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

1076 and many other organs. In both humans and mice,
genetic elimination of thrombopoietin or its receptor
reduces the platelet counts to 10% of normal values.
Moreover, blood levels of the hormone are inversely
related to the blood platelet count, together indicating
that the hormone is the primary regulator of platelet
production.
Administration of recombinant thrombopoietin
leads to a log-linear increase in the platelet count in
mice, rats, dogs, and nonhuman primates (Harker,
1999) that begins on the third day of administration. In
a number of human preclinical trials in several models
of chemotherapy- and radiation-induced myelosuppression,
thrombopoietin accelerated the recovery of
platelet counts and other hematologic parameters
(Kaushansky et al., 1998). Of note, however, the agent
failed to substantially affect hematopoietic recovery
when administered after myeloablative therapy and
stem cell transplantation, unless given to the stem cell
donor (Fibbe et al., 1995).
Two forms of recombinant thrombopoietin have
been developed for clinical use. One is a truncated version
of the native polypeptide, termed recombinant
human megakaryocyte growth and development factor
(rHuMGDF), which is produced in bacteria and then
covalently modified with polyethylene glycol to
increase the circulatory t 1/2
. The second is the full-length
polypeptide termed recombinant human thrombopoietin
(rHuTPO), which is produced in mammalian cells.
In vitro, both drugs are equally potent in stimulating
megakaryocyte growth.
SECTION IV
INFLAMMATION. IMMUNOMODULATION, AND HEMATOPOIESIS
In clinical trials, both drugs are safe in the patient populations
selected for study. However, efficacy results using these agents have
been mixed. In a small number of patients with gynecological cancers
who were receiving carboplatin (Vadhan-Raj et al., 2000), rHuTPO
therapy reduced the duration of severe thrombocytopenia and the
need for platelet transfusions. In a similar study of patients treated
with carboplatin plus cyclophosphamide, patients receiving a cycle of
chemotherapy supplemented with G-CSF plus thrombopoietin had
higher platelet counts at nadir and a shorter median duration of severe
thrombocytopenia than they did after cycles of therapy supplemented
only with G-CSF (Basser et al., 2000). When used to augment peripheral
blood counts in preparation for platelet donation, a single dose of
thrombopoietin in the platelet donors tripled their platelet counts,
allowed for a threefold increase in the number of platelets that could
be collected in a single apheresis, and led to a fourfold increase in
the mean platelet count noted in transfusion recipients (Kuter et al.,
2001). However, this particular regimen was associated with several
instances of anti-recombinant thrombopoietin antibodies that crossreacted
with the native hormone, resulting in subsequent thrombocytopenia
(Li et al., 2001).
In several studies, although the drug was safe, rHuMGDF
was not effective. In two studies of patients treated for 7 days with
standard aggressive therapy for acute leukemia, the addition of
recombinant thrombopoietin failed to accelerate platelet recovery
(Archimbaud et al., 1999). A similar lack of efficacy was seen when
the drug was used following autologous peripheral blood stem cell
transplantation (Bolwell et al., 2000). Failure to improve
hematopoiesis in some of these trials may have resulted from the
dosing regimen employed; the optimal dose and schedule of administration
in various clinical settings need to be established. After a
single bolus injection, platelet counts showed a detectable increase
by day 4, peaked by 12-14 days, and then returned to normal over the
next 4 weeks. The peak platelet response follows a log-linear dose
response. Platelet activation and aggregation are not affected, and
patients are not at increased risk of thromboembolic disease, unless
the platelet count is allowed to rise to very high levels. These kinetics
need to be taken into account when planning therapy in cancer
chemotherapy patients.
Due to concerns over the immunogenicity of these agents,
and to other considerations, efforts now are under way to develop
small molecular mimics of recombinant thrombopoietin, discovered
either through screening of phage display peptide libraries or of
small organic molecules that have been developed for clinical use.
Two of these agents are FDA approved for use in patients with
immune thrombocytopenic purpura (ITP) who have failed to respond
to more conventional treatments. Romiplostim (NPLATE) contains four
copies of a small peptide that binds with high affinity to the thrombopoietin
receptor, grafted onto an immunoglobulin scaffold.
Romiplostim was found safe and efficacious in two randomized controlled
studies in patients with ITP. Overall, ~84% of patients
responded to the drug with substantial increases in platelet levels, of
which approximately half were durable (platelets >50,000/μL for
6 of the last 8 weeks of study) (Kuter et al., 2008). The drug is
administered weekly by subcutaneous injection, starting with a dose
of 1 μg/kg, titrated to a maximum of 10 μg/kg, until platelet count
increases above 50,000/μL. Eltrombopag (PROMACTA) is a small
organic molecule that binds specifically to the thrombopoietin receptor
and is administered orally. The safety and efficacy of eltrombopag
were evaluated in two double-blind placebo-controlled
clinical studies of >200 adult patients with chronic ITP who had
completed at least one prior treatment course and who had severe
thrombocytopenia (Bussel et al., 2007). These studies demonstrated
that 70-81% of patients with ITP can be expected to respond to a
6-week course of 50-75 mg/day of eltrombopag. The recommended
starting dose is 30 g per day, titrated to 75 mg depending on platelet
response. Several of these agents are in clinical trials.
Drugs Effective in Iron
Deficiency and Other
Hypochromic Anemias
IRON AND IRON SALTS
Iron deficiency is the most common nutritional cause
of anemia in humans. It can result from inadequate iron