Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 15 CANCER CHEMOTHERAPY
Formulations and dose rates
Unreconstituted L-asparaginase should be stored at 4°C. Once reconstituted,
the drug should be used within 8 h and discarded if the
solution appears turbid. Some data exist to indicate that L-
asparaginase may be stored for up to 14 d following reconstitution
but this is not in accordance with the manufacturer’s label.
DOGS, CATS AND FERRETS
• Both 400 IU/kg and 10,000 IU/m 2 have been recommended
• L-asparaginase is safe and effective when given IP, IM or SC.
Intramuscular injections are associated with increased pain at
the injection site when compared to SC injections but, in a
group of dogs with lymphoma, dogs receiving IM
L-asparaginase had longer remission and survival times than
dogs receiving SC injections (191 versus 109 d and 286 versus
298 d respectively). Intravenous administration is associated
with a high incidence of hypersensitivity reactions and therefore
this route of administration is not recommended
Pharmacokinetics
Plasma l-asparaginase concentration has a primary
half-life of 14–22 h in humans. l-asparaginase does not
cross the blood–brain barrier but does deplete the CSF
of l-asparagine and consequently has an antitumor
effect in the central nervous system. The pharmacokinetics
of l-asparaginase has not been extensively studied
in dogs or cats. In a study of one dog with lymphoma
treated with l-asparaginase, plasma levels of l-
asparagine were undetectable and aspartic acid levels
were markedly elevated 24 h after treatment. Urinary
excretion of l-asparagine was also deceased. The halflife
of the enzyme in this dog was 18–24 h, similar to
the half-life in humans.
Adverse effects
● Toxicity of l-asparaginase is related to its immunogenicity
and depression of protein synthesis leading
to organ dysfunction (Table 15.5).
● Although l-asparaginase is a common component of
feline lymphoma protocols, reports of toxicity in the
cat are rare.
Known drug interactions
● The manufacturer’s recommendations for vincristine
indicate that vincristine should not be given in combination
with l-asparaginase because of severe
myelosuppression; consequently some veterinary
oncologists recommend spacing drug administration
by 12–48 h. Neutropenia is seen in up to 50% of
dogs at some centers treated with l-asparaginase and
vincristine, although it rarely results in clinical signs.
In one study evaluating 147 dogs, neutropenia
occurred in 40% of dogs receiving the combination
of drugs, irrespective of the interval between administration
of the two drugs. Hospitalization was necessary
in 16% of dogs.
● Theoretically, depletion of l-asparagine induces
tumor resistance to the effects of methotrexate but
since they are not typically given together, this interaction
is not clinically significant.
Table 15.5 L-asparaginase toxicity
Adverse effect Frequency Management Comments
Myelosuppression Rare Supportive care Not exacerbated by vincristine in
dogs
Anaphylaxis Rare? Pretreatment with shortacting
glucocorticoids and
antihistamines
Usually occurs with repeated
administrations, depends on
route of administration, higher
incidence if administered IV
Pancreatitis Less than 5% of dogs treated Supportive care May occur without elevations in
amylase and lipase because of
decreased synthesis
Clinical coagulopathy due to
decreased synthesis of
clotting factors
Diarrhea, nausea, vomiting,
anorexia, lethargy
Intramuscular injection site
discomfort
Decreased hepatic protein
synthesis
Reported in normal dogs and dogs
with lymphoma. Rarely occurs
Assess coagulation times if
hemorrhage is seen
Approximately 50% of dogs treated None usually required
Hospitalization rarely required
Approximately 50% of dogs treated None usually required Consider intraperitoneal
administration
Rare
Supportive care. Monitor for
coagulopathy and hepatic
encephalopathy
Use with caution in dogs and cats
with severe hepatic dysfunction
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