[show abstract][hide abstract] ABSTRACT: The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake.
Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m(2) nab-paclitaxel followed by gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents.
A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m(2), respectively. The MTD was 1,000 mg/m(2) of gemcitabine plus 125 mg/m(2) of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [(18)F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone.
The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.
Journal of Clinical Oncology 12/2011; 29(34):4548-54. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with metastatic disease are considered incurable. We previously showed that nabpaclitaxel (nanoparticle albumin-embedded paclitaxel) combined with anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, eradicates orthotopic small-sized breast tumors and metastasis. Here, we assessed this therapy in two models of advanced (450-600 mm(3)) breast tumors and delineated VEGF-A-dependent mechanisms of tumor resistance.
Mice with luciferase-tagged advanced MDA-MB-231 and MDA-MB-435 tumors were treated with saline, nab-paclitaxel (10 or 30 mg/kg), bevacizumab (4 mg/kg), or combined drugs. Lymphatic and lung metastases were measured by luciferase assay. Proinflammatory and survival pathways were measured by ELISA, Western blot and immunohistochemistry.
Nab-paclitaxel transiently suppressed primary tumors by 70% to 90% but had no effect on metastasis. Coadministration of bevacizumab increased the response rate to 99%, including 71% of complete responses in MDA-MB-231-bearing mice treated concurrently with 30 mg/kg of nab-paclitaxel. This combinatory regimen significantly reduced or eliminated preexisting lymphatic and distant metastases in MDA-MB-231 and MDA-MB-435 models. The mechanism involves paclitaxel-induced NF-κB pathway that upregulates VEGF-A and other tumor prosurvival proteins.
Bevacizumab prevents tumor recurrence and metastasis promoted by nab-paclitaxel activation of NF-κB pathway. Combination therapy with high-dosed nab-paclitaxel demonstrates the potential to eradicate advanced primary tumors and preexisting metastases. These findings strongly support translating this regimen into clinics.
Neoplasia (New York, N.Y.) 04/2011; 13(4):327-38. · 5.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: This pilot open-label clinical study evaluated the safety and pharmacokinetics of albumin-bound paclitaxel (nab-paclitaxel) in patients with advanced solid tumors and hepatic dysfunction.
Dosing was determined according to baseline bilirubin levels as described in the package insert for Taxol((R)) (paclitaxel), and patients received 130, 200 or 260 mg/m(2) nab-paclitaxel every 3 weeks.
Thirty patients with elevated baseline bilirubin and aspartate aminotransferase levels received nab-paclitaxel. The most commonly-occurring grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 neutropenia occurred in 10, 30 and 30% of patients receiving 130, 200 and 260 mg/m(2) nab-paclitaxel, respectively. Grade 3 fatigue presented in 50 and 30% patients receiving 130 and 200 mg/m(2) nab-paclitaxel, respectively (no grade 4 event). Only one (10%) patient had a grade 3 sensory neuropathy in the 260 mg/m(2) nab-paclitaxel arm. Treatment-related grade 3 bilirubinemia and elevated aspartate aminotransferase was observed in patients receiving 130 mg/m(2) (30 and 10%, respectively) and 260 mg/m(2) nab-paclitaxel (20 and 10%, respectively). One patient had a grade 4 bilirubinemia in the 200 mg/m(2) nab-paclitaxel arm. Total bilirubin levels were inversely correlated to paclitaxel clearance (p < 0001).
nab-Paclitaxel has an acceptable tolerability profile in patients with solid tumors and hepatic dysfunction. The safety and pharmacokinetic results support the same dose modification scheme recommended for cremophor-based paclitaxel.
