Docetaxel reactions

Docetaxel, another taxane, binds to tubulin to promote microtubule assembly. The pharmacokinetics of docetaxel are best described by a three-compartment model, with an a half-life of 0.08 hours, a 3 half-life of 1.6 to 1.8 hours, and a terminal half-life of 65 to 73 hours.14 Docetaxel has activity in the treatment of breast, non-small cell lung, prostate, bladder, esophageal, stomach, ovary, and head and neck cancers. Dexamethasone, 8 mg twice daily for 3 days starting the day before treatment, is used to prevent the fluid retention syndrome associated with docetaxel and possible hypersensitivity reactions. The fluid... 

Docetaxel Myelosuppression, severe fluid retention Alopecia, fatigue, stomatitis, nausea, vomiting, diarrhea, peripheral neuropathy, nail disorder, skin reactions, hypersensitivity reactions... 

Cisplatin-docetaxel diarrhea, cardiac toxicity, renal toxicity, neuropathy, weakness, hypersensitivity reactions, anemia Infection, thromocytopenia, nausea, vomiting, diarrhea, cardiac, High (day 1 only)... 

Docetaxel -semisynthetic taxane stabilizes tubulin polymers leading to death of mitotic cells -bone marrow suppression -nausea and vomiting -mucocutaneous effects (mucositis, stomatitis, diarrhea) -hypersensitivity reactions -fluid retention syndrome -fatigue -myalgias -alopecia (universal)... 

Both drugs are highly lipid soluble and as such are prepared and administered in dilutants (paclitaxel in Cremophor EL and docetaxel in polysorbate 80). Both medications are normally administered with dexamethasone, H, and H2 antagonists as premedications to decrease the incidence of the acute hypersensitivity reaction (HSR) (dyspnea with bronchospasm, urticaria, and hypotension) that has been observed to occur... 

Paclitaxel (Taxol) is a diterpenoid compound that contains a complex taxane ring as its nucleus (Figure 62.1). The side chain linked to the taxane ring at carbon 13 is essential for its antitumor activity. Modification of the side chain has led to identification of a more potent analogue, docetaxel (Taxotere), which has clinical activity against breast and ovarian cancers. Originally purified as the parent molecule from yew bark, paclitaxel can now be obtained for commercial purposes by semisynthesis from 10-desacetylbaccatin, a precursor found in yew leaves. It also has been successfully synthesized from simple off-the-shelf reagents in a complex series of reactions. 

Docetaxel should be administered the day after trastuzumab for the first cycle because of the potential for infusion-related reactions to trastuzumab, particularly during or after the first administration. Serious adverse reactions to trastuzumab infusion that have been reported infrequently include dyspnoea (shortness of breath), hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory distress and urticaria (itching). The majority of these events occur during or within 2.5 hours of the start of the first infusion. Should an infusion reaction occur, the infusion should be discontinued and the patient monitored until resolution of any observed symptoms - the infusion may be resumed when symptoms abate. If the first cycle is well tolerated then dosing of the drugs in future cycles may occur on the same day. 

Skin and subcutaneous tissue disorders Reversible cutaneous reactions have been observed and are generally mild to moderate. Reactions are characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently associated with pruritus. Eruptions generally occur within one week after the docetaxel infusion. Severe nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis. 

Genisson et al. also prepared two diastereomers of 2 -hydroxymethyl analogs through an asymmetric Baylis-Hillman reaction-like sequence to prepare a A-substimted 2 -methylene C-13 side chain (Scheme 3-3). After incorporation of the side chain to C-13 of 7,10-ii/-Troc-10-DAB, the product was then subjected to osmylation to yield 2 (R)- and 2 (5)-hydroxymethyl docetaxel 7a-b analogs stereoselectively. Both taxoids displayed less tubulin polymerization abilities than did paclitaxel, but the major product 2 / -isomer 7a is more active than the minor one 2 5-isomer 7b. ... 

Genisson, Y Massardier, C. Gautier-Luneau, I. Greene, A. E. Effective enantiose-lective approach to a-aminoalkylacrylic acid derivatives via a synthetic equivalent of an asymmetric Baylis-Hillman reaction application to the synthesis of two C-2 hydroxymethyl analogs of docetaxel. J. Chem. Soc. Perkin Trans. 1, 1996, 2869-2872. 

Docetaxel Nausea and vomiting hypersensitivity reactions Bone marrow depression fluid retention peripheral neuropathy alopecia arthralgias myalgias cardiac coxiciiy mild Gl disturbances mucositis... 

A 25% incidence of grade 2 or more severe immunological reactions to docetaxel has been reported after the use of oral prednisone (100 mg orally before treatment and 50 mg once on the morning of treatment and the following 2 days) in 20 patients with non-small-cell lung cancers (8). No other premedications were given routinely. If infusion-related symptoms occurred, the infusion was interrupted and diphenhydramine was given. On subsequent cycles those patients then were routinely premedicated with diphenhydramine 25 or 50 mg intravenously and cimetidine 300 mg intravenously. 

Both paditaxel and docetaxel may result in anaphylactoid or severe hypersensitivity reactions manifested by dyspnea, bronchospasm, angioedema, hypotension (occasionally HTN), and urticarial skin reactions. The reaction may be due to the active drug itself or to the vehicle (Cremophor or polysorbate 80). Additionally, patients receiving docetaxel may experience serious or life-threatening fluid retention. This syndrome is characterized by poorly tolerated peripheral or generalized edema, pleural effusion, dyspnea, ascites, and cardiac tamponade. 

