Page 1008 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 891

treatment. Mild-to-moderate nausea and vomiting is seen in 33% of Toxic Effects: Hypersensitivity reaction (HSR) was noted in up
patients. Stomatitis and diarrhea are less frequent. Transient eleva- to 30% of patients in the early phase I studies. HSR occurs early in
tions of transaminases have been reported. Among the miscellaneous the first or second infusion and may be caused by vehicle Cremophor
side effects noted are chest pain with or without electrocardiographic EL or paclitaxel itself. HSR consists of dyspnea, bronchospasm,
changes (6%, most with underlying cardiac disease), as well as urticaria, and hypotension. Most HSRs regress completely after stop-
bronchospasm and dyspnea (5%). Alopecia is seen in 10% of patients. ping the infusion and treatment with antihistamines, fluids, and
vasopressors. Prolonged infusions (>3 hours) and premedication
Therapeutic Indications in Hematology: Objective responses (dexamethasone 20 mg PO, 12 and 6 hours before treatment,
have been observed in approximately 33% of patients with Hodgkin diphenhydramine 50 mg, and ranitidine 150 mg IV 30 minutes
lymphoma or NHL. before treatment) have reduced the incidence of major HSRs to less
than 3%. Patients with a history of HSR may be rechallenged with
Paclitaxel (Taxol) and Docetaxel (Taxotere) paclitaxel at a markedly slower infusion rate, 20 mg dexamethasone
IV every 6 hours for four doses before treatment. Although not
Chemistry and Mechanism of Action: Both paclitaxel and formulated in Cremophor EL, HSRs can occur in up to 25% of
docetaxel are complex diterpene alkaloid esters consisting of a taxane patients receiving docetaxel. Most HSRs are minor, consisting of
system linked to an oxetane ring and a C-13 side chain that is neces- flushing, chest tightness, and low back pain. Premedication with
sary for their cytotoxic effects in mammalian cells. After binding to dexamethasone 8 mg PO twice daily for 3 days starting 1 day before
the N-terminal 31 amino acids of the β-tubulin subunit in the treatment with docetaxel considerably reduces the incidence of HSRs
tubulin oligomers or polymers, these taxanes kinetically stabilize and fluid retention. Neutropenia is the main toxicity of paclitaxel and
microtubule dynamics at plus ends. They also decrease the lag time docetaxel, but it is not cumulative. With higher doses of paclitaxel
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and shift the equilibrium toward tubulin polymerization into micro- (250 mg/m over 24 hours), this can be ameliorated with subsequent
tubule bundles. The disequilibrium of tubulin–microtubule polym- administration of granulocyte colony-stimulating factor. Severe
erization results in mitotic arrest and apoptosis of cells. Taxane-induced thrombocytopenia and anemia are rare. Symmetric, distal, peripheral
mitotic arrest is associated with phosphorylation of B-cell lymphoma sensory neuropathy is usually seen with higher doses or multiple doses
(BCL2) protein and increased intracellular levels of free BAX protein, of paclitaxel. This often limits chronic use of paclitaxel. Diffuse
which promote apoptosis. Compared with paclitaxel, docetaxel areflexia and neuronopathy are less commonly seen. Higher doses can
demonstrates 1.9-fold greater affinity for tubulin binding sites and also cause motor and autonomic neuropathy as well as myalgias,
greater potency in mediating BCL2 phosphorylation. especially in patients with preexisting neuropathy or when paclitaxel
is used with cisplatin. Severe peripheral neuropathy or myalgias are
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Absorption, Fate, and Excretion: Taxanes generally are admin- less common after repetitive docetaxel at 100 mg/m . Cardiac rhythm
istered by IV infusion lasting over 3, 24, or 96 hours (paclitaxel) or abnormalities, especially bradyarrhythmias and (rarely) heart blocks,
1 hour (docetaxel). Depending on the dose and schedule, peak plasma have been reported secondary to paclitaxel treatment. A direct causal
concentrations of paclitaxel range between 0.05 and 15.0 mM. Its link between paclitaxel and myocardial ischemic episodes and
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steady-state volume of distribution ranges between 48 and 182 L/m , tachyarrhythmias has not been established. Although noted, a direct
with rapid uptake in almost all tissues except the CNS and 98% link has also not been established between the occurrence of cardiac
plasma protein binding. Plasma decay for paclitaxel is biphasic, with conductance abnormalities or ischemia and docetaxel treatment.
