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Vincristine
Indications
Vincristine is a member of the vinca alkaloids group, which consists of organic compounds composed of carbon, hydrogen, nitrogen, and oxygen. These compounds are derived from the periwinkle plant Catharanthus roseus, formerly known as Vinca rosea.[1] Vincristine has a complex polycyclic structure comprising 3 rings, a structural feature crucial for its biological activity. This drug inhibits cell growth by halting mitosis and disrupting the polymerization of microtubules. Microtubules play a vital role in cell division, intracellular transport, and maintaining cellular shape. Vincristine binds to the tubulin protein, the building block of microtubules, and prevents its polymerization into microtubules.[2] This disrupts the formation of the mitotic spindle, which is essential for chromosome segregation during cell division. Consequently, vincristine induces cell cycle arrest and triggers apoptosis (cell death) in rapidly dividing cancer cells.
History of Vincristine
The history of vincristine can be traced back to the early 1950s when researchers commenced investigating the potential therapeutic properties of vinca alkaloids. Researchers discovered that vincristine showed anti-leukemic activity for acute lymphoblastic leukemia (ALL) in mice and children. In July 1963, vincristine received approval from the U.S. Food and Drug Administration (FDA) under the trade name Oncovin.
FDA-Approved Indications
Vincristine holds FDA approval for the treatment of several malignancies, including ALL, Burkitt lymphoma, B-cell ALL, lymphoid blast crisis of chronic myeloid leukemia, neuroblastoma, rhabdomyosarcoma, Wilms tumor, and Hodgkin and non-Hodgkin lymphomas.
Off-Label Uses
Vincristine is also used off-label for the treatment of central nervous system (CNS) tumors, Ewing sarcoma, medulloblastoma, Kaposi sarcoma, retinoblastoma, bladder cancer, gestational trophoblastic tumors, multiple myeloma, ovarian cancer, primary CNS lymphoma, small-cell lung cancer, and advanced thymoma in adult patients.[3] Other drugs in this class that have been approved for use in the United States include vinblastine and vinorelbine.[4][5]
In 2012, the FDA approved a new formulation of vincristine known as Marqibo (vinCRIStine sulfate LIPOSOME injection). This approval was specifically for treating adult patients with Philadelphia chromosome-negative (Ph-) ALL who were experiencing their second or subsequent relapse or whose disease had progressed after undergoing 2 or more anti-leukemia therapies.[6] Marqibo is a liposomal injection designed to enable the administration of higher doses of vincristine and extend its circulation in the bloodstream. The efficacy and safety of Marqibo were evaluated in a single-arm, open-label, multicenter study that included 65 patients diagnosed with Ph- ALL. These patients had either experienced 2 or more relapses or were unresponsive to 2 or more previous treatments.[7] The patients were administered Marqibo via intravenous (IV) route at a dosage of 2.25 mg/m2 over 1 hour, repeated once every 7 days until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR), which included complete remission (CR) and CR with incomplete hematologic recovery (CRi). The ORR stood at 34.6%, with a 95% confidence interval of 22.8% to 47.9%, comprising 15.4% CR and 19.2% CRi. The median duration of response was 28 days, with a range of 5 to 66 days.[8]
Mechanism of Action
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Mechanism of Action
Vincristine belongs to the vinca alkaloid class of chemotherapy drugs and acts as a microtubule-disrupting agent. Vincristine's mechanism of action primarily centers on its capacity to disrupt microtubule dynamics, particularly during the M and S phases, which is essential for cell division and several cellular processes. Another mechanism of action of vincristine includes interfering with nucleic acid and protein synthesis by blocking glutamic acid utilization.[9]
Vincristine's mechanism of action is characterized by several critical processes, as mentioned below, that collectively disrupt cancer cell growth and division.
Microtubule binding: Vincristine specifically binds to the plus ends of microtubules, dynamic protein polymers composed of tubulin subunits. Microtubules are essential cytoskeleton components and have pivotal roles in cell division, including mitosis and meiosis, intracellular transport, and the maintenance of cellular shape.
