Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 15 CANCER CHEMOTHERAPY
Pharmacokinetics
Melphalan is a member of the nitrogen mustard group
of alkylating agents. Variable and incomplete oral
absorption of melphalan has been reported in humans
and is likely to occur in companion animals. Melphalan
is thought to be degraded in vivo to two hydrolysis
products and possibly three metabolites.
Pharmacokinetic studies were performed in beagle
dogs dosed either orally or intravenously with 0.45 mg/
kg (9 mg/m 2 ) melphalan. In dogs dosed orally 18 h after
food was withheld, drug absorption was rapid, with
maximum serum concentration occurring at 30 min.
After intravenous administration, the parent compound
was eliminated in two phases with α and β half-lives of
14 and 66 min respectively.
Elimination of metabolites from serum after either
oral or intravenous administration was triphasic with
half-lives (t 1/2 ) of 7–8 min, 2.8 h and 180 h. Urinary
excretion was also triphasic, with 22% of the administered
dose excreted by 4 h and 44% excreted by 11 d.
By 5 d after administration, 22% of the administered
dose was excreted in the feces, but only an additional
3% was excreted over the next 6 d.
Tissue distribution studies showed that half an hour
after intravenous administration, the drug was principally
found in liver, gallbladder, bile, kidney and urinary
bladder, spleen, stomach contents and duodenal contents.
At this time, approximately 11% of the administered
parent compound was found in the bile. Melphalan
and its metabolites or hydrolysis products were not
sequestered in fat, nor did they cross the blood–brain
barrier to any significant extent.
After intravenous administration of 0.63 mg/kg to
dogs, the nadir of myelosuppression occurred at between
7 and 14 d. Up to 50% of animals had neutrophil counts
of less than 1.5 × 10 9 /L and platelet counts of less than
80 × 10 3 /L.
Adverse effects
● Myelosuppression is a dose-limiting adverse effect.
Cats may be more susceptible to this effect than dogs
and care should be exercised when using melphalan
to treat cats.
● Gastrointestinal effects may also occur (anorexia,
vomiting, diarrhea).
● Pulmonary infiltrates and fibrosis have been reported
in human patients but not yet in veterinary clinical
practice.
● May raise serum uric acid levels.
● Melphalan should be used with caution in patients
with pre-existing myelosuppression or infection, or
renal dysfunction.
● Safe use during pregnancy has not been established.
Gonadal function may be suppressed by
melphalan.
Known drug interactions
● Melphalan is likely to augment the myelosuppressive
effects of other antineoplastic agents and possibly
other drugs that suppress bone marrow function, e.g.
chloramphenicol, flucytosine, amphotericin B.
● As with other potent immunosuppressive drugs, live
virus vaccines should be used with caution or not at
all during therapy with melphalan.
● Enhanced nephrotoxicity has been reported in children
treated with melphalan and cyclosporin but has
not been reported in veterinary patients.
Procarbazine
Other names
Ibenzemethyzin, Natulane, Matulane, NSC 77213
Clinical applications
The primary indication for procarbazine is for treatment
of lymphoma, in combination with mechlorethamine,
vincristine, procarbazine and prednisolone
(MOPP) (see Appendix). MOPP has been reported to
be an effective rescue therapy for dogs and cats with
relapsed lymphoma.
Formulations and dose rates
DOGS
• In MOPP combination chemotherapy lymphoma rescue protocol:
50 mg/m 2 PO q.24 h for 7–14 d every 4 weeks
CATS
• In MOPP combination chemotherapy lymphoma rescue protocol:
10 mg PO q.24 h for 14 d
Pharmacokinetics
Procarbazine is a nonclassic alkylating agent. It is extensively
metabolized to active alkylating species in a multistep
oxidative process chiefly involving the cytochrome
P450 enzyme complex but also monoamine oxidase and
other cytosolic enzymes. In the dog, the plasma t 1/2 is
12 min. The drug and its metabolites accumulate primarily
in cerebrospinal fluid, liver, kidney, skin and
intestines of animals. Metabolites are excreted chiefly in
the urine. After administration of radioactively labeled
procarbazine to dogs, approximately 75% of the administered
radioactivity is excreted within 1 d and 90%
within 4 d, the remainder being retained within the
tissues. The mechanism of procarbazine cytoxicity is
unknown.
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