Expert Opinion on Drug Safety 07/2010; 9(4):515-23. · 2.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: SPARC up-regulation is a poor prognostic factor in head and neck cancer. It was hypothesized that because of a SPARC-albumin interaction, tumoral SPARC facilitates the accumulation of albumin in the tumor and increases the effectiveness of albumin-bound paclitaxel (nab-paclitaxel). This hypothesis was tested by correlating the response to nab-paclitaxel and SPARC tumor expression in a retrospective analysis of a 60-patient clinical study of nab-paclitaxel as monotherapy against head and neck cancer. Sixteen tumor specimens were available for analysis. There were 11 responders (CR/PR) and 5 nonresponders (SD/PD) among the 16 nab-paclitaxel-treated patients (12/16 SPARC-positive, 75%). Response to nab-paclitaxel was higher for SPARC-positive patients (10/12, 83%) than SPARC-negative patients (1/4, 25%). The SPARC-negative patients exhibited significantly lower response than the overall response rate among all 60 patients (1/4, 25% vs 45/60, 75%). Although preliminary, data are supportive of the hypothesis that SPARC overexpression may correlate with response to nab-paclitaxel. If confirmed in larger studies, treatment with nab-paclitaxel may convert a poor prognosis SPARC-positive patient population into a group with better clinical outcomes.
[show abstract][hide abstract] ABSTRACT: Epigenetic silencing of tumor suppressor genes is a new focus of investigation in the generation and proliferation of carcinomas. Secreted protein acidic and rich in cysteine (SPARC) is reportedly detrimental to the growth of ovarian cancer cells and has been shown to be epigenetically silenced in several cancers. We hypothesized that SPARC is downregulated in ovarian cancer through aberrant promoter hypermethylation. To that end, we analyzed SPARC expression in ovarian cancer cell lines and investigated the methylation status of the Sparc promoter using methylation-specific polymerase chain reaction. Our results show that SPARC mRNA expression is decreased in three (33%) and absent in four (44%) of the nine ovarian cancer cell lines studied, which correlated with hypermethylation of the Sparc promoter. Treatment with the demethylating agent 5-aza-2'-deoxycytidine rescued SPARC mRNA and protein expression. Addition of exogenous SPARC, as well as ectopic expression by an adenoviral vector, resulted in decreased proliferation of ovarian cancer cell lines. Investigation of primary tumors revealed that the Sparc promoter is methylated in 68% of primary ovarian tumors and that the levels of SPARC protein decrease as the disease progresses from low to high grade. Lastly, de novo methylation of Sparc promoter was shown to be mediated by DNA methyltransferase 3a. These results implicate Sparc promoter methylation as an important factor in the genesis and survival of ovarian carcinomas and provide new insights into the potential use of SPARC as a novel biomarker and/or treatment modality for this disease.
Neoplasia (New York, N.Y.) 03/2009; 11(2):126-35. · 5.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Seventeen patients were treated, with 14 receiving at least one cycle each of nab-paclitaxel 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 +/- 0.021 versus 0.024 +/- 0.009; P < 0.001).
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.
Clinical Cancer Research 08/2008; 14(13):4200-5. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Nab-paclitaxel is an albumin-bound 130-nm particle form of paclitaxel that has shown an improved efficacy in experimental tumor models and clinical studies compared with solvent-based paclitaxel. Anti-vascular endothelial growth factor A (VEGF-A) antibody bevacizumab is known to enhance antitumor activity of cytotoxic drugs. This study evaluated the effects of combined nab-paclitaxel and bevacizumab therapy on growth and metastatic spread of orthotopic breast tumors. Cytotoxic and clonogenic assays measured VEGF-A-dependent modulation of nabpaclitaxel toxicity on cultured tumor cells. Antitumor effects were assessed in mice with luciferase-tagged, well-established MDA-MB-231 tumors (250-310 mm3) treated with one, two, or three cycles of nab-paclitaxel (10 mg/kg, daily for five consecutive days), bevacizumab (2-8 mg/kg, twice a week), or with combination of both drugs. VEGF-A protected MDA-MB-231 cells against nab-paclitaxel cytotoxicity, whereas bevacizumab sensitized cells to the effect of the drug. Combined bevacizumab and nab-paclitaxel treatment synergistically inhibited tumor growth and metastasis resulting in up to 40% of complete regressions of well-established tumors. This therapy also decreased the incidence of lymphatic and pulmonary metastases by 60% and 100%, respectively. The significant increase in the cure of tumor-bearing mice in the nab-paclitaxel/bevacizumab combined group compared with mice treated with single drugs strongly advocates for implementing such strategy in clinics.