It is recommended that all patients receiving paditaxel receive pretreatment with corticosteroids (such as dexa-methasone) and antihistamines, both H, (diphenydramine) and Hj (cimetidine or ranitidine) antagonists. All patients must be premedicated with corticosteroids prior to receiving each cycle of docetaxel to reduce the incidence and severity of hypersensitivity reactions or fluid retention. Patients who experience severe hypersensitivity reactions should not be rechallenged. 

Metabolism/elimination Hepatic metabolism Adverse reactions Alopeda, nausea/vomiting/diarrhea, myelosuppression (dose-limiting, granulocytopenia, and thrombocytopenia), hepatic toxidty, peripheral neuropathy, hypersensitivity reactions, myalgias/arthralgias, rare cardiovascular events, fluid retention/pulmonary edema (docetaxel). 

Precautions Doses may be modified or therapy delayed for toxicity (myelosuppression). Adjust dose for hepatic impairment. Avoid use of docetaxel in patients with elevated bilirubin. Corticosteroids and antihistamines (i.e., cimetidine and diphenhydramine) are recommended to lessen risk for anaphylactoid reactions with paditaxel. Pretreatment with steroids is required for docetaxel to minimize risk for fluid retention and hypersensitivity. 

Examples of p-aminoalkylphosphonates prepared include the analogues (277) and (278) of the docetaxel C-13 side-chain (276). The diethyl esters have been synthesised previously but the authors claim that there are advantages in using the methyl esters in syntheses. Air-stable titanocene(IV) salt complexes, e.g. (279), have been prepared by the reaction of titanocene dichloride with phosphorus and sulfur p-amino acid analogues. ... 

The combination regimen of paclitaxel (or docetaxel) and carbo-platin frequently is responsible for producing hypersensitivity reactions. Each agent precipitates a distinct reaction, allowing for differentiation between causative factors. Hypersensitivity reactions have been observed with paclitaxel and docetaxel as frequently as 34% of... 

Adverse effects of paclitaxel and docetaxel are similar, being hypersensitivity reactions, bone marrow suppression, peripheral neuropathy, hair loss and cardiac arrhythmias. 

Paclitaxel has very limited solubility and must be administered in a vehicle of 50% ethanol and 50% polyethoxylated castor oil (CREMOPHOR EL), a formation likely responsible for a high rate of hypersensitivity reactions. Patients receiving this formulation are protected by pretreatment with a histamine Hj receptor antagonist such as diphenhydramine, an receptor antagonist such as cimetidine fsee Chapter 24), and a glucocorticoid such as dexamethasone (see Chapter 59). Docetaxel, which is somewhat more soluble, is administered in polysorbate 80 and causes a lower incidence of hypersensitivity reactions. Pretreatment with dexamethasone is required to prevent progressive, and often disabling, fluid retention. 

Toxicity Paclitaxel causes neutropenia, thrombocytopenia, a high incidence of peripheral neuropathy, and possible hypersensitivity reactions during infusion. Docetaxel causes neurotoxicity and bone marrow depression. 

Low water solubility is a significant drawback to the therapeutic utility of the taxanes. This is particularly true of paclitaxel, which has a more lipophilic acetate moiety at Cio compared to docetaxel s more polar hydroxyl group. Paclitaxel must be administered in a vehicle of 50% alcohol/50% polyoxyethylated caster oil, which can lead to an enhanced risk of hypersensitivity reactions (dyspnea, hypotension, angioedema, and uticaria)... 

On the basis of an in vitro study using human liver sliees and human liver mierosomes it has been coneluded that the metabolism of paclitaxel is unlikely to be altered by cimetidine, dexamethasone or diphenhydramine, all of which are frequently given to prevent the hypersensitivity reactions associated with paclitaxel or its vehicle, Cremophor (see b, below). The UK manufacturers say that paclitaxel clearance in patients is not affected by cimetidine premedication, although some authors have advised caution when using cimetidine with docetaxel or paclitaxel since cimetidine is known to affect the cytochrome P450 isoenzyme CYP3A4, which is responsible, in part, for the metabolism of these taxanes. 

Ojima developed a second route to docetaxel, in which the side-chain was introduced by deprotonation with sodium hexamethyldisilazide and reaction with a /3-lactam. [329]... 

Taxol and related compounds have also been prepared by coupling cis-glycidic acids with baccatin. Thus the (2R, 3S) glycidic acid 8.1.16 underwent smooth coupling to 7,10-ditroc-baccatin III to give the derivative 8.1.17, which could be converted to docetaxel in good yield by the successive steps of reaction with sodium azide, carbonate formation, and deprotection (301),... 

Finally, selective N-debenzoylation of taxol has been achieved by reaction with di-t-butyl dicarbonate with 2 -(benzyloxycarbonyl)-7-(triethylsilyl)taxol to give the carbamate 8.7.3, followed by treatment with base and deprotection. Using this chemistry, taxol can be converted to docetaxel in 39% yield, and various N-acyl analogs of taxol can also be prepared through intermediate 8.7.4 (340). 

---