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Vincristine Pharms

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Lezanne Schoeman

on 10 October 2013

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Transcript of Vincristine Pharms

Chronic lymphoblastic leukemia
“A walk to remember” is a story about a young girl diagnosed with leukaemia
Leukaemia is cancer that starts in the bone marrow
There are many types:
In children: Acute Lymphoblastic Leukaemia, Chronic Myelogenous leukaemia & Juvenile Myelomonocytic Leukaemia
In adults: Chronic Lymphocytic Leukaemia and Acute Myelogenous Leukaemia

Treatment options: chemotherapy, radiotherapy and a bone marrow transplant
Our choice of treatment: Chemotherapy drug Vincristine
Vinca alkaliod antineoplastic agent from the Madagascan Periwinkle plant
Antitumour properties since 1959
It is a mitotic inhibitor


Retained in cells for long periods of time = prolonged cellular effects but intracellular retention vary markedly among different vinca alkaloids. [2]
Drug transport into cells: via temperature-independent non-saturable mechanisms analogous to simple diffusion. [2]
Lipophilicity NB in drug accumulation and retention. [2] (Although lipophilic the large size of these agents restrict passage across BBB4)
Hepatic cytochrome P450: CYP3A41 & CYP3A [5,2]
So there is the potential for drug interactions with other drugs metabolised by CYP- 450 microsomal liver enzymes.
Hepatic impairment: Decrease the dose by 50% if direct bilirubin >3mg/dL [51μmol/L] [1]

Magnitude and avidity of drug binding in peripheral tissues is reflected by:
Half life: 10.5-155 hours (long t½ = neurotoxicity) [1,2]
DOSAGE (for acute lymphoblastic leukemia): 1.4mg/m2 IV Weekly1 (calculated according to BSA) (VSLI=2.25mg/m2)
Protein bound: 44% [1]
Volume of distribution: 8.4 L/kg1 (588L/70kg) (VSLI – even smaller) (For Vd and t½ large interpatient variation occurs)

Usually administered IV as a brief infusion.[1,2]
ONLY intravenous preparations available in South Africa (Schedule 4) e.g.:
Abic Vincristine Sulphate® (Pharmachemie)
Accord-Vincristine® (Mylan)
P & U Vincristine® (Pfizer)
Injections – vincristine sulphate 1 mg/ml
No absorption because drug is injected directly into systemic circulation therefore 100% BIOAVAILABILITY

Renal Clearance: 146mL/min1 (low clearance rate = neurotoxicity) (VSLI=slower clearance)
Renal impairment: Dose adjustment is not necessary1
Faeces (70-80%) [1,2]
urine (12-20%) [1,2]

Drug interactions
And many others…

Side effects
Hair loss (most common)
Sores: mouth and throat
Loss of appetite or weight
Stomach pain

More serious side effects
Rash/ itching
Difficulty breathing/swallowing
Increased/decreased urination
Swelling: face, arms, hands, feet, ankles, or lower legs

Local effect at injection site
VAs are potent vesicants - may cause tissue damage if escape from vasculature – known as tissue extravasation occurs. [2]
Method of prevention= good administration technique
Treatment: IV discontinued AND immediate application of heat for 1 hour four times daily for 3 to 5 days and the SC injection of hyaluronidase into the surrounding tissues for minimizing discomfort and latent cellulitis. [2]
If severe=debridement recommended. [2]
Discomfort, signs of phlebitis, and latent sclerosis may also occur along the course of an injected vein – risk increased if the vein is not adequately flushed after treatment. [2]
Block mitosis in M phase of the cell cycle- Metaphase
Cell cycle phase specific
Binds to microtubular proteins (tubulin) of mitotic spindles
Binding to the tubulin disables it from forming microtubules.
Crystallization-prevents chromosomal segregation and cell proliferation
Thus mitotic arrest or cell death

Mechanism of action
Primarily inhibition of mitosis in metaphase
Also interferes with:
Amino acid, glutathione and cyclic AMP metabolism
calmodulin-dependent Calcium transport ATPase activity
Cellular respiration
Nucleic acid and lipid biosynthesis
Mechanism of action
Unusual bleeding/bruising
Unusual tiredness/weakness
Pain, numbness, burning, or tingling in the hands or feet
Difficulty walking
Vincristine may increase the risk for other cancers.
Generally: adverse reactions are reversible and related to dosage

It should be administered by individuals experienced in the administration of vincristine sulfate injection.
The intrathecal administration of vincristine sulfate usually results in death
Contra indications
Demyelinating  from of Charcot–Marie–Tooth syndrome
If used in conjunction with neurotoxic agents
Hepatic impairment
Neuromuscular disorders
Peripheral nerve disorders
History of uric acid kidney stones

Pregnant women
Breastfeeding mothers
Caution in cases of infection (bacterial and fungal)
Effect of anticonvulsants ↑seizure activity
Drugs inhibiting metabolism and hepatic cytochrome P450
Severe constipation
Abdominal pain
Unusual bleeding/bruising
May lead to death
What's new?
New formulation: Vincristine sulphate liposomes injection (VSLI) = enhanced tumour tissue delivery and longer exposure time.
Approved by FDA in August 2012
Vincristine is effective if used correctly (correct doses and administration)
Used to treat a number of cancers including leukaemia
Interacts with numerous drugs and thus has many side effects and contra-indications
Constant new research being done to improve treatment & decrease side effects
1. Medscape®
2. DeVita VT Jr., Lawrence TS, Rosenberg SA, editors. DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 9th ed. Philadelphia: Wolters Kluwer Health/Lippincott, Williams & Wilkins; 2011.
3. Silverman JA, Reynolds L, & Deitcher SR. Pharmacokinetics and Pharmacodynamics of Vincristine Sulfate Liposome Injection (VSLI) in Adults With Acute Lymphoblastic Leukemia. J Clin Pharmacol. 2013 Jul 30. [cited 2013 Oct 2] Available from: http://0-onlinelibrary.wiley.com.innopac.up.ac.za/doi/10.1002/jcph.155/pdf
4. Greig NH, Soncrant TT, Shetty HU, Momma S, Smith QR & Rapoport SI. Brain uptake and anticancer activities of vincristine and vinblastine are restricted by their low cerebrovascular permeability and binding to plasma constituents in rat. Cancer Chemother Pharmacol. 1990;26(4):263-8.
5. www.drugbank.ca
6.Finkel R. Cubeddu L.X. Clark M.A. Lippincott’s Illustrated Reviews Pharmacology. 4th ed. Lippincott Williams & Wilkins: Baltimore; 2009.
7.Medlineplus,. 2013. Vincristine Injection. USA: U.S. National Library of Medicine. Available from: http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682822.html [Accessed on 3 October 2013].
8. ROSENTHAL, S. & KAUFMAN, S. 1974, "Vincristine neurotoxicity", Annals of Internal Medicine, vol. 80, no. 6, pp. 733-737

Group 34
Enzymes acted on
Cytochrome P450 3A5
Cytochrome P450 3A7
Cytochrome P450 3A4

Multidrug resistance protein 1
Canalicular multispecific organic anion transporter 1 and2
Solute carrier family 22 member 3
Multidrug resistance-associated protein 1 and 7
Bile salt export pump
ATP-binding cassette subfamily G member 2
Therapeutic index
Very narrow
Adults can experience severe symptoms at a dosage of 3mg/m2
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