Randomized Crossover Pharmacokinetic Study of Solvent-Based Paclitaxel and nab-Paclitaxel

Abstract

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...

Comparative study of the antitumor activity of Nab-paclitaxel and intraperitoneal solvent-based paclitaxel regarding peritoneal metastasis in gastric cancer

“…Additional studies involving other tumor models and in vivo mechanism-related studies have confirmed the high accumulation characteristics of Nab-PTX (24,25,29,32). It is generally considered that the free or unbound form of the drug is the active fraction, since drug bound to proteins or other macromolecules may be unable to cross cell membranes (30).…”

“…The advantage of Nab-PTX is its water solubility, achieved without the use of Cre-EL and ethanol. Indeed, Gardner et al (32) reported that the formulation of Nab-PTX allowed a much higher fraction of unbound paclitaxel than that of Sb-PTX, and that the maximal concentration of unbound paclitaxel was ~10-fold higher for Nab-PTX in their pharmacokinetic study.…”

Clinical Outcomes of Women with Metastatic Breast Cancer Treated with Nab-Paclitaxel: Experience from a Single Academic Cancer Centre

“…Paclitaxel is entrapped by the formation of plasma Cremophor EL micelles, which can cause reduced drug clearance, nonlinear pharmacokinetics, and free drug fraction 14 . The dose-dependent antitumour response from paclitaxel can be decreased as a result 15 . It is this drug a Schedule of nab-paclitaxel was not a significant predictor of overall survival, nor was the interaction between nab-paclitaxel schedule and achievement of clinical benefit.…”

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“…Indeed, several preclinical studies reported an approximately 10-fold endothelial binding of nab-paclitaxel, and 4-fold higher levels of transocytosis through endothelial cells in contrast to the solvent based paclitaxel allowing for a dose dependent antitumor activity [43,44].…”