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

1708 prior to therapy is required to prevent progressive fluid retention and
minimize the severity of hypersensitivity reactions.
Mechanism of Action. Interest in paclitaxel was stimulated by the
drug’s unique ability to promote microtubule formation at cold temperatures
and in the absence of GTP. It binds specifically to the
β-tubulin subunit of microtubules and antagonizes the disassembly
of this key cytoskeletal protein, with the result that bundles of microtubules
and aberrant structures derived from microtubules appear in
the mitotic phase of the cell cycle. Arrest in mitosis follows. Cell
killing is dependent on both drug concentration and duration of cell
exposure. Drugs that block cell-cycle progression prior to mitosis
antagonize the toxic effects of taxanes.
Drug interactions have been noted; the sequence of cisplatin
preceding paclitaxel decreases paclitaxel clearance and produces
greater toxicity than the opposite schedule (Rowinsky and
Donehower, 1995). Paclitaxel decreases doxorubicin clearance and
enhances cardiotoxicity, while docetaxel has no apparent effect on
anthracycline pharmacokinetics.
In cultured tumor cells, resistance to taxanes is associated in
some lines with increased expression of the mdr-1 gene and its product,
P-glycoprotein; other resistant cells have β-tubulin mutations,
and these latter cells may display heightened sensitivity to vinca alkaloids
(Cabral, 1983). Other resistant cell lines display an increase in
survivin, an anti-apoptotic factor, α aurora kinase, an enzyme that
promotes completion of mitosis. The taxanes preferentially bind to
the βII-tubulin subunit of microtubules; therefore, cells may become
resistant by upregulating the βIII-isoform of tubulin (Ranganathan
et al., 1998). The basis of clinical drug resistance is not known. Cell
death occurs by apoptosis, but the effectiveness of paclitaxel against
experimental tumors does not depend on an intact p53 gene product.
Preclinical studies have suggested that nab-paclitaxel has an
increased antitumor effect in breast cancer and a higher intratumoral
drug concentration compared to cremophor-delivered paclitaxel. The
reasons are not clear but may relate to maintenance of the drug in the
nanoparticle micellar system or to increased expression of SPARC
[Secreted Protein, Acidic and Rich in Cysteine; aka osteonectin, a
matri-cellular linkage protein expressed in pro-fibrotic states and
linked to myriad pathologies [Kos and Wilding, 2010; Chlenski and
Cohn, 2010]) on tumor cells, leading to an increased drug uptake.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Absorption, Fate, and Excretion. Paclitaxel is administered as a 3-hour
infusion of 135-175 mg/m 2 every 3 weeks or as a weekly 1-hour
infusion of 80-100 mg/m 2 . Prolonged infusions (96 hours) also have
been evaluated in different tumor histologies and are active. The drug
undergoes extensive metabolism by hepatic CYPs (primarily
CYP2C8 with a contribution of CYP3A4); <10% of a dose is
excreted in the urine intact. The primary metabolite identified thus
far is 6-OH paclitaxel, which is inactive, but multiple additional
hydroxylation products are found in plasma (Cresteil et al., 1994).
Paclitaxel clearance is nonlinear and decreases with increasing
dose or dose rate. In studies of 96-hour infusions of 140 mg/m 2
(35 mg/m 2 /day), the presence of hepatic metastases >2 cm in diameter
decreased clearance and led to high drug concentrations in
plasma and greater myelosuppression. Paclitaxel disappears from
the plasma compartment with a t 1/2
of 10-14 hours and a clearance
of 15-18 L/hr/m 2 . The critical plasma concentration for inhibiting
bone marrow elements depends on duration of exposure but likely
lies at ~50-100 nM (Huizing et al., 1993).
Nab-paclitaxel achieves a higher serum concentration of
paclitaxel compared to CREMOPHOR-solubilized paclitaxel, but the
increased clearance of nab-paclitaxel results in a similar drug exposure
(Gardner et al., 2008). Nab-paclitaxel is most often administered
intravenously over 30 minutes at 260 mg/m 2 every 3 weeks;
however, alternate dosing regimens are being evaluated. Like the
other taxanes, nab-paclitaxel should not be given to patients with an
absolute neutrophil count <1500 cells/mm 3 . Docetaxel pharmacokinetics
are similar to those of paclitaxel, with an elimination t 1/2
of
~12 hours. Clearance is primarily through CYP3A4- and CYP3A5-
mediated hydroxylation, leading to inactive metabolites (Clarke and
Rivory, 1999). In contrast to paclitaxel, the pharmacokinetics of docetaxel
are linear for doses ≤115 mg/m 2 .
Dose reductions in patients with abnormal hepatic function
have been suggested, and 50-75% doses of taxanes should be used
in the presence of hepatic metastases >2 cm in size or in patients
with abnormal serum bilirubin. Drugs that induce CYP2C8 or
CYP3A4, such as phenytoin and phenobarbital, or those that inhibit
the same cytochromes, such as antifungal imidazoles, significantly
alter drug clearance and toxicity.
Paclitaxel clearance is markedly delayed by cyclosporine A
and a number of other drugs employed experimentally as inhibitors
of the P-glycoprotein. This inhibition may be due to a block of CYPmediated
metabolism or effects on biliary excretion of the parent
drug or metabolites.
Therapeutic Uses. The taxanes have become central components of
regimens for treating metastatic ovarian, breast, lung, GI, genitourinary,
and head and neck cancers. In current regimens, these drugs are
administered once weekly or once every 3 weeks. The appropriate
use of the steroid-sparing nab-paclitaxel still is being evaluated in
clinical trials; in a randomized phase III study comparing 175 mg/m 2
of paclitaxel to 260 mg/m 2 of nab-paclitaxel in women with metastatic
breast cancer, the nab-paclitaxel arm had a higher response rate
and longer time to progression compared to the paclitaxel arm
(Gradishar et al., 2005).
Clinical Toxicities. Paclitaxel exerts its primary toxic effects on the
bone marrow. Neutropenia usually occurs 8-11 days after a dose and
reverses rapidly by days 15-21. Used with filgrastim [granulocytecolony
stimulating factor (G-CSF)], doses as high as 250 mg/m 2 over
24 hours are well tolerated, and peripheral neuropathy becomes dose
limiting. Many patients experience myalgias for several days after
receiving paclitaxel. In high-dose schedules, or with prolonged use,
a stocking-glove sensory neuropathy can be disabling, particularly in
patients with underlying diabetic neuropathy or concurrent cisplatin
therapy. Mucositis is prominent in 72- or 96-hour infusions and in
the weekly schedule.
Hypersensitivity reactions occurred in patients receiving
paclitaxel infusions of short duration (1-6 hours) but have largely
been averted by pretreatment with dexamethasone, diphenhydramine,
and histamine H 2
-receptor antagonists, as noted above.
Premedication is not necessary with 96-hour infusions. Many
patients experience asymptomatic bradycardia, and occasional
episodes of silent ventricular tachycardia also occur and resolve
spontaneously during 3- or 24-hour infusions.
Nab-paclitaxel produces increased rates of peripheral neuropathy
compared to CREMOPHOR-delivered paclitaxel but rarely
causes hypersensitivity reactions.