Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

PLATINUM ANALOGS
activity against canine bladder tumors but more recent
reports did not strongly support this use.
Intralesional cisplatin has been reported to be an
effective treatment for sarcoids and squamous cell carcinomas
in horses. Cisplatin is contraindicated in cats
because at clinically useful doses it causes acute death
as a result of severe respiratory toxicity.
Although cisplatin is efficacious in canine osteosarcoma
and some carcinomas, it is largely being abandoned
in favor of carboplatin. Carboplatin has fewer
side effects and is simpler to use because cumbersome
diuresis protocols are not required, resulting in the
added potential benefit of less exposure of humans to
toxic drugs.
Mechanism of action
Cisplatin is a cell cycle phase-nonspecific drug. However,
its effects are greatest in the S phase. In plasma, the high
concentration of saline maintains cisplatin in the
uncharged and unreactive dichloro form. When cisplatin
moves intracellularly, the low chloride concentration
of the intracellular fluid favors the formation of the
reactive charged aquated form. The reactive cisplatin
molecule covalently binds to guanine-containing base
pairs of the DNA molecule and consequently disrupts
DNA function by forming both intra- and interstrand
cross-links.
Mechanisms of drug resistance
Three main categories of drug resistance have been
described for platinum complexes. First, decreased
transport across the cell membrane results in resistance
due to decreased intracellular drug accumulation.
Second, platinum activity can be quenched by conjugation
with thiourea or other sulfhydryl-containing
proteins such as glutathione. Augmented repair of platinum-induced
DNA adducts may also contribute to
tumor resistance.
• Intravenous administration of cisplatin requires vigorous
hydration with 0.9% saline to prevent nephrotoxicosis. One
protocol used successfully administers cisplatin IV over 20 min
after 0.9% saline is infused IV for 3–4 h at a rate of 18.3 mL/kg
bodyweight per h. After the cisplatin infusion, saline infusion
was continued at the same rate for an additional 1–2 h.
Additional diuretic agents such as mannitol and furosemide
may be used to supplement the diuretic effect of saline
• Experimentally, intraperitoneally administered methimazole has
been used to protect against nephrotoxicity in dogs not
receiving saline diuresis in conjunction with cisplatin therapy
Regional delivery
• Regional delivery of cisplatin has been investigated by some
and may have a therapeutic advantage in specifi c cases
• This has been accomplished by direct injection of the drug in a
matrix or suspended in medical-grade sesame oil to obtain
sustained drug release in tumors in dogs, cats and horses.
Sesame oil-cisplatin emulsion is prepared by sterilizing sesame
oil and emulsifying 3.3 mg of cisplatin per mL of oil. The
emulsion is administered at a dose of 1 mg/cm 3 of tumor.
Saline diuresis is not required with this route of administration
Biodegradable sponges
• Cisplatin in biodegradable sponges has been implanted into the
surgical wound following resection of osteosarcoma or soft
tissue sarcomas in dogs, with an improvement in local control
in cases of osteosarcoma
Intracavity
• Intracavity administration of cisplatin for treatment of
mesothelioma and carcinomatosis has been successful in some
dogs. The dose was 50 mg/m 2 into the pleural or peritoneal
space and hydration with saline was used to prevent
nephrotoxicosis
• For intrapleural administration, cisplatin was diluted in 250 mL/
m 2 0.9% sodium chloride
• For intraperitoneal delivery 1 L/m 2 was infused over 15 min
through a 16G catheter
Regional perfusion
• Intra-arterial administration of cisplatin has been used in dogs
with long-bone osteosarcoma prior to limb-sparing surgery
Formulations and dose rates
Cisplatin (1 mg/mL in 0.9% sodium chloride) was reported to be
stable in plastic infusion bags for up to 14 d at 25°C and 37°C. Once
reconstituted, the drug should not be stored in the refrigerator as it
may precipitate at 4°C. Solutions in the concentration range of 0.1–
0.2 mg/mL do not precipitate and are reportedly stable for 4 days at
4°C. If bacteriostatic water is used for reconstitution, a 1 mg/mL
solution is stable for 72 h at room temperature or 3 weeks when
frozen. Powder for injection and the injection formulation of the drug
should be stored away from light. Cisplatin is sensitive to daylight but
not adversely affected by artifi cial room lighting.
Intravenous
• Cisplatin is administered at a dose of 60–70 mg/m 2 IV to
dogs
Pharmacokinetics
In dogs, cisplatin exhibits a biphasic elimination profile.
The initial plasma half-life is short (20 min), but the
terminal phase is very long (120 h). Some 80% of a dose
can be recovered as free platinum in the urine within
48 h of dosing in dogs. The long terminal phase results
from concentration of the drug in liver, intestines and
kidney. Cisplatin is also highly bound to serum proteins.
After intravenous administration to dogs, plasma platinum
elimination is biphasic, with α- and β-phase halflives
of less than 1 h and days respectively. Over 90%
of plasma platinum is protein bound and consequently
inactive. Free platinum elimination is also biphasic, with
both phases less than 1 h. Platinum from cisplatin is
rapidly distributed to most tissues, with highest levels
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