Vinca Alkaloids – Vincristine, Vinblastine, Vinorelbine, Vinflunine, Vindesine

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History

  • Naturally occurring or semisynthetic nitrogenous bases present in pink periwinkle plant Catharanthus roseus G Don. (Vinca Rosea Linn)
  • Early uses included for control of hemorrhage, Scurvy, toothache & diabetes
  • In the late 1950s, antimitotic and cancer chemotherapeutic potential was discovered by groups both at Eli Lilly Research Laboratories and at the University of Western Ontario
  • Scientists first observed its anticancer properties in a lab in 1962 with the observation of regression of lymphocytic leukemia in rats.
  • FDA approved vincristine in March 1984.

Classification

Natural

  • Vincristine
  • Vinblastine

Semi synthetic

  • Vindesine
  • Vinorelbine
  • Vinflunine (Biflourinated)

Mechanism of Action

  • By interacting with tubulin, disrupting microtubule function.
  • At low concentration inhibits microtubule dynamics
  • Depolymerize microtubules and destroy mitotic spindles at high concentration
  • Also disrupt migration, intracellular transport, movement of organelles,secretory processes, membrane trafficking & interruption of growth factor signals from surface to nucleus.
  • Disrupt structural integrity of platelets

What are microtubules?

  • Vital and dynamic cellular organelles that play a critical role in cell division, directional transport of vesicles and organelles, signaling, cell shape and polarity.
  • Composed of 13 linear protofilaments of polymerized α β tubulin heterodimers arranged in parallel around a cylindrical axis
  • Tubulin polymerization is mediated by a nucleation-elongation mechanism. One end of the microtubule(+), is kinetically more dynamic than the other(-).
  • Microtubule dynamics are governed by two principal processes.
    • Treadmilling: is the net growth at one end of the microtubule and the net shortening at the opposite end.
    • Dynamic instability: is a process in which the microtubule ends switch spontaneously between states of slow sustained growth and rapid shortening.

Pharmacokinetics

  • Administered IV
  • Large volumes of distribution, high clearance rates, Long T1/2 , hepatic metabolism, and biliary /fecal excretion.
  • Triphasic T ½
  • At conventional adult dosages peak plasma concentrations (Cpeak), of few minutes -100 to 500 nmol, and > 1 to 2 nmol for long durations
  • T ½(terminal) : VCR>VDS>VBL

Mechanism of Resistance

  • Resistance to the vinca alkaloids develops rapidly in vitro with continuous exposure to these agents.
  • Pleiotropic or multidrug resistance (MDR), which results in decreased drug accumulation and retention
  • Second well characterized mechanism of vinca alkaloids resistance related to tubilin isotype .
  • Cross-resistance to taxanes, anthracyclines, epipodophyllotoxins, actinomycin D, and colchicine

Vincristine

vincristine-vinca alkaloid

Absorption, Distribution and Metabolism

  • Available as 1mg/mL, 1-mL
  • Administered only by the IV route.
  • Binds extensively to both plasma proteins (reported values in the range of 48 to 75%) and formed blood elements, particularly platelets
  • Widely and rapidly distributed into body tissues within 30 minutes of administration.
  • Poor penetration across the blood- brain barrier and into the CSF.
  • Plasma disposition is triphasic
  • T 1/2 α< 5 min due to rapid tissue distribution and binding
  • T 1/2β  50 to 155 minutes,
  • T 1/2γ 23 to 85 hours, long terminal half-life because of the high drug binding in peripheral tissues.
  • Metabolized and excreted primarily by the hepatobiliary system
  • Metabolized in the liver by the cytochrome P450 microsomal system.
  • The majority of vincristine (80%) is excreted in bile and feces.
  • Only 15%–20% of the drug is recovered in urine.

Indications

Dosage

  • Adult dose 1.4 mg/m 2 .
  • Infant aged 1 yr or less dose 0.03 to 0.05 mg/kg weekly
  • The total individual dose should be limited to 2 mg to prevent the development of neurotoxicity.
  • Continuous infusion: 0.4 mg/day IV continuous infusion for 4 days, as part of the VAD regimen for multiple myeloma.

