Page 1007 - Hematology_ Basic Principles and Practice ( PDFDrive )

890 Part VII Hematologic Malignancies

A P P E N D I X 57.2

CLINICAL PHARMACOLOGY OF ANTIMICROTUBULE AGENTS

Vincristine (Oncovin) and Vinblastine (Velban) with leukopenia more pronounced than thrombocytopenia. Anemia
is uncommon. Neurotoxicity can also occur but is significantly less
Chemistry and Mechanism of Action: Both vincristine and common than with vincristine. Vinblastine is also a vesicant.
vinblastine are asymmetric dimeric compounds that bind to the
protein tubulin at a site distinct from that for the taxanes. At low Potential Drug Interactions: Both vinca alkaloids have been
concentrations vincristine and vinblastine inhibit microtubule reported to increase the accumulation of methotrexate and etoposide
dynamics. At higher concentrations they disrupt microtubules that in tumor cells. Acute shortness of breath and bronchospasm can
constitute the mitotic spindle, resulting in metaphase arrest. They are occur when vincristine or vinblastine is given in conjunction with
relatively M-phase specific. Owing to their lipophilicity, vinca alka- mitomycin C. Because asparaginase may impair the hepatic clearance
loids are rapidly taken into cells and achieve several-hundred-fold of vincristine, it is preferable to administer the vincristine 12–24
higher intracellular than extracellular concentrations. Whereas over- hours before L-asparaginase. Vincristine may decrease the absorption
expression of the multidrug resistance transporters P-glycoprotein and plasma levels of orally administered drugs such as digoxin.
(PGP) or multidrug resistance protein can reduce the intracellular Dilantin may increase the cytotoxicity of vincristine in multidrug-
accumulation, alterations in the α- or β-tubulins can affect drug– resistant tumor cells; however, this remains to be demonstrated in the
target interaction for vinca alkaloids. clinic. When concurrently administered, erythromycin may increase
the toxicity of vinca alkaloids, especially vinblastine.
Absorption, Fate, and Excretion: After IV injection, both drugs
are rapidly distributed to the body tissues, especially the red blood Therapeutic Indications in Hematology: The vinca alkaloids
cells and platelets. Their elimination follows a triphasic pattern. The are among the most important drugs in the treatment of hematologic
elimination half-lives are as follows α, less than 5 minutes; β, 50–155 malignancies. They have a broad spectrum of activity and are often
minutes; and γ, 20–85 hours. Both vinca alkaloids are primarily incorporated into many chemotherapy regimens used in the treat-
eliminated through the liver into the bile and feces, making patients ment of ALL, Hodgkin lymphoma, NHL, CLL, and MM.
with obstructive liver disease more susceptible to toxic effects. A 50%
reduction in the dose is recommended for serum bilirubin concentra- Vinorelbine (Navelbine)
tions of 1.5–3.5 mg/dL. Dose modification for renal dysfunction is
not indicated. After brief IV bolus administration, peak plasma Chemistry and Mechanism of Action: Vinorelbine is a semi-
vincristine concentrations of 100–400 mM are achieved, which synthetic derivative of vinblastine (5′-nor-hydrovinblastine) with an
decline to less than 10 mM in 2–4 hours. Continuous infusion doses eight-member catharanthine ring. Similar to other vinca alkaloids, it
2
of 1.0 mg/m /day produce vincristine plasma concentrations ranging also binds to tubulin, inhibits microtubule assembly, and produces a
from 1 to 10 nM. mitotic arrest of cells. These occur at concentrations that relatively
spare axonal microtubules, which may reduce neurotoxicity.
Preparation and Administration: Vincristine is commercially
available in 1-, 2-, and 5-mg vials. Each milliliter contains 1 mg of Absorption, Fate, and Excretion: Short (6–10 minutes) IV
2
vincristine sulfate, 100 mg of mannitol, 1.3 mg of methylparaben, infusions of 30 mg/m produce peak plasma concentrations approxi-
and 0.2 mg of propylparaben. Vincristine is a powerful vesicant that mately 1.0 µg/mL with a triphase decay. Rapid α (<5 minutes) and
should be administered only IV into a freely running infusion of β (49–168 minutes) half-lives result in a rapid decline in the plasma
normal saline or dextrose solution. If the drug is given by continuous concentration in the first hour posttreatment followed by a prolonged
infusion, it must be infused through a central IV line. In case of terminal half-life of 18–49 hours, reflecting slow efflux from the
extravasation, infusion should be discontinued and any residual drug peripheral compartment. The volume of distribution at steady state
aspirated through the line. The manufacturer also recommends is 20–75.6 L/kg. The drug is extensively bound to platelets, lympho-
infiltrating the area with 1–2 mL of hyaluronidase, 150 U/mL, and cytes, and plasma proteins. The major site of metabolism is the liver,
then applying warm compresses for 72 hours to facilitate dispersion with 33%–80% of the drug excretion in feces and approximately
of the drug. Vinblastine is commercially available as a lyophilized 20% in urine.
powder and a 1-mg/mL solution in 10-mg vials. The lyophilized drug
is reconstituted by adding sodium chloride for injection (which may Preparation and Administration: Vinorelbine is available for
be preserved with either phenol or benzyl alcohol) to the 10-mg vial. injection in single use as 10 mg/mL in 1- or 5-mL vials without
Administration of vinblastine should follow the same guidelines preservatives. The calculated dose is diluted to 1.5–3.5 mg/mL for a
described for vincristine. slow injection (6–10 minutes) by a syringe with 5% dextrose or 0.9%
saline, or between 0.5 or 2.0 mg/mL in an IV bag. Because vinorel-
Toxic Effects: Vincristine’s dose-limiting toxic effect is neurotoxic- bine is a strong vesicant, it should be administered through a freely
ity, which appears to be related to its relative polarity. Peripheral flowing IV access avoiding all extravasation.
neurotoxicity usually manifests as sensory impairment, decreased
deep-tendon reflexes, and paresthesias. Less commonly, severe painful Toxic Effects: Vinorelbine shares many of the principal toxicities
dysesthesias, ataxia, foot drop, and cranial nerve palsy (e.g., affecting of vinblastine. Myelosuppression is dose limiting but not cumulative,
the extraocular and laryngeal muscles) can occur. Autonomic neuro- with nadirs occurring 7–10 days after administration.
toxicities include constipation, abdominal cramps, and ileus, which Anemia and thrombocytopenia occur infrequently. Because of
may be prevented by use of mild laxatives. Alopecia occurs frequently, lower affinity for axonal versus spindle microtubules, neurotoxicity is
but myelosuppressive effects are minimal. Rare side effects include less prominent with vinorelbine. Mild-to-moderate peripheral neu-
inappropriate secretion of antidiuretic hormone and ischemic cardiac ropathy and constipation occur in approximately 30% of patients,
toxicity. Vinblastine’s dose-limiting toxic effect is myelosuppression, and the incidence of neuropathy increases with the duration of