Inhibition of microtubule polymerization: Vincristine interferes with microtubule polymerization by binding to tubulin subunits within the microtubule lattice. This binding prevents the addition of new tubulin subunits to the growing microtubule, thereby inhibiting microtubule elongation.[10]
Disruption of mitotic spindle formation: During the mitosis phase of cell division, microtubules form the mitotic spindle, a dynamic structure responsible for segregating chromosomes into daughter cells. Vincristine's interference with microtubule dynamics disrupts the formation and functionality of the mitotic spindle.
Cell cycle arrest: Due to the disrupted spindle formation caused by vincristine, treated cells cannot progress through the cell cycle. This results in cell cycle arrest at the metaphase stage, where chromosomes fail to align and segregate correctly.
Induction of apoptosis: Prolonged metaphase arrest triggers a cellular response that ultimately leads to apoptosis or programmed cell death. The inability of the cell to complete mitosis due to microtubule disruption initiates a cascade of events culminating in cell death.
Effect on rapidly dividing cells: Vincristine's mechanism of action selectively targets rapidly dividing cells, such as cancer cells, as they heavily depend on adequately functioning microtubules during cell division. Normal, non-dividing cells are relatively less affected, contributing to the reduction of certain adverse effects.
Pharmacokinetics
A comprehensive understanding of vincristine's pharmacokinetics is essential for optimizing its dosage, administration, and monitoring, thus ensuring the safety and effectiveness of cancer treatment.
Absorption: Vincristine is administered via an IV route and is rapidly and completely absorbed into the systemic circulation. The peak plasma concentration is reached within minutes after injection.[11]
Distribution: Vincristine has a substantial volume of distribution, ranging from 2.3 to 8 L/kg in adults and 1.5 to 4.9 L/kg in children.[12] The drug exhibits high binding affinity to plasma proteins, primarily albumin, and blood cells, especially platelets. Vincristine has limited penetration through the blood-brain barrier and tends to accumulate in the cerebrospinal fluid. The drug is distributed to various tissues and organs, including the liver, kidney, spleen, lung, heart, and muscle.[11] Vincristine exhibits a strong affinity for tubulin, a protein essential for forming microtubules, which are involved in cell division and transport.
Metabolism: Vincristine undergoes extensive metabolism in the liver, primarily mediated by the cytochrome P450 (CYP) enzyme system, notably CYP3A4 and CYP3A5.[11] The primary metabolite is 4-O-desacetyl-vincristine, which possesses specific antitumor activity but is notably less potent than the parent drug. Other minor metabolites include N-deformyl-vincristine, N-deformyl-4-O-desacetyl-vincristine, and 4-O-desacetyl-N-deformyl-vincristine. The metabolism of vincristine is influenced by the genetic polymorphisms of CYP3A4 and CYP3A5 enzymes, as well as by drug interactions involving inhibitors or inducers of these enzymes.[12]
Elimination: Vincristine is primarily eliminated in the bile and feces as metabolites.[13] Only 20% of the drug is excreted unchanged in the urine, which is a relatively small amount.[12] The elimination half-life of vincristine follows a biphasic pattern, with an initial rapid phase lasting approximately 5 minutes and a subsequent slower terminal phase of about 85 minutes in adults and 25 minutes in children.[12] Vincristine exhibits a clearance rate of approximately 146 mL/min, which can vary significantly among individuals and is influenced by factors such as age, body weight (BW), liver function, renal function, and concurrent medication usage. The elimination half-life of vincristine typically ranges from 10 to 155 hours.[14]
Administration
Dosage Form
Vincristine is available in an IV formulation.
Strength
Vincristine is available in a concentration of 1 mg/mL.
Adult Dosage
In the treatment of acute leukemia, vincristine is administered as per the regimen mentioned below.
- Induction phase: 1.4 mg/m2 on days 1, 8, 15, and 22.
- Consolidation phase: 1.4 mg/m2 on days 1, 8, 15, and 22.
- Maintenance phase: 1.4 mg/m2 every 3 months for 2.5 years.
