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

1742 and rapidly interconverting non-polar S(–) and R(+) isomers, the
equilibrium favoring the R product. The R-enantiomer is associated
with the teratogenic and biological activities, while the S accounts
for the sedative properties of thalidomide.
Thalidomide is given in dosages of 200-1200 mg/day. In
treating MM, doses usually are escalated by 200 mg/day every
2 weeks until dose-limiting side effects (sedation, fatigue, constipation,
or a sensory neuropathy) supervene. With extended treatment,
the neuropathy may necessitate dose reduction or
discontinuation of treatment for a period of time. Thalidomide
absorption from the GI tract is slow and highly variable [4 hours
mean time to reach peak concentration (T max
), with a range of 1-7
hours]. It distributes throughout most tissues and organs, without
significant binding to plasma proteins. Peak levels are achieved
in 3-4 hours, and the t 1/2
of disappearance of the enantiomers is
~6 hours. Elimination of thalidomide is mainly by spontaneous
hydrolysis in all body fluids; the S-enantiomer is cleared more rapidly
than the R-enantiomer. Thalidomide and its metabolites are
excreted in the urine, while the non-absorbed portion of the drug
is excreted unchanged in feces, but clearance of active drug is primarily
attributable to hydrolysis. The inactive hydrolysis products
undergo a complex pattern of CYP-mediated metabolism. Studies
in elderly prostate cancer patients showed a significantly longer
plasma t 1/2
at highest doses (1200 mg daily) versus lowest doses
(200 mg daily) (Figg et al., 1999). No dose adjustment is necessary
in the presence of renal failure.
Thalidomide enhances the sedative effects of barbiturates
and alcohol and the catatonic effects of chlorpromazine and
reserpine. Conversely, CNS stimulants (such as methamphetamine
and methylphenidate) counteract the depressant effects of
thalidomide.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Lenalidomide. Lenalidomide (REVLIMID) constitutes the
lead compound in the new class of immunomodulatory
thalidomide derivatives and exhibits a panoply of
pharmacological properties (direct suppression of the
tumor cell growth in culture, T-cell and NK-cell activation,
suppression of TNF α and other cytokines, antiangiogenesis,
and promotion of hematopoietic stem cell
differentiation) (List, 2007).
Pharmacokinetics and Therapeutic Use. The standard dosage
of lenalidomide is 25 mg/day for 21 days of a 28-day cycle. The
drug is rapidly absorbed following oral administration, reaching
peak plasma levels within 1.5 hours. The C max
and AUC values
increase proportionately with increasing dose, over a single-dose
range of 5-400 mg. The t 1/2
of parent drug in plasma is 9 hours at
the 400-mg dose. Approximately 70% of the orally administered
dose of lenalidomide is excreted intact by the kidney. The AUC
progressively rises in patients with moderate to severe renal
failure (creatinine clearance <50 mL/min). Based on pharmacokinetic
considerations, downward dose adjustments to 10 mg/day
for creatinine clearance of 30-50 mL/h and to the same dose every
2 days for creatinine clearance <30 mL/h are recommended for
patients with renal failure. The safety and efficacy of these
adjusted doses have not been established in prospective studies
(Chen et al., 2007).
This orally administered agent has exhibited potent antitumor
activity in MM, MDS, and chronic lymphocytic leukemia
(CLL); causes fewer adverse side effects; and lacks the teratogenicity
of thalidomide.
Adverse Effects of Thalidomide and Lenalidomide
Thalidomide is well tolerated at doses <200 mg daily. The most
common adverse effects reported in cancer patients are sedation and
constipation, while the most serious one is peripheral sensory neuropathy,
which occurs in 10-30% of patients with MM or other
malignancies in a dose- and time-dependent manner (Richardson
et al., 2004). Thalidomide-related neuropathy is an asymmetrical,
painful, peripheral paresthesia with sensory loss, commonly presenting
with numbness of toes and feet, muscle cramps, weakness,
signs of pyramidal tract involvement, and carpal tunnel syndrome.
The incidence of peripheral neuropathy increases with higher cumulative
doses of thalidomide, especially in elderly patients. Although
symptoms improve upon drug discontinuation, long-standing sensory
loss may not reverse. Particular caution should apply in cancer
patients with pre-existing neuropathy (e.g., related to diabetes) or
prior exposure to drugs that can cause peripheral neuropathy (e.g.,
vinca alkaloids, bortezomib), especially because there has been little
progress in defining effective strategies to alleviate neuropathic
symptoms.
Adverse effects of lenalidomide are much less severe, as it
causes little sedation, constipation, or neuropathy. The drug
depresses bone marrow function and is associated with significant
leukopenia in 20% of patients. In rare instances, patients develop
hepatotoxicity and renal dysfunction. In some CLL patients,
lenalidomide causes dramatic lymph node swelling and tumor lysis,
a syndrome called the tumor flare reaction. Patients with renal dysfunction
receiving the standard dose of 25 mg/day are particularly
prone to this reaction; thus, clinical trials in CLL are proceeding at
much lower doses of 10 mg/day, with escalation as tolerated. CLL
patients should receive pretreatment hydration and allopurinol to
avoid the consequences of tumor swelling and tumor lysis. A negative
interaction with rituximab, an anti-CD20 antibody, may result
from lenalidomide’s downregulation of CD20, an interaction that
has clinical implications for their combined use in lymphoid malignancies
(Lapalombella et al., 2008).
Thromboembolic events occur with increased frequency in
patients receiving thalidomide or lenalidomide, but particularly in
combination with glucocorticoids and with anthracyclines
(Musallam et al., 2008). Anticoagulation reduces this risk and seems
indicated in patients presenting with risk factors for clotting, but anticoagulant
prophylaxis has not been evaluated prospectively.
PROTEASOME INHIBITION:
BORTEZOMIB
Bortezomib (VELCADE), an inhibitor of proteasomemediated
protein degradation, has earned a central role
in the treatment of MM.
Chemistry. Bortezomib, [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-
[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid, has a
unique boron-containing structure: