurotoxicity (e.g., paraesthesia, dysesthesia, pain), myalgia, asthenia, fluid retention, nausea, vomiting, and diarrhea.

Innotubilin Drug Interaction

Moderate: pegfilgrastim, pegfilgrastim, denosumab, denosumabMinor: dexamethasone, dexamethasoneUnknown: aspirin, aspirin, trastuzumab, trastuzumab, leuprolide, leuprolide, metoprolol, metoprolol, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Innotubilin Disease Interaction

Major: infections, edema, eye disorder, hepatic dysfunction, myelosuppressionModerate: alcoholism, paresthesia

Volume of Distribution

The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. * 113 L

Elimination Route

The pharmacokinetic profile is consistent with a three-compartment model. The area under the curve (AUC) was dose proportional following doses of 70 mg/m2 to 115 mg/m2 with infusion times of 1 to 2 hours.

Half Life

Dose-dependent. Doses of 70 mg per square meter of body surface area (mg/m 2 ) or higher produce a triphasic elimination profile. With lower doses, assay limitations precluded detection of the terminal elimination phase. The half-life of the alpha, beta, and gamma phase are 4 minutes, 36 minutes, and 11.1 hours, respectively.

Clearance

• 21 L/h/m2 [Total body clearance, cancer patients after IV administration of 20–115 mg/m2]

Elimination Route

Innotubilin was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively.

Pregnancy & Breastfeeding use

Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Severe hypersensitivity to docetaxel. Neutrophil count of <1500 cell/mm3. Severe liver impairment. Pregnancy & lactation.

Acute Overdose

There were a few reports of overdosage. There is no known antidote for docetaxel overdose. In case of overdose, the patient should be kept in a specialised unit and vital functions closely monitored. In case of overdosage, exacerbation of adverse events may be expected. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.

Storage Condition

Do not store above 25°C. Protect from light.Shelf-Life:

• 20 mg/mL: 2 years.
• 80 mg/4 mL: 3 years.

Infusion Solution: The infusion solution should be used within 6 hrs at room temperature (below 25°C).

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