ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast ffi ovary > prostate > colon. The LD 50 and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophorbased paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophorbased paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007.Paclitaxel is a naturally occurring complex diterpenoid product extracted from the bark of the western yew, Taxus brevifolia (1). The unique mechanism of paclitaxel of stabilizing tubulin polymer and promoting microtubule assembly effectively inhibits mitosis, motility, and intracellular transport within cancerous cells and results in antineoplastic activity against a wide variety of malignancies (2 -4). Paclitaxel is widely used for the treatment of breast, lung, and advanced ovarian cancers (5).Because paclitaxel has very little aqueous solubility, Cremophor-based paclitaxel uses a Cremophor EL/ethanol vehicle. The amount of Cremophor EL necessary to deliver the requisite doses of paclitaxel is significantly higher than that given with any other marketed drug containing Cremophor EL, reaching plasma concentrations up to 0.4% and remaining >0.1% for 24 hours following a dose of 175 mg/m 2 (6). The Cremophor EL -containing paclitaxel formulation causes severe allergic, hypersensitivity, and anaph...

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...

No abstract

Background Omicron variant viruses spread rapidly, even in individuals with high vaccination rates. This study aimed to determine the utility of the antibody against spike protein level as a predictor of the disease course of coronavirus disease 2019 (COVID-19) in vaccinated patients. Methods Between December 11, 2021, and February 10, 2022, we performed a prospective observational cohort study in South Korea, which included patients infected with Delta and Omicron variants. A multivariable logistic regression analysis to determine the association between antibody levels and outcomes was conducted. The relationship between antibody levels and cycle threshold (Ct) values was confirmed using a generalized linear model. Results From 106 vaccinated patients (39 Delta and 67 Omicron), the geometric mean titers of antibodies in patients with fever (≥37.5°C), hypoxia (≤94% of SpO2), pneumonia, C-reactive protein (CRP) elevation (>8 mg/L), or lymphopenia (<1100 cells/μL) were 1201.5 U/mL, 98.8 U/mL, 774.1 U/mL, 1335.1 U/mL, and 1032.2 U/mL, respectively. Increased antibody levels were associated with a decrease in the occurrence of fever (adjusted odds ratio [aOR], 0.23; 95% CI, 0.12–0.51), hypoxia (aOR, 0.23; 95% CI, 0.08–0.7), CRP elevation (aOR, 0.52; 95% CI, 0.29–0.0.94), and lymphopenia (aOR, 0.57; 95% CI, 0.33–0.98). Ct values showed a positive correlation between antibody levels (P = .02). Conclusions Antibody levels are predictive of the clinical course of COVID-19 in vaccinated patients with Delta and Omicron variant infections. Our data highlight the need for concentrated efforts to monitor patients with severe acute respiratory syndrome coronavirus 2 infection who are at risk of low antibody levels.