Vincristine should be administered via IV as a brief 5- to 10-minute infusion. The Institute for Safe Medication Practices (ISMP) and the World Health Organization (WHO) strongly recommend vincristine be dispensed in a 25 to 50 ml mini bag. If a mini bag is unavailable, vincristine may be administered as a slow 1-minute IV push. Notably, administration via any other route can lead to fatal consequences. For patients receiving medications intended for CNS administration, it is essential to administer vincristine separately and not simultaneously.[15]
As vincristine is a vesicant, it is imperative to exercise utmost caution to ensure the correct needle or catheter placement both before and during IV infusion to prevent extravasation. In cases of extravasation, it is imperative to promptly halt and disconnect the infusion while leaving the needle or cannula in its current position. To minimize potential complications, the extravasated solution should be gently aspirated without flushing the line. Subsequently, the hyaluronidase antidote should be administered, the needle or cannula removed, and a warm and dry compression applied for 20 minutes, 4 times a day, during the first 2 days following the extravasation. Finally, reevaluation should occur, and the remaining vincristine dose should be administered via IV route through a distinct vein.[16][17]
Specific Patient Populations
Hepatic impairment: Vincristine undergoes substantial metabolism within the hepatic cytochrome P450 (CYP) enzyme system, primarily mediated by CYP3A4 and CYP3A5. This metabolic pathway can be compromised in patients with hepatic dysfunction or those concurrently using potent enzyme inhibitors. Therefore, if the direct bilirubin level exceeds 3 mg/dL, a 50% reduction in the vincristine dose is recommended. Vincristine should be used cautiously and under vigilant monitoring for patients with obstructive jaundice or significant hepatic impairment.
Renal impairment: Vincristine is primarily eliminated as metabolites in the bile and feces, with only a minor fraction of the drug being eliminated unchanged in the urine. Therefore, dosage adjustment of vincristine is generally unnecessary in patients with renal impairment. Nevertheless, it is noteworthy that vincristine can induce neurotoxicity, which can be exacerbated by renal failure.
Pregnancy considerations: According to data from nonclinical studies, administering vincristine to pregnant or potentially pregnant women can cause fetal harm. There are reports of fetal death, spontaneous abortion, stillbirth, and congenital malformations associated with vincristine exposure during pregnancy. Therefore, females of reproductive potential should use effective contraception methods.
Breastfeeding considerations: The excretion of this drug in human milk has not been established based on clinical data.
Pediatric patients: The vincristine dosage for children is typically calculated based on their body surface area (BSA) or BW, generally within the range of approximately 1.5 to 2 mg/m2. For pediatric patients with a body weight of 10 kg or less, the initial vincristine dosage should be 0.05 mg/kg, administered once a week. To prevent excessive toxicity, the maximum single dose of vincristine is capped at 2 mg, irrespective of BSA or BW. Pediatric patients are carefully monitored for vincristine-related neurotoxicity, and dosage adjustments may be considered to manage the adverse effects of the drug.
Older patients: The maximum single dose of vincristine for older patients is limited to 2 mg, irrespective of their BSA or BW, to avoid excessive toxicity. In older patients, the most frequently observed adverse effects of vincristine include neurotoxicity, constipation, alopecia, and myelosuppression.
Adverse Effects
Vincristine exhibits various adverse effects that can affect multiple organ systems and vary in severity. Notable organ systems encompassed by vincristine's potential adverse effects include cardiovascular, CNS, dermatological, endocrine and metabolic, gastrointestinal, genitourinary, hepatic, renal, respiratory, neuromuscular, otic, and ophthalmic systems.
Some adverse effects that can occur during vincristine administration, categorized by body system, are outlined below.[18]
Neurotoxicity: This is the most prevalent and dose-limiting adverse effect of vincristine, often manifesting as peripheral neuropathy, which can impact sensory, motor, and autonomic nerves.[19] The symptoms of this condition include numbness, tingling, pain, weakness, difficulty walking or using the hands, loss of reflexes, constipation, urinary retention, orthostatic hypotension, and impotence. Neurotoxicity can also affect the CNS, causing seizures, confusion, hallucinations, depression, cranial nerve palsies, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Neurotoxicity typically exhibits reversibility upon discontinuation or dose reduction of vincristine, although in some instances, it may persist for months or even years.
