Purpose: To compare the preclinical and clinical pharmacokinetic properties of paclitaxel formulated as a Cremophor-free, albumin-bound nanoparticle (ABI-007) and formulated in Cremophorethanol (Taxol). Experimental Design: ABI-007 andTaxol were given i.v. to Harlan Sprague-Dawley male rats to determine pharmacokinetic and drug disposition. Paclitaxel pharmacokinetic properties also were assessed in 27 patients with advanced solid tumors who were randomly assigned to treatment with ABI-007 (260 mg/m 2 , 30 minutes; n = 14) or Taxol (175 mg/m 2 , 3 hours; n = 13), with cycles repeated every 3 weeks. Results:The volume of distribution at steady state and clearance for paclitaxel formulated as Cremophor-free nanoparticle ABI-007 were significantly greater than those for paclitaxel formulated with Cremophor (Taxol) in rats. Fecal excretion was the main elimination pathway with both formulations. Consistent with the preclinical data, paclitaxel clearance and volume of distribution were significantly higher for ABI-007 than for Taxol in humans [21.13 versus 14.76 L/h/m 2 (P = 0.048) and 663.8 versus 433.4 L/m 2 (P = 0.040), respectively]. Conclusions: Paclitaxel formulated as ABI-007 differs from paclitaxel formulated asTaxol, with a higher plasma clearance and a larger volume of distribution. This finding is consistent with the absence of paclitaxel-sequestering Cremophor micelles after administration of ABI-007. This unique property of ABI-007 could be important for its therapeutic effectiveness.Paclitaxel, a naturally occurring hydrophobic diterpenoid product extracted from the bark of the western yew (Taxus brevifolia; ref. 1), exerts its anticancer effects by promotion of tubulin polymerization, stabilization of microtubules, blockade of cells at the G 2 -M interface, and induction of apoptosis (2, 3). Paclitaxel is used as standard therapy for ovarian, breast, and non -small cell lung cancer and has recognized antitumor activity in several other malignancies (4).Currently, paclitaxel is marketed commercially in a formulation that contains a solvent system of Cremophor and dehydrated ethanol USP (Taxol, Bristol-Myers Squibb Co., Princeton, NJ; ref. 4). However, the amount of Cremophor in paclitaxel per administration is relatively high and has been associated with serious toxicities, including severe, sometimes fatal, hypersensitivity reactions (5 -8). Consequently, patients who receive Taxol must be premedicated with steroids and antihistamines to reduce the risk of such reactions, and special non -di(2-ethylhexyl) phthalate tubing and in-line filters are required for i.v. administration (4). Therefore, the toxicologic and pharmacologic behavior of Cremophor in the context of chemotherapeutic treatment with paclitaxel is important.ABI-007 (Abraxane, American BioScience, Inc., Santa Monica, CA), a Cremophor-free, albumin-bound, nanoparticle paclitaxel (mean diameter, f130 nm), was developed to retain the therapeutic benefits of paclitaxel but eliminate the toxicities associated with Cremophor in the Taxo...

Drug interactions in oncology are of particular importance owing to the narrow therapeutic index and the inherent toxicity of anticancer agents. Interactions with other medications can cause small changes in the pharmacokinetics or pharmacodynamics of a chemotherapy agent that could significantly alter its efficacy or toxicity. Improvements in in vitro methods and early clinical testing have made the prediction of potentially clinically significant drug interactions possible. We outline the types of drug interaction that occur in oncology, the mechanisms that underlie these interactions and describe select examples.

Abstract:Paclitaxel is an antineoplastic agent derived from the bark of the western yew, Taxus brevifolia, with a broad spectrum of activity. Because paclitaxel promotes microtubule assembly, neurotoxicity is one of its side effects. Clinical use of paclitaxel has led to peripheral neuropathy and this has been demonstrated to be dependent upon the dose administered, the duration of the infusion, and the schedule of administration. Vehicles in the drug formulation, for example Cremophor in Taxol ® , have been investigated for their potential to induce peripheral neuropathy. A variety of neuroprotective agents have been tested in animal and clinical studies to prevent paclitaxel neurotoxicity. Recently, novel paclitaxel formulations have been developed to minimize toxicities. This review focuses on recent advances in the etiology of paclitaxel-mediated peripheral neurotoxicity, and discusses current and ongoing strategies for amelioration of this side effect.

Purpose: Abraxane (ABI-007) is a 130-nm albumin-bound (nab) particle formulation of paclitaxel, devoid of any additional excipients. We hypothesized that this change in formulation alters the systemic disposition of paclitaxel compared with conventional solvent-based formulations (sb-paclitaxel; Taxol), and leads to improved tolerability of the drug. Patients and Methods: Patients with malignant solid tumors were randomized to receive the recommended single-agent dose of nab-paclitaxel (260 mg/m 2 as a 30-minute infusion) or sb-paclitaxel (175 mg/m 2 as a 3-hour infusion). After cycle 1, patients crossed over to the alternate treatment. Pharmacokinetic studies were carried out for the first cycle of sb-paclitaxel and the first two cycles of nab-paclitaxel. Results: Seventeen patients were treated, with 14 receiving at least one cycle each of nabpaclitaxel and sb-paclitaxel. No change in nab-paclitaxel pharmacokinetics was found between the first and second cycles (P = 0.95), suggesting limited intrasubject variability. Total drug exposure was comparable between the two formulations (P = 0.55) despite the dose difference. However, exposure to unbound paclitaxel was significantly higher after nab-paclitaxel administration, due to the increased free fraction (0.063 F 0.021versus 0.024 F 0.009; P < 0.001).Conclusion: This study shows that paclitaxel disposition is subject to considerable variability depending on the formulation used. Because systemic exposure to unbound paclitaxel is likely a driving force behind tumoral uptake, these findings explain, at least in part, previous observations that the administration of nab-paclitaxel is associated with augmented antitumor efficacy compared with solvent-based paclitaxel.nab-paclitaxel (ABI-007; Abraxane) is an albumin-bound particle formulation of paclitaxel, devoid of any solvent excipients. Paclitaxel, an antimicrotubule chemotherapeutic agent currently used alone or in combination with other anticancer drugs in the treatment of a wide range of solid tumor malignancies, is highly lipophilic and insoluble in water (1, 2). As such, it has traditionally been formulated as Taxol (sb-paclitaxel), in a mixture of Cremophor EL (polyoxyethylated castor oil) and ethanol, to allow for i.v. infusion (3). Due to the incidence of severe hypersensitivity reactions to Cremophor EL, patients are routinely pretreated with histamine blockers and steroids (4). In addition to the need for premedication, the presence of Cremophor EL has been shown to affect the pharmacokinetics of paclitaxel, due to micellar encapsulation of the drug (3). This leads to a decreased fraction of unbound drug, which limits drug distribution and clearance, and eventually results in nonlinear pharmacokinetics by decreasing the uptake of paclitaxel in RBC and tissues, thereby interfering with metabolism and biliary secretion.Conversely, nab-paclitaxel can be simply dissolved in saline for infusion. An initial phase I clinical trial has shown that this drug is tolerated up to a maximum tolerated dose o...