DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Cisplatin
Absorption, Fate, and Excretion. After intravenous administration,
cisplatin has an initial plasma elimination t 1/2
of 25-50 minutes; concentrations
of total (bound and unbound) drug fall thereafter, with a
t 1/2
of ≥24 hours. More than 90% of the platinum in the blood is
covalently bound to plasma proteins. The unbound fraction, composed
predominantly of parent drug, diminishes within minutes.
High concentrations of cisplatin are found in the tissues of the kidney,
liver, intestine, and testes but poorly penetrate into the CNS.
Only a small portion of the drug is excreted by the kidney during
the first 6 hours; by 24 hours, up to 25% is excreted, and by 5 days,
up to 43% of the administered dose is recovered in the urine, mostly
covalently bound to protein and peptides. Biliary or intestinal excretion
of cisplatin is minimal.
Therapeutic Uses. Cisplatin (PLATINOL, others) is given only by the
intravenous route. The usual dosage is 20 mg/m 2 /day for 5 days,
20-30 mg weekly for 3-4 weeks, or 100 mg/m 2 given once every
4 weeks. To prevent renal toxicity, it is important to establish a chloride
diuresis by the infusion of 1-2 L of normal saline prior to treatment.
The appropriate amount of cisplatin then is diluted in a
solution containing dextrose, saline, and mannitol and administered
intravenously over 4-6 hours. Because aluminum reacts with and
inactivates cisplatin, the drug should not come in contact with needles
or other infusion equipment that contain aluminum during its
preparation or administration.
Cisplatin, in combination with bleomycin, etoposide, ifosfamide,
or vinblastine, cures 90% of patients with testicular cancer.
Used with paclitaxel, cisplatin or carboplatin induces complete
response in the majority of patients with carcinoma of the ovary.
Cisplatin produces responses in cancers of the bladder, head and
neck, cervix, and endometrium; all forms of carcinoma of the lung;
anal and rectal carcinomas; and neoplasms of childhood.
Interestingly, the drug also sensitizes cells to radiation therapy and
enhances control of locally advanced lung, esophageal, and head and
neck tumors when given with irradiation.
Clinical Toxicities. Cisplatin-induced nephrotoxicity has been
largely abrogated by adequate pretreatment hydration and chloride
diuresis. Amifostine (ETHYOL, others) is a thiophosphate cytoprotective
agent that reduces renal toxicity associated with repeated administration
of cisplatin, but is not commonly used. Ototoxicity caused
by cisplatin is unaffected by diuresis and is manifested by tinnitus
and high-frequency hearing loss. The ototoxicity can be unilateral
or bilateral, tends to be more frequent and severe with repeated
doses, and may be more pronounced in children. Marked nausea and
vomiting occur in almost all patients and usually can be controlled
with 5-HT 3
antagonists, NK1-receptor antagonists, and high-dose
corticosteroids (see Chapter 46).
At higher doses, or after multiple cycles of treatment, cisplatin
causes a progressive peripheral motor and sensory neuropathy,
which may worsen after discontinuation of the drug and may be
aggravated by subsequent or simultaneous treatment with taxanes or
other neurotoxic drugs. Cisplatin causes mild to moderate myelosuppression,
with transient leukopenia and thrombocytopenia.
Anemia may become prominent after multiple cycles of treatment.
Electrolyte disturbances, including hypomagnesemia, hypocalcemia,
hypokalemia, and hypophosphatemia, are common. Hypocalcemia
and hypomagnesemia secondary to tubular damage and renal
electrolyte wasting may produce tetany if untreated. Routine measurement
of Mg 2+ concentrations in plasma is recommended.
Hyperuricemia, hemolytic anemia, and cardiac abnormalities are
rare side effects. Anaphylactic-like reactions, characterized by facial
edema, bronchoconstriction, tachycardia, and hypotension, may
occur within minutes after administration and should be treated by
intravenous injection of epinephrine and with corticosteroids or antihistamines.
Like other DNA adduct–forming drugs, cisplatin has
been associated with the development of AML, usually ≥4 years after
treatment.
Carboplatin
The mechanisms of action and resistance and the spectrum of clinical
activity of carboplatin (CBDCA, JM-8) are similar to cisplatin
(see “Cisplatin”). However, the two drugs differ significantly in their
chemical, pharmacokinetic, and toxicological properties.
Because carboplatin is much less reactive than cisplatin,
the majority of drug in plasma remains in its parent form, unbound
to proteins. Most drug is eliminated via renal excretion, with a t 1/2
in plasma of ~2 hours. A small fraction of platinum binds irreversibly
to plasma proteins and disappears slowly, with a t 1/2
of
≥5 days.
Carboplatin is relatively well tolerated clinically, causing less
nausea, neurotoxicity, ototoxicity, and nephrotoxicity than cisplatin.
Instead, the dose-limiting toxicity is myelosuppression, primarily
thrombocytopenia. It is more likely to cause a hypersensitivity reaction;
in patients with a mild reaction, premedication, graded doses of
drug, and more prolonged infusion lead to desensitization.
Carboplatin and cisplatin are equally effective in the treatment
of suboptimally debulked ovarian cancer, non–small cell
lung cancer, and extensive-stage small cell lung cancer; however,
carboplatin may be less effective than cisplatin in germ cell, head
and neck, and esophageal cancers (Go and Adjei, 1999).
Carboplatin is an effective alternative for responsive tumors in
patients unable to tolerate cisplatin because of impaired renal
function, refractory nausea, significant hearing impairment, or
neuropathy, but doses must be adjusted for renal function. In addition,
it may be used in high-dose therapy with bone marrow or
peripheral stem cell rescue. The dose of carboplatin should be
adjusted in proportion to the reduction in creatinine clearance
(CrCl) for patients with a CrCl <60 mL/min. The following formula
is useful for calculation of dose:
Dose (mg) = AUC × (GFR + 25)
where the target AUC (area under the plasma concentration–time
curve) is ~5-7 min/mg/mL for acceptable toxicity in patients receiving
single-agent carboplatin (GFR = glomerular filtration rate).
Carboplatin (PARAPLATIN) is administered as an intravenous
infusion over at least 15 minutes, using the above-mentioned formula
for dose calculation, and is given once every 21-28 days.
Oxaliplatin
Absorption, Fate, and Excretion. Oxaliplatin, like cisplatin, has a
very brief t 1/2
in plasma, probably as a result of its rapid uptake by
tissues and its reactivity. Maximum concentrations in plasma range
from 1-1.5 μg platinum/mL for patients receiving 80-130 mg/m 2
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CHAPTER 61
CYTOTOXIC AGENTS