Page 1019 - Hematology_ Basic Principles and Practice ( PDFDrive )

902 Part VII Hematologic Malignancies

A P P E N D I X 57.5

CLINICAL PHARMACOLOGY OF PLATINUM ANALOGS

Cisplatin (Platinol) when cisplatin is administered with bleomycin and methotrexate
because cisplatin-induced renal damage may delay the excretion and
Chemistry and Mechanism of Action: Cisplatin [cisdiamined thus increase the toxicity of these agents.
ichloroplatinum(II)] is an inorganic heavy-metal complex. This
complex can have cis- and trans-isomers; the cis-isomer is the active Therapeutic Indications in Hematology: Cisplatin is used in
antitumor drug. In the relatively higher chloride concentrations of the treatment of refractory lymphomas, usually in combination with
plasma, cisplatin is uncharged in the dichloroform and passes through ara-C and high-dose dexamethasone.
plasma membranes. Intracellularly, the low chloride concentrations
allow the displacement of the chloride ligands by water to form the Carboplatin (Paraplatin)
positively charged aquated complex. This forms covalent cross-links
7
between two nucleophilic atoms of macromolecules such as the N Chemistry and Mechanism of Action: Carboplatin is a second-
positions of guanine and adenine in DNA. The cytotoxicity of cispla- generation platinum (II) complex. Its mechanism of action is very
tin correlates closely with total platinum binding to DNA, to inter- similar to that of cisplatin. However, the carboxyl ester groups in this
7
strand cross-links and to the formation of intrastrand bidentate N platinum complex are less easily displaced and less chemically reac-
adducts at d(GpG) and d(ApG), resulting in intrastrand cross-links tive. The peak levels of DNA cross-linking also occur 6–12 hours
that bend the DNA helix and inhibit DNA synthesis. Cisplatin later for carboplatin than for cisplatin.
damage to DNA induces apoptosis of sensitive cells.
Absorption, Fate, and Excretion: Carboplatin is primarily
Absorption, Fate, and Excretion: After IV injection, the drug eliminated through the kidneys. Its elimination is slower than cispla-
concentrates in the liver, kidneys, and bowel. Plasma levels of cisplatin tin with a terminal half-life between 2 and 6 hours. After IV injection,
decay in a biphasic manner, with an initial half-life of 25–49 minutes approximately 60% of the total drug is excreted within 24 hours.
and a terminal half-life of 58–73 hours. Although 15% of the
administered cisplatin is excreted unchanged in the urine, up to 90% Preparation and Administration: Carboplatin is commercially
of the administered dose of the drug can be recovered from the urine. available as a lyophilized powder in 50- and 150-mg vials containing
carboplatin and mannitol. It is reconstituted with sterile water to a
Preparation and Administration: Cisplatin is commercially final concentration of 10 mg/mL. For injection, further dilution with
available as a lyophilized powder, supplied in 10- and 50-mg vials 5% dextrose and water or normal saline to a concentration of 0.5 or
also containing mannitol, sodium chloride, and hydrochloric acid, 2 mg/mL, in which it is stable for 8 hours at room temperature.
and as an aqueous solution in 50- and 100-mg vials. Reconstitution Carboplatin is often administered by IV injection over 15–30
of the powder for injection is achieved by adding sterile water to make minutes. Patients with reduced renal function (creatinine clearance
a 1-mg/mL solution. The reconstituted solution should be further of <60 mL/min) should have the dose of carboplatin decreased
diluted in normal saline (usually 500 mL to 1 L) and administered according to the formula described by Egorin et al. 22
over 1–3 hours. To prevent nephrotoxic effects, 25–50 g of mannitol For previously untreated patients:
is often added to the saline solution, and patients are aggressively
2
(
hydrated before and after cisplatin infusion. Magnesium sulfate Dosage mg m )
(12–24 mEq) is commonly added to the saline solution to preclude = ( . 0 091 )( Creatinine clearance Body surface area) )
−
the development of hypomagnesemia. × [Pretreatment platelet count Platelet nadir desired
r
Pretreatment platelet count ×100] + 86
Toxic Effects: Nephrotoxicity is the dose-limiting toxic effect.
Cisplatin produces a dose-dependent impairment of renal tubular For heavily pretreated patients:
function manifested by an increase in serum creatinine as well as 2
(
potassium and magnesium wasting. The renal dysfunction is usually Dosage mg m )
reversible, but repeated treatments may produce a cumulative and = ( . 0 091 )( Creatinine clearance Body surface area) )
−
permanent mild-to-moderate impairment of renal function. Adminis- × [(Pretreatment platelet count Platelet nadir desired
tration of other nephrotoxic agents such as aminoglycosides, even Prettreatment platelet count ×100) −17] + 86
between courses, can potentiate its toxicity. Nausea and vomiting are
23
usually severe and require the use of aggressive antiemetic support. A formula developed by Calvert and colleagues also takes into
2
When doses greater than 70 mg/m are used, it is also important to account the patient’s pretreatment renal function, as follows:
protect against delayed nausea and vomiting by administering anti-
×
(
(
(
[
emetic agents (e.g., prochlorperazine plus dexamethasone) for 3 days Dose mg) = Target AUC mg mL min) H GFR mL min)+ 25 ]
after therapy. Myelosuppression is usually mild. High-frequency
2
hearing loss, tinnitus, and frank deafness may occur. Peripheral neuro- where the dose in mg (not mg/m body surface area) equals target
toxicity, characterized by paresthesias or sensory loss in a glove-and- AUC (area under the plasma clearance curve) × GFR (glomerular
stocking distribution or as muscular weakness, is relatively common in filtration rate) + 25.
2
patients who receive total cumulative doses of greater than 500 mg/m . In previously untreated adults, the AUC can be estimated at 7
The peripheral neuropathy may take many months to resolve, if it does when carboplatin is used alone and 4.5 when used in combination.
at all. Vestibular toxicity and anaphylactic reactions may occur rarely. If AUC is set lower, less toxicity is expected.
Potential Drug Interactions: Aminoglycosides and amphotericin Toxic Effects: The dose-limiting toxic effect is myelosuppression,
may enhance cisplatin nephrotoxicity. Caution should be exercised thrombocytopenia being more significant than leukopenia.