Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

PLATINUM ANALOGS
● Cisplatin is compatible with sodium chloride 0.9%.
It may be incompatible with dextrose/saline combinations,
5% dextrose in water and metoclopramide,
depending on pH, concentration, temperature and
diluents.
● As with other cytotoxics, the myelosuppressive
effects of cisplatin may be enhanced by other myelosuppressive
drugs
● Serum levels of phenytoin may be reduced following
cisplatin infusion.
● Caution should be used when combining cisplatin
with other nephrotoxic drugs such as aminoglycosides
or amphotericin B, as they may potentiate
nephrotoxicity. The combination of cisplatin and
piroxicam has been reported to be tolerated in dogs
treated for oral malignant melanoma and squamous
cell carcinoma although renal function must be monitored
carefully.
Special considerations
There is a potential occupational risk to veterinary hospital
staff involved in the care of dogs hospitalized for
the administration of cisplatin. Cisplatin is excreted in
urine and, in dogs receiving saline diuresis and diuretics,
urine production is copious. Dogs receiving cisplatin
should be allowed to urinate outdoors. When the inevitable
urination occurs in the hospital, personnel wearing
full personal protective equipment (gloves, gowns, face
protection and foot covers) should clean up with absorbent
disposable towels rather than flushing the urine
down a drain, which may aerosolize the drug.
Carboplatin
Other names
CBDA, JM-8
Clinical applications
Carboplatin is a less potent, less emetogenic and much
less nephrotoxic analog of cisplatin. Carboplatin has a
similar spectrum of activity to cisplatin. Clinical trials
demonstrate that carboplatin’s efficacy is close to
that of cisplatin for canine osteosarcoma. However, it
should be used with caution as an alternative to cisplatin
for dogs with renal disease, as it may exacerbate preexisting
nephropathy. Carboplatin also has demonstrated
some efficacy against canine melanomas and
some carcinomas. However, transitional cell carcinoma of
the bladder does not appear responsive to carboplatin.
In cats, carboplatin has been used to manage head
and neck carcinomas and adenocarcinomas, mammary
carcinomas and vaccine-associated sarcomas. Intralesional
carboplatin has been reported as an effective
agent for carcinomas and sarcomas in dogs and cats.
Mechanism of action
Carboplatin is similar to cisplatin in that it disrupts
DNA function by covalent binding to the DNA base
pairs. It is also a cell cycle-nonspecific drug.
Mechanisms of drug resistance
Like cisplatin, decreased transport of carboplatin across
the cell membrane, augmented DNA repair and quenching
of platinum reactivity by sulfhydryl compounds
confer drug resistance.
Formulations and dose rates
Because aquation of carboplatin occurs more quickly in a high-chloride
environment than in a low-chloride environment, it was originally
thought that mixing carboplatin with any solution containing chloride
should be avoided. This is now an outdated recommendation, since
more recent reports show that carboplatin 1 mg/mL is stable in 0.9%
sodium chloride for 24 h at 25°C and 4°C and 10 mg/mL is stable for
at least 5 d at 4°C. For extended storage, however, water is a satisfactory
diluent and indeed, one form supplied by the manufacturer is a
10 mg/mL solution in water.
DOGS
• 300 mg/m 2 IV over 15–60 min every 3–4 weeks
CATS
• 200 mg/m 2 IV over 15–60 min every 4 weeks
Pharmacokinetics
Pharmacokinetic parameters have been determined for
300 mg/m 2 of carboplatin administered over 30 min in
tumor-bearing dogs. The volume of distribution at
steady state was 39.3 L/m 2 . Total body clearance was
119.8 mL/min/m 2 . The area under the time–concentration
curves was 1.85% dose-min/mL. Half-life was
233.1 min and 47% of the administered drug was eliminated
in the urine in the first 4 h following administration.
Half-life, area under the curve and total body
clearance were not dose dependent.
Compared with cisplatin, the rate of aquation to
the active form is slower, causing differences in the
pharmacokinetic disposition and toxicity profile of the
two drugs. One of the major degradation products
is cisplatin. After intravenous administration of carboplatin
to dogs, the plasma platinum elimination is
biphasic, with α and β half-lives slightly longer than
cisplatin.
Carboplatin does not bind to plasma proteins as
extensively as cisplatin and remains in the plasma as free
drug longer than cisplatin. Tissue distribution is similar
to cisplatin. The major route of excretion is by glomerular
filtration alone, with approximately 70% of an
administered dose excreted in the urine within 4 d.
Tissue levels decline slowly, similarly to cisplatin.
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