Paclitaxel Repackaged in an Albumin-Stabilized Nanoparticle: Handy or Just a Dandy?

Abstract

Pharmaceutical excipients have a vital role in drug formulations, a role that has tended to be neglected as evidenced by the lack of regulatory procedures to assess excipient safety outside a new drug application process. In contrast to earlier views, many of the currently used excipients are not inert vehicles, but can exert a range of intrinsic adverse effects and have the potential to cause clinically significant drug interactions. One of the best-studied excipients is polyoxyethylated castor oil (Cremophor El; Basf, Ludwigshafen, Germany), which is being used as a vehicle for the solubilization of a wide variety of hydrophobic drugs, including anesthetics, photosensitizers, sedatives, immunosuppressive agents, and anticancer drugs, such as teniposide and paclitaxel. The amount of Cremophor administered with such drugs averages 5 mL (range, 1.5-10 mL), although paclitaxel is an exception as the amount is much higher per administration, about 25 mL at the recommended dose of 175 mg/m once every three weeks. For this reason, there has been a surge of interest within both industry and academia in Cremophor’s toxicological and pharmacologic profile in the context of chemotherapeutic treatment with paclitaxel. Cremophor presents a number of serious concerns when administered intravenously, including various intrinsic toxic side effects that limit the amount of paclitaxel that can be safely administered. The best known among these is an acute hypersensitivity reaction characterized by dyspnea, flushing, rash, and generalized urticaria, which effects coincide with the use of intravenous paclitaxel formulated in Cremophor. Mostly, the hypersensitivity reaction occurs within the first two courses of paclitaxel and it can be prevented by reducing the infusion rate and by the use of steroids and histamine antagonists, which are the reasons of the general belief that it resembles a nonimmunological reaction, based on degranulation of mast cells or basophils. More recently, it was postulated that complement activation is an important contributing mechanism to the hypersensitivity reactions from paclitaxel due to binding of naturally occurring anticholesterol antibodies to the hydroxyl-rich surface of Cremophor micelles. Despite extensive premedication, the overall frequency of minor reactions is still estimated as high as 44%, with major reactions, necessitating discontinuation of paclitaxel therapy, occurring in approximately 1.5% to 3% of patients. Various studies have also shown that Cremophor alters the pharmacokinetic profile of many drugs administered intravenously, including paclitaxel and agents that might be concomitantly administered, such as doxorubicin, epirubicin, and etoposide, by increasing the systemic exposure to the drug and reducing its systemic clearance. Depending on the dose and intravenous infusion rate, this phenomenon contributes to a distinct nonlinear pharmacokinetic profile of paclitaxel, which is most noticeable with 3-hour infusion regimens in the clinically relevant dose range of 100 mg/m to 225 mg/m. The phase I study reported by Nyman et al in the present issue of the Journal of Clinical Oncology on weekly administrations of a Cremophor-free, albumin-bound nanoparticle formulation of paclitaxel (ABI-007), adds to the current knowledge related to paclitaxel chemotherapy. Although hypersensitivity reactions were not expected and steroid premedication was not intended to be given, 11 patients in the study where premedicated from cycle 1 onward, thereby slightly decreasing the strength of the observation. Yet, the authors could suggest that ABI-007 can be administered as a short, 30-minute infusion on a weekly basis without steroid premedication, with no occurrence of hypersensitivity reactions and with paclitaxel delineating a JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 31 NOVEMBER 1 2005