Cremophor EL vehicle

Paclitaxel causes disturbances in cardiac rhythm, but the relevance of these effects has not been fully elucidated. Originally, aU patients in trials of paclitaxel were under continuous cardiac monitoring, owing to the risk of hypersensitivity reactions, and cardiac disturbances were therefore more likely to be detected. Many trials limited eligibility to patients without a history of cardiac abnormalities and to those who were not taking medications likely to alter cardiac conduction. The incidence of cardiac dysrhythmias in the population under study not treated with paclitaxel is unknown, and it is therefore not always possible to attribute dysrhythmias to paclitaxel in these patients. The Cremophor EL vehicle does not appear to be implicated in the incidence of dysrhythmias, although hypotension associated with hypersensitivity reactions may occur (13). 

Local venous effects, including erythema, tenderness, and discomfort, can occur at the injection site during paclitaxel infusion (13). Inflammation is evident within hours and usually resolves within 21 days. Inflammation occurs in areas of drug extravasation along with prolonged soft tissue injuries, and necrotic changes have been reported in one patient at the site of extravasation (41). Inflammation is most likely to be due to the drug, but the Cremophor EL vehicle may be implicated, as it produces mild inflammation in animals (41). 

The mechanism of paclitaxel-induced hypersensitivity reactions is uncertain. The symptoms suggest histamine release from mast cells to be a likely cause. Cremophor EL is thought to play a significant role in inducing hypersensitivity reactions. Cremophor EL causes similar reactions in dogs by direct release of histamine [17 ]. Hypersensitivity reactions have also been directly linked to complement activation secondary to binding of naturally occurring anticholesterol antibodies to the hydroxyl-rkh surface of Cremophor EL micelles [75 ]. However, there is evidence that paclitaxel alone, without the Cremophor EL vehicle, can also cause hypersensitivity reactions [76 ]. 

Of the two widely known solubilized preparations of intravenous anaesthetics on the market, one, Althesin (Glaxo, UK) contains a mixture of steroids. The more active anaesthetic is alphaxolone (9 mg ml ) (XX) and a less active alphadalone acetate (3mgml ) (XXI) has been added to improve the solubility of the alphaxolone in the Cremophor EL vehicle (20%). 

Figure 7.37 Plasma diazepam levels following intramuscular administration of diazepam O in propylene glycol vehicle x in a Cremophor EL vehicle compared with intravenous administration of the propylene glycol preparation. From Kan to [171] with permission.

Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer 2001 (Sep) 37(13) 1590-1598. 

Gelderblom, H., J. Verweij, K. Nooter, and A. Sparreboom. 2001. Cremophor EL The drawbacks and advantages of vehicle selection for drug formulatiEor. J. Cancei37 1590-1598. 

Cremophore EL Cremophore EL, a polyethoxylated castor oil used as a vehicle in various intravenous injections, has also been found to enhance the intraocular penetration of the drugs. Bijl et al. [83] reported that for Cremophore EL (10% and 20%), flux values of cyclosporine A across the fresh cornea were significantly higher than for corneal tissue without the enhancer for the first 16 h of the experiment. Steady-state flux rates were reached for cyclosporine A across the corneal tissue after approximately 2 h in the presence of 10% and 20% Cremophore EL. This observation can probably be explained on the basis of increased aqueous solubility of cyclosporine A in the presence of this emulsifier. Cremophore EL also improved the penetration of cyclosporine A through the epithelial and stromal layers of the cornea [83],... 

Formulation studies are performed to develop a suitable vehicle to solubilize the drug for administration to patients, generally by intravenous injection or infusion in the case of cancer. The low solubility of many natural products in water poses considerable problems, but these can be overcome by use of co-solvents or emulsifying agents (surfactants) such as Cremophore EL (polyoxyethylated castor oil). 

During a Phase I/II trial of high-dose intravenous ciclosporin, there was a high incidence of anaphylactoid reactions associated with improper mixing during preparation of the infusions, perhaps due to large initial bolus infusions of the vehicle, Cremophor EL (174). 

Effects of pachtaxel on the respiratory system are generally related to hypersensitivity reactions. One case of pneumonitis was possibly due to a hypersensitivity reaction to either paclitaxel or its vehicle Cremophor EL treatment with corticosteroids resulted in improvement (23). One patient developed tachjrpnea and cyanosis and subsequently died of pulmonary edema 7 days after receiving an infusion of pachtaxel (19). 