Toxicity/Adverse Effects/Side Effects

Neurotoxicity

  • Dose-limiting toxicity.
  • peripheral, symmetric mixed sensory-motor, and autonomic polyneuropathy
  • Peripheral neuropathy (paraesthesias, wrist drop, foot drop ,loss of deep tendon reflexes),
  • Autonomic nervous system dysfunction (orthostasis, sphincter problems, and paralytic ileus),
  • Cranial nerve palsies, ataxia, cortical blindness, seizures, and coma.
  • Bone, back, limb, jaw, and parotid gland pain may also occur.
  • Neurotoxicity is due to axonal degeneration and decreased axonal transport as a result of the interference with axonal microtubule function.
  • NCV : diminished amplitude of sensory and motor nerve action potentials and prolonged distal latencies.
  • Predisposing conditions
      • Charcot-Marie-Tooth disease
      • Hereditary and sensory neuropathy type 1
      • Guillain-Barre syndrome
      • Childhood poliomyelitis
      • Hepatic dysfunction or obstructive liver disease
  • Only treatment for neurotoxicity is discontinuation of drugs or reduction of dose or frequency of administration .
  • Many antidotes, including thiamine, vitamin B12, folinic acid, and pyridoxine have been tried with no success.
  • Gangliosides , glutamic acid with VCR are useful
  • ACTH analogue ORG 2766 has also been shown to protect against VCR-induced neuropathy
  • Neurotoxicity is observed infrequently with both VBL and VDS

GI Toxicity

  • Gastrointestinal toxicity due to autonomic dysfunction may be caused by all the vinca alkaliods .
  • Abdominal pain, and paralytic ileus are common. (A prophylactic bowel regimen for constipation is recommended.)
  • Nausea, vomiting & diarrhea can also occur, but rare.
  • Mucosities stomatitis ,pharangitis also occurs commonly with VBL than VRL or VDS and less common with VCR

Genitourinary

  • bladder atony
  • polyuria, dysuria, incontinance and urinary retention.

Endocrine

  • SIADH (exp VFL)
  • hypothalamus ,neurohypophyseal tract or posterior pituitary.
  • Patient receiving intensive  hydration is  prone for severe hyponatremia and seizures

Extravasation

  • All vinca alkaloids are potent vesicants and may cause severe tissue damage.
  • If extravasation is suspected, treatment should be discontinued, and aspiration of any residual drug remaining in the tissues should be attempted.
  • hot packs may limit damage
  • Application of heat for 1hr 4times daily for 3-5days ,
  • Injection hyaluronidase 150-1500 u sc through six clockwise injections in a circumferential manner.
  • Change the needle in each injection
  • This treatment  minimizing the discomforted and latent cellulitis .
  • Surgical consultation for early debridement.
  • Discomfort , signs of phlebitis and latent sclerosis may occurs along the course of injected vein.
  • Risk of phlebitis is increased if the vein is not adequately flushed after treatment

Other Toxicities

  • Alopecia (10%-20%), skin rash, and fever
  • Hypersensitivity reactions
  • Azoospermia and amenorrhea may be permanent

Drug Interactions

  • Vincristine is a substrate for cytochrome P450 (CYP) 3A4
  • Vincristine reduces the blood levels of phenytoin Cisplatin and paclitaxel
  • With Cisplatin and Paclitaxel, may increase the risk and severity of neurotoxicity
  • L- Asparaginase-When used in combination with L- asparaginase,VCR should be administered 12–24 hours before, as L-asparaginase inhibits VCR  clearance
  • Methotrexate-VCR increases the cellular uptake of methotrexate resulting in enhanced antitumor activity and host toxicity
  • Filgrastim –concurrent use of vincristine with filgrastim may result in severe atypical neuropathy

Dose Modification

  • Bilirubin 1.5-3 mg/dl reduce by 50%
  • > 3mg/dl omit
  • Renal dysfunction no data.

Vinblastin

vinblastine-vinca alkaloid

  • Plant alkaloid extracted from the periwinkle plant Catharanthus rosues.
  • Cell cycle specific with acts on mitotic phase.
  • Inhibits tubulin polymerisation , disrupting formation of microtubule assembly during mitosis.
  • Arrest in cell division and cell death.
  • Inhibits the DNA ,RNA and protein synthesis.

Absorption ,Distribution & Metabolism

  • Poor and erratic absorption in oral route .
  • Widely and rapidly distributed in body tissues.
  • Binds to platelets , RBCs and WBCs within 30 mints of administration.
  • Poor penetration into the CSF.
  • Metabolized in the liver by cytochrom p450
  • Desacetyl vinblastine , one of the metabolite of vinblastine is as active as parents drugs.
  • Majority of vinblastine is excreted in metabolite form via the enterohepatic biliary system.
  • 10% through feces.
  • 14% by the kidneys.