Neoplasia (New York, N.Y.) 07/2008; 10(6):613-23. · 5.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Solvent-based delivery vehicles for chemotherapy agents have been instrumental in providing a means for hydrophobic agents to be administered intravenously. These solvents, however, have been associated with serious and dose-limiting toxicities. Solvent-based formulations of taxanes, a highly active class of cytotoxic agents, are associated with hypersensitivity reactions, neutropenia, and neuropathy. Nanoparticle technology utilizing the human protein albumin exploits natural pathways to selectively deliver larger amounts of drug to tumors while avoiding some of the toxicities of solvent-based formulations. 130 nM albumin-bound (nab) paclitaxel (nab-paclitaxel; Abraxane) was recently approved for use in patients with metastatic breast cancer who have failed combination therapy. In a randomized, phase III study in metastatic breast cancer, nab-paclitaxel was found to have improved efficacy and safety compared with conventional, solvent-based paclitaxel. Preliminary data also suggest roles for nab-paclitaxel as a single agent and in combination therapy for first-line treatment of metastatic breast cancer as well as in other solid tumors, including non-small-cell lung cancer, ovarian cancer, and malignant melanoma. The nab technology promises to have broad utility in cancer therapy, and clinical trials are underway using nab formulations of other water-insoluble anticancer agents such as docetaxel and rapamycin.
Advanced Drug Delivery Reviews 06/2008; 60(8):876-85. · 12.89 Impact Factor
[show abstract][hide abstract] ABSTRACT: Paclitaxel-eluting stents inhibit restenosis; however, this technology has drawbacks (e.g., stent thrombosis, requirement for long-term antiplatelet therapy, and cost--particularly for patients with multivessel disease). Systemic treatment with a novel 130-nm, albumin-bound particle form of paclitaxel (nab-paclitaxel) has been shown to reduce restenosis in animals.
This study was designed to establish the safety and optimal dose of systemic nab-paclitaxel for reducing in-stent restenosis in humans. If well tolerated, systemic nab-paclitaxel may be used with any available bare-metal stent and at potentially lower cost than drug-eluting stents.
Patients received nab-paclitaxel 10, 30, 70, or 100 mg/m(2) intravenously after stenting of a single de novo lesion >or= 3 mm in diameter. Study endpoints included safety and major adverse cardiac events (MACE) at 2 and 6 months.
Data were obtained for all 23 enrolled patients (mean age 66 +/- 10 years, 74% men, 26% with diabetes). No significant adverse events (AE) were attributable to nab-paclitaxel at 10 or 30 mg/m(2). Moderate neutropenia, moderate sensory neuropathy, and mild to moderate, reversible alopecia occurred only at doses of 70 and 100 mg/m(2); therefore, doses of 70 mg/m(2) or higher were considered unacceptable in this patient population. No MACE were reported at 2 months. At 6 months, 4 target lesion revascularizations (TLR) for restenoses were reported (2 each in the 10- and 100-mg/m(2)-dose groups).
Systemic nab-paclitaxel was well tolerated at doses below 70 mg/m(2) in this group of patients; no unexpected AE were noted. Additional studies are under way to explore intravenous and intracoronary administration of nab-paclitaxel.
[show abstract][hide abstract] ABSTRACT: The purpose of the present work was to describe the development and validation of a series of tests to assess the quality of four-dimensional (4D) computed-tomography (CT) imaging as it is applied to radiation treatment planning. Using a commercial respiratory motion phantom and a programmable moving platform with a CT phantom, we acquired 4D CT datasets on two commercial multislice helical CT scanners that use different approaches to 4D CT image reconstruction. Datasets were obtained as the platform moved in various patterns designed to simulate breathing. Known inserts in the phantom were contoured, and statistics were generated to evaluate properties important to radiation therapy--namely, accuracy of phase-binning, shape, volume, and CT number. Phase-binning accuracy varied by as much as 5% for a 4D procedure in which images were reconstructed and then binned, but exhibited no variation for a 4D procedure in which projections were binned before reconstruction. The magnitude of geometric distortion was found to be small for both approaches, as was the magnitude of volume error. Partial-volume effects in the direction perpendicular to the transverse planes of reconstruction affected volume accuracy, however. Computed tomography numbers were reproduced accurately, but 4D images exhibited more variation in CT number than static CT images did. Characterization of such properties can be used to better understand and optimize the various parameters that affect 4D CT image quality.