Abraham JS, Bentley FR, Garrison RN, Cryer HM.The influence ofthe cyclosporine vehicle, cremophor EL, on renal microvascular blood flow in the rat. Transplantation 1991 52 101-105. 

Sanchez H, Bigard X, Veksler V, et al. Immunosuppressive treatment affects cardiac and skeletal muscle mitochondria by the toxic effect of vehicle. / Mol Cell Cardiol 2000 32 323-331. Bowers VD, Locker S, Ames S, et al. The hemodynamic effects of Cremophor-EL. Transplantation 1991 51 847-850. 

Dose-dependent clearance and distribution was then later observed in a Phase 1 study in children with solid tumors (Sonnichsen et al., 1994). In a study in adults with ovarian cancer, Gianni et al. (1995) used a 3-compartment model with saturable intercompart-mental clearance into Compartment 2 and saturable, Michaelis-Menten elimination kinetics from the central compartment to describe the kinetics after 3 hour and 24 hour infusion. Now at this point one would typically assume that the mechanism for nonlinear elimination from the central compartment is either saturable protein binding or saturable metabolism. But the story is not that simple. Sparreboom et al. (1996a) speculated that since Cremophor EL is known to form micelles in aqueous solution, even many hours after dilution below the critical micellular concentration, and can modulate P-glycoprotein efflux, that the nonlinearity in pharmacokinetics was not due to paclitaxel, but due to the vehicle, Cremophor EL. This hypothesis was later confirmed in a study in mice (Sparreboom et al., 1996b). 

Sparreboom, A., van Tellingen, O., Nooijen, W.J., and Beij-nen, J.H. Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Research 1996b 56 2112-2115. 

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. 

Pups are injected in the neck using 26-27G needles (injection volume 100 pL/10 g). SR141716 is dissolved in a mixture of ethanol, cremophor EL, and saline (1 1 18, the vehicle), as described previously (11). 

The problem of reactions to Althesin raised a number of questions, some of which will be discussed here. First, confirmation was needed since in some cases there was suspicion that agents other than Althesin, e. g., muscle relaxants, might have been involved. Even in those reacting to Althesin, the vehicle (Cremophor EL) was a possible culprit . 

This was the first substance to be suspected of playing a role in Althesin reactions, because of some of its already known properties, and because nobody would believe that steroids could be allergenic. Cremophor EL is a macromolecular liquid consisting of polyoxyethylated castor oil. It is a water-miscible agent, and acts as a micellophore. Thus, it is widely used as a vehicle for lipid-soluble drugs, such as propanidid. It can similarly be used with diazepam. 

The mechanism of induction of histamine release by alphaxalone and alphadolone shown by the leucocyte test in susceptible individuals is not clear at present, but it appears to be like Cremophor EL. This means that it could be due either to an anaphylactic or anaphylactoid (direct histamine release) reaction. We did not find histamine release with these agents from the leucocytes of normal volunteers. We were unable to elicit a positive Prausnitz-Kiistner reaction in two patients in whom a reaction occurred after a second exposure to Althesin, and in whom the vehicle did not produce any response, either in the direct skin test or in the leucocyte test. 

Traditionally both saturable distribution and elimination were thought to be the main mechanisms underlying the non-linear pharmacokinetics of paclitaxel [17 ]. However, the formulation vehicle Cremophor EL also has a major effect. The clearance of Cremophor EL increases significantly and disproportionately with prolongation of the infusion [18 , 19 ]. Indeed, unbound paclitaxel has linear pharmacokinetics, with a half-life of about 22 hours [2(T, 2V],... 

In recent years, a Cremophor-free formulation of paclitaxel has been developed, with the trade name Abraxane. It uses nanoparticle albumin-bound (nab) technology as a vehicle for the delivery of paclitaxel. Abraxane is a Cremophor-free, 130-nanometer particle form of paclitaxel, which delivers paclitaxel as a suspension of albumin particles in saline. It therefore avoids the adverse reactions that are associated with Cremophor EL. It does not need premedication with glucocorticoids and antihistamines. In animals albumin-bound paclitaxel has increased and prolonged antitumor activity and more effective intratumor accumulation of paclitaxel, compared with Cremophor-based paclitaxel [93 ]. It is currently licensed for second-line treatment of metastatic breast cancer. 

Propylene glycol and 20 % Cremophor EL have been compared as vehicles for diazepam [170] in view of the number of reports of thrombophlebitis associated with intravenous diazepam. The Cremophor vehicle caused significantly less postinjection thrombophlebitis possibly because it prevents the precipitation of the drug substance at the site of injection by its solubilizing effect. Ease of injection... 

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