Myelosuppression: Myelosuppression refers to the inhibition of bone marrow function, leading to a decreased production of blood cells. Vincristine can cause mild-to-moderate myelosuppression, mainly affecting platelets and white blood cells. The symptoms include bleeding, bruising, infection, fever, and anemia. Although myelosuppression is generally reversible following discontinuation or dose reduction of vincristine, in some cases, it may necessitate supportive measures such as blood transfusions or growth factor administration.
Alopecia: Alopecia is characterized by hair loss from the scalp and other body areas. This condition can occur as an adverse effect of vincristine and result in partial or complete hair loss in a majority of patients. Typically, hair regrowth occurs after the discontinuation or completion of vincristine therapy, although it may exhibit a different color or texture.
Gastrointestinal toxicity: This condition includes symptoms such as nausea, vomiting, diarrhea, abdominal pain, mucositis characterized by inflammation of the mouth and throat, and anorexia characterized by loss of appetite. These effects are usually of mild-to-moderate severity and can often be effectively managed by the use of antidiarrheals, antiemetics, which are medications to prevent nausea and vomiting, analgesics, which are pain relievers, and nutritional support.
Other adverse effects: Vincristine can also cause other less common or rare adverse effects, such as hypersensitivity reactions (allergic reactions), extravasation (leakage of the drug into the surrounding tissues), phlebitis (inflammation of the veins), skin rash, photosensitivity (increased sensitivity to sunlight), headache, dizziness, tinnitus (ringing in the ears), blurred vision, hypertension (high blood pressure), arrhythmias (irregular heartbeats), cardiomyopathy (heart muscle damage), pulmonary edema (fluid accumulation in the lungs), hepatotoxicity (liver damage), nephrotoxicity (kidney damage), pancreatitis (inflammation of the pancreas), hyperuricemia (high levels of uric acid in the blood), gout (a type of arthritis caused by uric acid crystals in the joints), and secondary malignancies (new cancers caused by chemotherapy).
Drug-Drug Interactions
Vincristine can interact with numerous other drugs metabolized by the liver enzyme CYP3A4 or transported by the protein P-glycoprotein (P-gp). Such interactions can either elevate or diminish the blood concentrations of vincristine, thereby influencing its efficacy and toxicity. Some examples of drugs that can interact with vincristine are mentioned below.
CYP3A4 inhibitors: These drugs inhibit the activity of CYP3A4 and reduce the metabolism of vincristine.[20] This can lead to elevated plasma concentrations, heightening the risk of neurotoxicity and myelosuppression. Some examples of CYP3A4 inhibitors are ketoconazole, itraconazole, voriconazole, posaconazole, fluconazole, erythromycin, clarithromycin, telithromycin, diltiazem, verapamil, grapefruit juice, and cimetidine. When these drugs are coadministered with vincristine, it may be necessary to reduce the vincristine dose or extend the interval between doses.
CYP3A4 inducers: These drugs enhance the activity of CYP3A4, leading to increased metabolism of vincristine. Consequently, this can result in lower plasma concentrations and decreased vincristine efficacy. Some examples of CYP3A4 inducers are rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, primidone, St John's wort, and efavirenz. When coadministered with these drugs, it may be necessary to consider increasing the vincristine dose or shortening the interval between doses.
P-gp inhibitors: These drugs inhibit the function of P-gp and diminish the efflux of vincristine from cells. Consequently, this can lead to higher intracellular concentrations, potentially increasing efficacy and toxicity.
P-gp inducers: These drugs stimulate the expression or function of P-gp, leading to increased efflux of vincristine from cells. This can result in lower intracellular concentrations and decreased efficacy of vincristine.
Contraindications
Certain medical conditions and factors may preclude using vincristine treatment in patients. Among these contraindications, a few are mentioned below.
Charcot-Marie-Tooth syndrome: This hereditary disorder affects the peripheral nerves and causes progressive muscle weakness and sensory loss. Vincristine can exacerbate the symptoms of this condition and induce severe neurotoxicity. Hence, vincristine is contraindicated for patients with Charcot-Marie-Tooth syndrome or a family history of this disorder.[21][22][21]
Hypersensitivity: Vincristine can cause hypersensitivity reactions (allergic reactions) in some patients. The symptoms include skin rash, itching, hives, flushing, fever, chills, dyspnea (difficulty breathing), bronchospasm (narrowing of the airways), anaphylaxis (severe allergic reactions), and angioedema (swelling of the face, lips, tongue, or throat). These reactions can be life-threatening and require immediate medical attention.