Availability

  • VBL is supplied in 10-mg vials at a concentration of 1 mg /mL with the preservatives phenol or benzyl alcohol and a 0.9% sodium chloride diluent
  • VBL is administered as a IV bolus

Indications

Dosage

  • Available as 10-mg vials at a concentration of 1 mg per mL.
  • VBL is administered as a IV bolus
  • Hodgkin’s lymphoma: 6 mg/m 2 IV on days 1 and 15, as part of the ABVD regimen.
  • Testicular cancer: 0.15mg/kg IV on days 1 and 2, as part of the PVB

Drug Interations

Vinblastine should be used cautiously in patients receiving medications that inhibit drug metabolism via the hepatic cytochrome P450 system, e g;

  • Calcium channel blockers,
  • Cimetidine,
  • Cyclosporine,
  • Erythromycin,
  • Metoclopramide, and ketoconazole.
  • Vinblastine reduces blood levels of phenytoin
  • Risk of Raynaud’s syndrome with the combination of vinblastine and bleomycin

Toxicities/Adverse effects

  • Hematologic- Myelosuppression, particularly neutropenia, is the principal toxicity of VBL. Thrombocytopenia and anemia are less common
  • Gastrointestinal- Mucositis, pharyngitis, and stomatitis occur more frequently with VBL than with VCR ,others include constipation, ileus, and abdominal pain
  • Neurologic- much less common and severe with VBL than with VCR;
  • Myocardial infarctions and cerebrovascular accidents particularly with cisplatin and bleomycin ,Raynaud’s phenomenon has been reported.
  • Pulmonary: Acute pulmonary edema occurs rarely after treatment with VBL
  • Dermatologic: Mild and reversible alopecia commonly occurs.
  • Hypertension is the most common cardiovascular side effect due to autonomic

Dose Modifications

  • Bilirubin 1.5-3 mg/dl reduce by 50%
  • > 3mg/dl omit
  • Renal dysfunction no data.

Vinorelbine

vinorelbine-vinca alkaloid

Absorption ,Distribution & Metabolism

  • Administered only by iv route .
  • Widely and rapidly distributed into the body tissues with large volume of distributions.
  • Metabolised in the liver by cyp450.
  • Deacetyl vinorelbine, is one of the metabolite of vinorelbine has been shown same antitumor activity as parent drugs.
  • T ½ is 27to 43 h. Mean plasma clearance is about 1 to 1.26 L/h/kg.
  • Majority of drugs (50%) excreted in feces via entero biliary circulation.
  • 15-20% eliminated by the kidneys. Substantial hepatic elimination in humans, with large amounts recovered in feces after IV administration

Indications

Dosage and Administration

  • Infuse IV over 10 min into the side port of a freely flowing IV line.
  • 30 mg /m2 d1 and d8.

Drug Interactions

  • Vinorelbine should be used cautiously in patients receiving medications that inhibit drug metabolism via the hepatic cyp450, eg, Phenytoin
  • Cisplatin increases the risk of myelosupression
  • Mitomycin C increases the risk of allergic reaction.

Toxicities/Adverse Effects

  • Myelosupression –dose limiting toxicity neutropenia
  • Nausea and vomiting moderate
  • Gi toxicities – constipation (35%), diarrhea (17%), stomatitis (<20%),anorexia .
  • Transeant levetion of LFT
  • Neurotoxicity mild
  • Alopecia 10-15%
  • Extravasation – vasicant
  • SIADH
  • Hypersensitivity reaction seen when it is used with mitomycin c
  • Generalized fatigue –cumulative doses

Dose Modification

  • Liver dysfunction
      • Bilirubin 2.1–3 mg/dl reduce by 50%
      • Bilirubin >3 mg/dl reduce by 75%
      • >75% liver metastases reduce by 50%
  • Renal dysfunction – no data

Vindesine

It is a synthetic derivative of vinblastine. 10 times more potent than vinblastine in causing mitotic arrest in in vitro.

Pharmacokinetics

  • The pharmacologic behavior of VDS is similar to that of the other vinca alkaloids
  • The liver is the principal organ responsible for the disposition of VDS. The agent is principally metabolized by cy P-450 isoform CYP3A

Indications

Availability

  • 5-mg lyophilized powder & 25-mg mannitol, along with 5 mL sterile diluent for reconstitution
  • The diluent contains 0.9% sodium chloride and benzyl alcohol for reconstitution to a drug concentration of 1 mg per mL and a pH of approximately 4.2 to 4.5.

