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

1072 estimated as ~17% based on a meta-analysis of nearly 14,000 cancer
patients (Bohlius et al., 2008). The cause(s) of this effect is
presently unclear, but some studies suggest that tumor cells bearing
the erythropoietin receptor are more likely to be affected by the use
of ESAs (Henke et al., 2003). Although epoetin alfa is not associated
with direct pressor effects, blood pressure may rise, especially during
the early phases of therapy when the hematocrit is increasing.
ESAs should not be used in patients with preexisting uncontrolled
hypertension. Patients may require initiation of, or increases in, antihypertensive
therapy. Hypertensive encephalopathy and seizures
have occurred in chronic renal failure patients treated with epoetin
alfa. The incidence of seizures appears to be higher during the first
90 days of therapy with epoetin alfa in patients on dialysis (occurring
in ~2.5% of patients) when compared with subsequent 90-day
periods. Headache, tachycardia, edema, shortness of breath, nausea,
vomiting, diarrhea, injection site stinging, and flu-like symptoms
(e.g., arthralgias and myalgias) also have been reported in conjunction
with epoetin alfa therapy. Pure red-cell aplasia in association
with neutralizing antibodies to native erythropoietin has been
observed in patients treated with specific epoetin alfa formulations
(see earlier discussion). Resistance to therapy can be caused by multiple
factors (see following discussion).
SECTION IV
INFLAMMATION. IMMUNOMODULATION, AND HEMATOPOIESIS
Anemia of Chronic Renal Failure. Patients with anemia secondary to
chronic kidney disease are ideal candidates for epoetin alfa therapy
because the disorder represents a pure erythropoietin deficiency
state. The response in predialysis, peritoneal dialysis, and hemodialysis
patients depends on the severity of the renal failure, the erythropoietin
dose and route of administration, and iron availability
(Besarab et al., 1999, Kaufman et al., 1998). The subcutaneous route
of administration is preferred over the intravenous route because
absorption is slower and the amount of drug required is reduced
by 20-40%.
The dose of epoetin alfa should be adjusted to obtain a gradual
rise in the hematocrit over a 2- to 4-month period to a final hematocrit
of 33-36%. Treatment to hematocrit levels >36% is not
recommended because patients treated to a hematocrit >40% showed
a higher incidence of myocardial infarction and death (Besarab et
al., 1998). The drug should not be used to replace emergency transfusion
in patients who need immediate correction of a life-threatening
anemia.
Patients are started on doses of 80-120 units/kg of epoetin
alfa, given subcutaneously, three times a week. It can be given on a
once-weekly schedule, but somewhat more drug is required for an
equivalent effect. If the response is poor, the dose should be progressively
increased. The final maintenance dose of epoetin alfa can vary
from as little as 10 units/kg to >300 units/kg, with an average dose
of 75 units/kg, three times a week. Children <5 years of age generally
require a higher dose. Resistance to therapy is common in
patients who develop an inflammatory illness or become iron deficient,
so close monitoring of general health and iron status is essential.
Less common causes of resistance include occult blood loss,
folic acid deficiency, carnitine deficiency, inadequate dialysis,
aluminum toxicity, and osteitis fibrosa cystica secondary to
hyperparathyroidism.
The most common side effect of epoetin alfa therapy is aggravation
of hypertension, which occurs in 20-30% of patients and most
often is associated with a rapid rise in hematocrit. Blood pressure
usually can be controlled either by increasing antihypertensive therapy
or ultrafiltration in dialysis patients or by reducing the epoetin
alfa dose to slow the hematocrit response.
Darbepoetin alfa also is approved for use in patients who are
anemic secondary to chronic kidney disease. The recommended
starting dose is 0.45 μg/kg administered intravenously or subcutaneously
once weekly, with dose adjustments depending on the
response. Like epoetin alfa, side effects tend to occur when patients
experience a rapid rise in hemoglobin concentration; a rise of <1
g/dL every 2 weeks generally has been considered safe.
Anemia in AIDS Patients. Epoetin alfa therapy has been approved for
the treatment of HIV-infected patients, especially those on zidovudine
therapy (Fischl et al., 1990). Excellent responses to doses of
100-300 units/kg, given subcutaneously three times a week, generally
are seen in patients with zidovudine-induced anemia. In the face
of advanced disease, marrow damage, and elevated serum erythropoietin
levels (>500 IU/L), therapy is less effective.
Cancer-Related Anemias. Epoetin alfa therapy, 150 units/kg three
times a week or 450-600 units/kg once a week, can reduce the transfusion
requirement in cancer patients undergoing chemotherapy.
Evidence-based guidelines for the therapeutic use of recombinant
erythropoietin in patients with cancer have been published (Rizzo et
al., 2002). Briefly, the guidelines recommend the use of epoetin alfa
in patients with chemotherapy-associated anemia when hemoglobin
levels fall below 10 g/dL, basing the decision to treat less severe anemia
(Hb, 10-12 g/dL) on clinical circumstances. For anemia associated
with hematologic malignancies, the guidelines support the use
of recombinant erythropoietin in patients with low-grade myelodysplastic
syndrome, although the evidence that the drug is effective in
anemic patients with multiple myeloma, non-Hodgkin’s lymphoma,
or chronic lymphocytic leukemia not receiving chemotherapy is less
robust. A baseline serum erythropoietin level may help to predict the
response; most patients with blood levels >500 IU/L are unlikely to
respond to any dose of the drug. Most patients treated with epoetin
alfa experienced an improvement in their anemia, sense of wellbeing,
and quality of life (Littlewood et al., 2001). This improved
sense of well-being, particularly in cancer patients, may not be solely
due to the rise in the hematocrit. Erythropoietin receptors have been
demonstrated in cells of the central nervous system (CNS), and erythropoietin
has been found to act as a cytoprotectant in several models
of CNS ischemia. Thus high levels of the hormone may directly
affect cancer patients’ sense of well-being.
Darbepoetin alfa also has been tested in cancer patients undergoing
chemotherapy and preliminary studies appear promising.
However, recent case reports have suggested a direct effect of both
epoetin alfa and darbepoetin alfa in stimulation of tumor cells. For
example, patients with cancer of the head and neck randomized to
receive recombinant erythropoietin had a statistically significant
increase in likelihood of tumor progression during the duration of the
study (Henke et al., 2003). A meta-analysis of a large number of
patients and clinical trials estimates the risk at ~10% higher than nontreated
cancer patients (Bohlius et al., 2008). This finding is being
evaluated by the FDA and warrants serious attention.
Surgery and Autologous Blood Donation. Epoetin alfa has been used
perioperatively to treat anemia and reduce the need for erythrocyte
transfusion. Patients undergoing elective orthopedic and cardiac procedures
have been treated with 150-300 units/kg of epoetin alfa once