Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 15 CANCER CHEMOTHERAPY
In the case of mast cell tumors, it should only be
considered for the treatment of dogs with tumors unsuitable
for surgery and radiation therapy. Anecdotal evidence
suggests that it may be combined with vinblastine
to treat these patients effectively, but it is not known
whether this combination is more effective than CCNU
alone.
Formulations and dose rates
DOGS
• 60–90 mg/m 2 PO every 3–8 weeks
CATS
• 50–60 mg/m 2 PO every 3–6 weeks
Pharmacokinetics
CCNU is a nitrosourea alkylating agent. After oral or
intravenous administration, CCNU is rapidly broken
down to various intermediates by hepatic microsomal
metabolic transformation. Following oral administration,
little or no parent drug is detectable in plasma.
High lipid solubility and relative lack of ionization at
physiological pH enable CCNU or its metabolites to
readily cross the blood–brain barrier. In dogs given
450 mg/m 2 radioactively labeled CCNU intravenously,
radioactivity rapidly entered cerebrospinal fluid. The
primary excretion route in dogs is renal, with approximately
85% of administered radioactivity excreted
within 24 h.
Adverse effects
● Neutropenia is the dose-limiting toxicity. Dogs
treated with 5 mg/kg (approx. 150 mg/m 2 ) became
neutropenic, with the nadir at 7 d (1 × 10 9 cells/L)
and recovery by 20 d. More recently, in 17 dogs
treated for mast cell tumor with CCNU 50 mg/m 2 ,
the median neutrophil count after 7 d was 1.4 × 10 9
cells/L (mean, 1.7 × 10 9 cells/L). Five dogs developed
fever, of whom four were neutropenic; all recovered
with supportive care. In another study, in dogs with
lymphoma treated with the same dose rate of CCNU,
delayed and cumulative neutropenia and thrombocytopenia
were observed.
● Unexplained fever has been reported as an uncommon
idiosyncratic toxicity in dogs.
● Hepatotoxicity was reported in dogs treated in preclinical
studies with more than 125 mg/m 2 . CCNU
hepatotoxicity is delayed, cumulative and dose
related, but is uncommon in clinical cases. In approximately
half of the dogs developing CCNU hepatotoxicity,
it was fatal. Elevation of serum ALT activity
may be an early marker of CCNU hepatotoxicity.
Serum biochemical profiles should be monitored in
dogs receiving CCNU.
● Gastrointestinal toxicity is mild and self-limiting.
● Evidence of renal toxicity, manifest as elevated
plasma urea concentration, has been observed in preclinical
studies with dogs.
● CCNU should be used with caution in myelosuppressed
patients.
● CCNU toxicity may be exacerbated in patients with
renal pathology that interferes with excretion.
Known drug interactions
As with other cytotoxic agents, the myelosuppressive
effects of CCNU may be enhanced by other myelosuppressive
drugs.
Chlorambucil
Other Names
Leukeran
Clinical applications
The combination of chlorambucil and prednisone is an
effective treatment for chronic lymphocytic leukemia. It
is easy to administer and there is a low probability of
myelotoxicity.
Chlorambucil is also used as a component of maintenance
therapy for lymphoma and may be substituted for
cyclophosphamide in animals with cyclophosphamideinduced
cystitis although this may not be necessary (see
cyclophosphamide below).
Other neoplastic diseases for which chlorambucil
may be useful include multiple myeloma (particularly in
cats), polycythemia rubra vera, macroglobulinemia,
ovarian adenocarcinoma and nonresectable mast cell
tumors in dogs.
Chlorambucil is also commonly used in the management
of immune-mediated disorders in cats.
Formulations and dose rates
Recommended dose rates vary widely, permitting considerable scope
for dosage adjustment according to the needs of an individual
patient.
DOGS AND CATS
• 2 mg/m 2 (up to 6 mg/m 2 ) or 0.2 mg/kg PO q.24 h or q.48 h
• 20 mg/m 2 or 1.4 mg/kg PO q.1–4 weeks
Pharmacokinetics
Chlorambucil belongs to the nitrogen mustard group of
alkylating agents. It is well absorbed from the gastrointestinal
tract of rats and humans and is mainly distributed
to liver, kidney and plasma in the rat. In addition
to a degree of spontaneous hydrolysis, the drug is extensively
metabolized in the liver to phenylacetic acid
mustard and its derivatives.
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