Black Box Warnings and Precautions
Vincristine sulfate injection should be administered to patients by healthcare professionals experienced in its administration. The dosage should be determined based on the patient's actual or ideal BW, whichever is less.
Extravasation: The IV needle or catheter must be in the proper position before infusion or injection of any medication. Incorrect positioning can result in medication leakage into the surrounding tissue during IV administration. Medication leakage can cause significant irritation; therefore, injection or infusion must be promptly discontinued if extravasation occurs.
For IV use only: Vincristine is exclusively indicated for IV use, and it can be fatal if administered through any other route. The administration of vincristine via intrathecal routes typically leads to fatal outcomes. Therefore, all syringes containing vincristine must be properly labeled and equipped with the provided auxiliary sticker. The auxiliary label must clearly state: "For IV use only. Fatal if given by other routes."
Monitoring
Patients receiving vincristine should undergo monitoring for several critical aspects, including the infusion site, the patient's neurological functions, and various laboratory values. Regular monitoring of laboratory values is essential, including serum electrolytes, such as serum sodium and serum uric acid, hepatic function assessments, and a complete blood count with a differential. In addition, vigilant monitoring for signs and symptoms of peripheral neuropathy is crucial.
Toxicity
The administration of vincristine should never be considered an emergency, as several fatal cases have occurred due to the inadvertent administration of vincristine via the incorrect route or at a rapid rate. Therefore, nurses or other healthcare providers responsible for administering vincristine should consistently verify the label for the prescribed dose, duration, and route of administration.
Neurotoxicity: The most prevalent and dose-limiting toxicity associated with vincristine is neurotoxicity, which can impact the peripheral, central, and autonomic nervous systems.[22] The signs and symptoms of neurotoxicity include numbness, tingling, pain, weakness, difficulty walking or using the hands, loss of reflexes, constipation, urinary retention, and orthostatic hypotension. Neurotoxicity typically exhibits reversibility upon discontinuation or dose reduction of vincristine, although in some instances, it may persist for months or even years.
Management of Overdose
If severe or progressive neurotoxicity ensues, it is advisable to either reduce the dose of vincristine or discontinue its use. Symptomatic treatment may include analgesics (pain relievers), anticonvulsants (seizure medications), antidepressants, laxatives, anticholinergics (drugs that block the action of acetylcholine), and physical therapy. Certain medicines that have the potential to exacerbate neurotoxicity, such as isoniazid, phenytoin, metronidazole, and erythromycin, should either be avoided or used cautiously.
Enhancing Healthcare Team Outcomes
Although vincristine is effective against various malignancies, it is also associated with a spectrum of toxicities, including neurotoxicity, myelosuppression, and gastrointestinal disturbances. Effectively navigating the intricate landscape of vincristine treatment necessitates collaboration among healthcare professionals from diverse backgrounds, including oncologists, pharmacists, nurses, and allied healthcare providers. Healthcare professionals must be educated and take the necessary precautions to administer the drug to their patients properly. Only experienced healthcare professionals should exclusively administer vincristine. Regular laboratory tests and clinical examinations should be used to monitor serum electrolytes and hepatic function, conduct neurological assessments, and observe for signs and symptoms of peripheral neuropathy.
Oncologists should ensure that oncology therapies are tailored to the individual patients' needs and are selected following a comprehensive patient evaluation. Furthermore, they should ensure that all physicians, nurses, physician assistants, nurse practitioners, and pharmacists involved in the treatment are well-informed about the monitoring parameters and potential adverse events, ultimately contributing to enhanced patient outcomes. Through collaborative efforts, interprofessional healthcare teams can customize vincristine therapy to suit each patient's circumstances, thereby optimizing its benefits while mitigating risks. Interprofessional collaboration among healthcare professionals during vincristine administration is the cornerstone of contemporary oncology care. This approach facilitates patient support and disease management and instills optimism throughout the journey toward cancer remission and survivorship.
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