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Journal of Clinical Oncology, Vol 23, No 31 (November 1), 2005: pp. 7765-7767 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.7135
Paclitaxel Repackaged in an Albumin-Stabilized Nanoparticle: Handy or Just a Dandy?Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, MD; The Department of Medical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 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.1 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.2 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/m2 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.2 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.3 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.4 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.2 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/m2 to 225 mg/m2.5,6 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),7 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 linear pharmacokinetic profile. Of particular interest is the authors' finding that peripheral sensory neuropathy is still dose-limiting in some patients, adding to a growing body of evidence that taxanes are intrinsically neurotoxic. However, this neurotoxicity can be worsened by a Cremophor-containing formulation, as the excipient can also cause axonal swelling, vesicular degeneration, and demyelination.8 The incidence and severity of taxane-related neurotoxicity is known to be dependent on the cumulative dose. Since the number of patients treated with high cumulative doses is limited in the current phase I study,7 the frequency of neurotoxicity also has to be interpreted with some caution. Neurotoxicity is certainly a limiting factor that needs to be taken into account when designing studies in which ABI-007 is given in combination with other drugs. The current study evidently was part of a broader phase I program,9 following which a 3-weekly schedule of ABI-007 was pursued in a phase II study10 and the phase III study in patients with metastatic breast cancer that led to registration of the drug in the United States for this indication.11 It is of importance to point out that the clinical relevance of the weekly schedule of ABI-007, in theory, may be somewhat limited. This schedule produces a high incidence of drug-related fatigue similar to weekly regimens of other taxanes.12 Importantly, while for paclitaxel formulated in Cremophor randomized studies comparing a weekly to a 3-weekly schedule are lacking except for a study with paclitaxel followed by fluorouracil, doxorubicin, and cyclophosphamide,13 for docetaxel result of such studies favored the 3-weekly schedule,14 although the weekly schedule was significantly less myelotoxic. The latter seems to be the case for ABI-007 as well.7,9 The data of the dose-finding study with ABI-007 also suggest a considerable (>50%) increase in maximum-tolerated dose of paclitaxel compared with the conventional formulation, which may have contributed to the notion of responses being observed in patients previously failing on paclitaxel formulated in Cremophor.7 On the other hand, these data should be balanced against dosing data for the two paclitaxel formulations on equipotency in experimental models, data that are currently lacking in the published literature. It is likely that the increased tolerability to ABI-007 compared with paclitaxel formulated in Cremophor is in part related to an approximately 40% increased systemic clearance of total paclitaxel.15 However, the pharmacokinetic data should be interpreted with caution. Indeed, there are several factors contributing to the complexity of the pharmacologic handling of paclitaxel delivered in Cremophor or by alternative vehicles, including the fact that the circulating drug is present in various distinguishable forms (ie, vehicle associated, blood cell associated, protein bound, and unbound), and that clearance occurs as a result of several processes with different elimination rates (eg, distribution of vehicle micelles or nanoparticles carrying the drug, leaking of drug from the micelles or nanoparticles, and clearance of unbound drug). Therefore, pharmacokinetic/pharmacodynamic relationships for paclitaxel-induced hematologic toxicity5,6 and peripheral neuropathy16 established based on total plasma concentrations following the administration of paclitaxel formulated in Cremophor are not likely to be valid in the absence of Cremophor, and hence such relationships should be reconsidered for ABI-007. Studies comparing the pharmacokinetics of unbound paclitaxel following the administration of ABI-007 or paclitaxel formulated in Cremophor and the associations with drug-induced side effects are ongoing and will shed light on these aspects. In the case that paclitaxel is transiently sequestered in nanoparticles in the circulation,17 it should also be considered that paclitaxel delivery to tumors is potentially regulated in vivo, at least in part, by albumin-receptor binding on endothelial cells (gp60) and in the tumor interstitium (SPARC), and that such processes could contribute to altered intratumoral distribution of paclitaxel and improved efficacy independent of circulating drug concentrations. There are many future challenges to further improve the therapeutic index of this fascinating and active repackaged form of paclitaxel. For example, at the recommended ABI-007 dose of 150 mg/m2 in weekly regimens, the interindividual pharmacokinetic variability in the area under the plasma concentration-time curve of paclitaxel is relatively high at approximately 62%.7 Prior studies have suggested that the primary elimination pathways of paclitaxel are through CYP2C8- and CYP3A4-mediated metabolism18,19 and ABCB1 (P-glycoprotein) mediated biliary and intestinal excretion.20 However, the number of genes implicated in paclitaxel disposition has been growing in recent years, and now also include the hepatocellular uptake transporter SLCO1B3 (OATP1B3, OATP8),21 and the ATP-binding cassette transporters ABCC2 (cMOAT, MRP2)22 and ABCC10 (MRP7).23 Prospective studies are currently ongoing to search for relationships between toxicity (and possibly response) and polymorphisms in the enzymes and transporters involved in the pharmacokinetics and pharmacodynamics of paclitaxel following ABI-007 administration. Such studies using pharmacogenetic strategies are of high importance and may identify inherited causes of interindividual pharmacologic variability and eventually result in a major advance in the individualized use of taxanes. Finally, in addition to further exploring dose-dense regimens with ABI-007 as proposed by Nyman et al,7 it will also be of great interest to evaluate metronomic strategies as ABI-007 exhibits potent antiangiogenic and antitumor activity when used at low doses in experimental models, particularly in comparison with paclitaxel formulated in Cremophor.24,25 Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
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13. Green MC, Buzdar AU, Smith T, et al: Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23:5983-5992, 2005 14. Engels FK, Verweij J: Docetaxel administration schedule: From fever to tears? A review of randomised studies. Eur J Cancer 41:1117-1126, 2005
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20. Sparreboom A, van Asperen J, Mayer U, et al: Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci U S A 94:2031-2035, 1997 21. Smith NF, Acharya MR, Desai N, et al: Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel. Cancer Biol Ther 4:815-818, 2005[Medline] 22. Huisman M, Chhatta AA, Van Tellingen O, et al: MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int J Cancer 116:824-829, 2005[CrossRef][Medline]
23. Hopper-Borge E, Chen ZS, Shchaveleva I, et al: Analysis of the drug resistance profile of multidrug resistance protein 7 (ABCC10): Resistance to docetaxel. Cancer Res 64:4927-4930, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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