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

1684 However, adequate hydration and co-administration of
mesna have reduced its bladder toxicity.
Therapeutic Uses. Ifosfamide is approved for treatment of relapsed
germ cell testicular cancer and is frequently used for first-time treatment
of pediatric and adult sarcomas. It is a common component of
high-dose chemotherapy regimens with bone marrow or stem cell rescue;
in these regimens, in total doses of 12-14 g/m 2 , it may cause
severe neurological toxicity, including hallucinations, coma, and death,
with symptoms appearing 12 hours to 7 days after beginning the ifosfamide
infusion. This toxicity is thought to result from a metabolite,
chloroacetaldehyde. In addition, ifosfamide causes nausea, vomiting,
anorexia, leukopenia, nephrotoxicity, and VOD of the liver.
In nonmyeloablative regimens, ifosfamide is infused intravenously
over at least 30 minutes at a dose of ≤1.2 g/m 2 /day for
5 days. Intravenous mesna is given as bolus injections in a dose equal
to 20% of the ifosfamide dose concomitantly and an additional 20%
again 4 and 8 hours later, for a total mesna dose of 60% of the ifosfamide
dose. For ifosfamide doses ≤2 g/m 2 , oral mesna, at a dose
equal to 40% of the ifosfamide dose, can be substituted for the second
and third IV mesna doses, given at 2 and 6 hours after each
dose of ifosfamide, for a total mesna dose equal to the ifosfamide
dose. Alternatively, mesna may be given concomitantly in a single dose
equal to the ifosfamide dose. Patients also should receive at least 2 L
of oral or intravenous fluid daily. Treatment cycles are repeated every
3-4 weeks after hematological recovery.
Pharmacokinetics. The parent compound, ifosfamide, has an elimination
t 1/2
in plasma of ~1.5 hours after doses of 3.8-5 g/m 2 and a
somewhat shorter t 1/2
at lower doses, although its pharmacokinetics
are highly variable from patient to patient due to variable rates of
hepatic metabolism. Hydroxylation by CYPs generates an active
phosphoramide mustard.
Toxicity. Ifosfamide has virtually the same toxicity profile as
cyclophosphamide, although it causes greater platelet suppression,
neurotoxicity, nephrotoxicity, and in the absence of mesna, urothelial
damage.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Melphalan. This alkylating agent primarily is used to
treat multiple myeloma and, less commonly, in highdose
chemotherapy with marrow transplantation.
Pharmacological and Cytotoxic Actions. The general pharmacological
and cytotoxic actions of melphalan are similar to those of other
bifunctional alkylators. The drug is not a vesicant.
Absorption, Fate, and Excretion. Oral melphalan is absorbed in an
inconsistent manner and, for most indications, is given as an intravenous
infusion. The drug has a t 1/2
in plasma of ~45-90 minutes,
and 10-15% of an administered dose is excreted unchanged in the
urine. Patients with decreased renal function may develop unexpectedly
severe myelosuppression.
Therapeutic Uses. Melphalan (ALKERAN) for multiple myeloma is
given in doses of 4-10 mg orally for 4-7 days every 28 days, with
dexamethasone or thalidomide. Treatment is repeated at 4-week intervals
based on response and tolerance. Dosage adjustments should
be based on blood cell counts. Melphalan also may be used in myeloablative
regimens followed by bone marrow or peripheral blood
stem cell reconstitution. For this use, the dose is 180-200 mg/m 2 .
Clinical Toxicity. The clinical toxicity of melphalan is mostly hematological
and is similar to that of other alkylating agents. Nausea and
vomiting are less frequent. The drug causes less alopecia and, rarely,
renal or hepatic dysfunction.
Chlorambucil. This agent is almost exclusively used in
treating CLL, and in this disease has largely been
replaced by fludarabine and cyclophosphamide.
Pharmacological and Cytotoxic Actions. The cytotoxic effects of chlorambucil
on the bone marrow, lymphoid organs, and epithelial tissues
are similar to those observed with other nitrogen mustards. As
an orally administered agent, chlorambucil is well tolerated in small
daily doses and provides flexible titration of blood counts. Nausea
and vomiting may result from single oral doses of ≥20 mg.
Absorption, Fate, and Excretion. Oral absorption of chlorambucil is
adequate and reliable. The drug has a t 1/2
in plasma of ~1.5 hours,
and is hydrolyzed to inactive products.
Therapeutic Uses. In treating CLL, the standard initial daily dose of
chlorambucil (LEUKERAN) is 0.1-0.2 mg/kg, given once daily and
continued for 3-6 weeks. With a fall in the peripheral total leukocyte
count or clinical improvement, the dosage is titrated to maintain neutrophils
and platelets at acceptable levels. Maintenance therapy (usually
2 mg daily) often is required to maintain clinical response.
Clinical Toxicity. In CLL, chlorambucil treatment may continue for
months or years, achieving its effects gradually and often without
significant toxicity to a compromised bone marrow.
Although it is possible to induce marked hypoplasia of the bone
marrow with excessive doses, its myelosuppressive effects are moderate,
gradual, and rapidly reversible. GI discomfort, azoospermia, amenorrhea,
pulmonary fibrosis, seizures, dermatitis, and hepatotoxicity
rarely may be encountered. A marked increase in the incidence of acute
myelocytic leukemia (AML) and other tumors was noted in the treatment
of polycythemia vera and in patients with breast cancer receiving
chlorambucil as adjuvant chemotherapy (Lerner, 1978).
Bendamustine. This drug is approved for treatment of
CLL and non-Hodgkin’s lymphoma.
Bendamustine is given as a 30-minute intravenous infusion in
dosages of 100 mg/m 2 /day on days 1 and 2 of a 28-day cycle. Lower
doses may be indicated in heavily pretreated patients. It is rapidly
degraded through sulfhydryl interaction and adduct formation with
macromolecules, and <5% of the parent drug is excreted in the urine
intact. N-demethylation and oxidation produces metabolites that have
antitumor activity, but less than that of the parent molecule. The parent
drug has a t 1/2
in plasma of ~30 minutes (Teichert et al., 2007).
The clinical toxicity pattern of bendamustine is typical of
classical alkylators, with a rapidly reversible myelosuppression and
mucositis, both generally tolerable in the 28-day regimen.
MISCELLANEOUS ALKYLATING DRUGS
Although nitrogen mustards containing chloroethyl
groups constitute the most widely used class of alkylating
agents, alternative alkylators with greater chemical
stability and well-defined activity in specific types
of cancer have value in clinical practice.