α and β half-lives of 0.34 and 5.8 hours, respectively. Saturable Nausea, vomiting, diarrhea, and stomatitis are uncommon and gener-
distribution and elimination appear to be responsible for paclitaxel’s ally mild to moderate. Alopecia is universal with both drugs. Skin
nonlinear pharmacokinetics. This means that paclitaxel dose escala- toxicity is more severe and common with docetaxel. It is characterized
tion in shorter schedules may result in disproportionate increases in by an erythematous pruritic maculopapular rash affecting the fore-
area under the concentration–time curve and peak plasma concentra- arms and hands. Onychodystrophy with discoloration, ridging, and
tion. It is metabolized to 6-hydroxy paclitaxel by the CYP3A isoform brittleness of fingernails also occurs. Docetaxel can cause cumulative
of the PU 50 mixed-function oxidases in the hepatic microsomes. Total fluid retention, resulting in peripheral edema, third-space fluid col-
fecal and urinary excretion of paclitaxel and its metabolites is approxi- lection, and weight gain, which usually resolves slowly after stopping
mately 70% and 10%, respectively. Although dose modification is docetaxel. Concurrent treatment with dexamethasone, as noted
not necessary for renal insufficiency, a 50% reduction in dose is earlier, delays the onset and decreases the incidence of these side
recommended even for moderate hyperbilirubinemia or significant effects.
elevations in hepatocellular enzymes. When administered as a 1-hour
IV infusion, docetaxel has linear pharmacokinetics that fit a three- Potential Drug Interaction: When paclitaxel infusion (24
compartment model. Similar to paclitaxel, docetaxel also has a high hours) is administered after cisplatin, there is a 33% reduction in
clearance rate (0.36 L/hour), a steady-state volume of distribution the clearance rate of paclitaxel. This produces suboptimal antitumor
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(67.3 L/m ), and a terminal half-life of 12 hours. Docetaxel also has cytotoxicity and more profound neutropenia. Hence, the sequence
high protein binding (97%) and extensive tissue distribution. The of paclitaxel followed by cisplatin is commonly recommended.
drug or its metabolites also have high fecal (80%) and low urinary The use of carboplatin after paclitaxel has been reported to cause
elimination (5%). Metabolism of docetaxel also primarily occurs in less thrombocytopenia than carboplatin alone. Mucositis is more
hepatic microsomal P450 mixed-function oxidases, CYP3A, CYP2B, pronounced when paclitaxel is used before doxorubicin, a sequence
and CYP1A. that reduces the clearance of doxorubicin. Hematologic toxicity is
more prominent with the sequence of cyclophosphamide followed
Preparation and Administration: Paclitaxel is available as a by paclitaxel compared with the reverse sequence of administration.
30-mg/5 mL single-dose vial in polyoxyethylated castor oil (Cremo- Anticonvulsants such as phenytoin and phenobarbital induce the
phor EL) 50% and dehydrated alcohol, USP 50%. The contents of metabolism of paclitaxel and docetaxel by the P450 mixed-function
the vial must be diluted before use. Docetaxel for injection is available oxidases. Conversely, in vitro studies have shown that inhibitors of
as a concentrate in polysorbate 80 in two vial contents the P450 system can interfere with the metabolism of both drugs.
(23.6 mg/0.59 mL or 94.4 mg/2.36 mL) along with the appropriate These inhibitors include erythromycin, testosterone, ketoconazole,
diluent (1.83 or 7.33 mL) in separate vials. Adding diluent that is and fluconazole.
13% (w/w) ethanol in water for injection to the concentrate produces
a final premix concentration of 10 mg docetaxel/mL. The required Therapeutic Indications in Hematology: Both paclitaxel and
amount of premix is transferred by a calibrated syringe into 0.9% docetaxel have significant activity against previously treated patients
saline or 5% dextrose to produce a final concentration of 0.3 or with NHL. Paclitaxel is also very active against HIV-associated
0.9 mg/mL. The IV infusion is administered over 1 hour. Kaposi sarcoma.