Dosage

  • Bolus injection or a brief infusion at a dose of 2 to 4 mg/ m2 every 7 to 14 days
  • Either an intermittent or continuous infusion over 1 to 5 days.
  • Intermittent or continuous infusion schedules usually use VDS doses of 1 to 2 mg/m2 per day for 1 to 2 days or 1.2 mg/m2 per day for 5 days every 3 to 4 weeks

Dose Modifications

  • Firm dose modifications have not been established
  • Dose reductions should be considered in the presence of moderate to severe hepatic dysfunction

Toxicities and Interactions

  • Same toxicities that occur with VCR and VBL. Major dose-limiting toxicities are hematologic and neurologic.
  • peripheral and autonomic nervous system manifestations, are similar to those described for VCR but less severe.
  • Increase the plasma clearance of methotrexate (MTX)
  • Mitomycin : acute bronchospasm
  • Phenytoin : decreased the level of phenytion.

Venflunine

venflunine-vinca alkaloid

  • Vinflunine (VFL) bifluorinated semi-synthetic vinca alkaloid.
  • Obtained by superacidic chemistry from its parent compound, vinorelbine.
  • Mechanism of action is the same as the other vinca alkaloids .
  • VFL has superior antitumor activity in vitro and in vivo compared with vinorelbine as well as its excellent safety profile.
  • The affinity of VFL binding to tubulin is considerably lower than that of other vinca alkaloids.
  • VFL does not prevent other vinca alkaloids from binding to unassembled tubulin.
  • The binding affinity : vincristine > vinblastine > vinorelbine > vinflunine
  • Binding  affinities are  inverse correlation with  inhibition of cell proliferation.
  • Vnf in platinum treated patient of urinary bladder cancer
  • Dose 320mg/m2

Comparison of Different Vinca Alkaloids

Vincristine sulfate Vinblastine sulfate Vindesine sulfate Vinorelbine tartrate Vinflunine ditartrate
Adult dosage 1.0–1.4 mg/m2/wk 6–8 mg/m2/wk 3–4 mg/m2/wk 15–30 mg/m2/wk 320mg/m2 q 3 wk
Pharmacokinetic Triexponential Triexponential Triexponential Triexponential Triexponential
Elimination Half lives
α (min) <5 <5 <5 <5 <5
β (min) 50–155 53-99 55-99 49-168
γ (h) 23-85 20-64 20-24 18-49 38.7
Clearance (L/h/kg) 0.16 0.74 0.25 0.4-1.29 0.64
Primary mechanism of disposition Hepatic metabolism and biliary excretion
Mechanism of action Low concentrations inhibit microtubule dynamics (dynamic instability and treadmilling) High concentrations inhibit polymerization of tubulin
Principal toxicity Peripheral neuropathy Neutropenia Neutropenia Neutropenia Neutropenia
Other toxicities Constipation, SIADH, infusion site reactions, jaw pain Thrombocytopenia, anemia, alopecia, peripheral neuropathy (mild), SIADH, constipation, diarrhea, nausea and vomiting, infusion site reactions, mucositis, alopecia, jaw pai Peripheral neuropathy (moderate), alopecia, infusion site reactions, nausea and vomiting, diarrhea, SIADH, mucositis, alopecia, jaw pain Peripheral neuropathy (moderate), alopecia, infusion site reactions, nausea and vomiting, diarrhea, SIADH, mucositis, alopecia, jaw pain Anemia, thrombocytopenia, fatigue, constipation, diarrhea, nausea and vomiting, mucositis, infusion site reactions, abdominal pain, peripheral neuropathy (mild), jaw pain
Precautions Patients with abnormal liver function should be treated with caution

Liposomal Vincristine

  • Liposomal vincristine is indicated adult Ph – ALL  in second or greater relapse
  • Progressive disease even after two or more anti-leukemia therapies
  • Clinical benefit such as improvement in overall survival has not been

Dosage and Administration

  • Intravenous use only.
  • Dose of 2.25 mg/m2 intravenously over 1 hour once every 7 days

Contraindications

  • liposomal vincristine is contraindicated in patients with demyelinating conditions, eg, Charcot-Marie-Tooth syndrome .
  • Also contraindicated in patients with hypersensitivity to vincristine or any of the other components of lipo-vcr.
  • Contraindicated for intrathecal administration

Toxicity/Adverse Effects

  • constipation
  • nausea
  • pyrexia
  • fatigue
  • peripheral neuropathy
  • febrile neutropenia
  • diarrhea
  • anemia, decreased appetite, and insomnia

Drug Interactions

Lipo-vcr  is expected to interact with drugs known to interact with non-liposomal vincristine sulfate.

Dose Modifications

  • Grade 3 neurotoxicity : withhold the drugs
  • If persistent grade 3 toxicity then discontinue.

If peripheral neuropathy is recovered the to grade 1 then reduced the dose to 2mg/m2.

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