Journal of Applied Clinical Medical Physics 02/2007; 8(3):2362. · 0.96 Impact Factor
[show abstract][hide abstract] ABSTRACT: Low-dose metronomic chemotherapy treatments, especially when combined with 'dedicated' antiangiogenic agents, can induce significant antitumor activity without serious toxicity in various preclinical models. It remains unclear, however, whether some cytotoxic drugs are better suited for metronomic regimens than others. Paclitaxel appears to be a strong candidate for metronomic chemotherapy given its ability to inhibit endothelial cell functions relevant to angiogenesis in vitro at extraordinarily low concentrations and broad-spectrum antitumor activity. Clinically relevant concentrations of the formulation vehicle cremophor EL in Taxol, however, were previously reported to nullify the antiangiogenic effect of paclitaxel, the result of which would hamper its usefulness in metronomic regimens. We hypothesized that ABI-007, a cremophor EL-free, albumin-bound, 130-nm form of paclitaxel, could potentially alleviate this problem.
The antiangiogenic activity of ABI-007 was assessed by multiple in vitro assays. The in vivo optimal dose of ABI-007 for metronomic chemotherapy was determined by measuring circulating endothelial progenitors in peripheral blood. The antitumor effects of metronomic and maximum tolerated dose ABI-007 and Taxol were then evaluated and compared in severe combined immunodeficient mice bearing human MDA-MD-231 breast cancer and PC3 prostate cancer xenografts.
ABI-007 significantly inhibited rat aortic microvessel outgrowth, human endothelial cell proliferation, and tube formation. The optimal metronomic dose of ABI-007 was determined to be between 3 and 10 mg/kg. Metronomic ABI-007 but not Taxol, significantly suppressed tumor growth in both xenograft models. Furthermore, the antitumor effect of minimally toxic metronomic ABI-007 approximated that of the maximum tolerated dose of Taxol.
Our results underscore the influence of formulation vehicles on the selection of cytotoxic drugs for metronomic chemotherapy.
Clinical Cancer Research 08/2006; 12(14 Pt 1):4331-8. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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 congruent with 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 Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based 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.
Clinical Cancer Research 02/2006; 12(4):1317-24. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: ABI-007 is a novel solvent-free, albumin-bound, 130-nm particle formulation of paclitaxel designed to avoid solvent-related toxicities and to deliver paclitaxel to tumors via molecular pathways involving an endothelial cell-surface albumin receptor (gp60) and an albumin-binding protein expressed by tumor cells and secreted into the tumor interstitium (secreted protein acid rich in cysteine). This study determined the maximum-tolerated dose (MTD) of ABI-007 monotherapy administered weekly (three weekly doses, repeated every 4 weeks) and assessed the pharmacokinetics of paclitaxel administered as ABI-007.
Patients with advanced nonhematologic malignancies received ABI-007 without premedication at dose levels from 80 to 200 mg/m(2) as a 30-minute intravenous infusion once a week for 3 weeks, followed by 1 week of rest (one cycle).
Thirty-nine patients were treated with an average of five cycles of ABI-007; 33% of patients received > or = six cycles of treatment. MTDs for heavily and lightly pretreated patients were 100 and 150 mg/m(2), respectively; and the dose-limiting toxicities were grade 4 neutropenia and grade 3 peripheral neuropathy, respectively. Maximum paclitaxel concentration and area under the curve increased linearly with dose. Dose-dependent changes in plasma clearance did not occur. Partial responses were observed in five patients with breast, lung, and ovarian cancers, all of whom had previously been treated with paclitaxel containing polyoxyethylated castor oil in the formulation.
This study demonstrated that weekly ABI-007 can be administered at doses exceeding those typically used for paclitaxel containing polyoxyethylated castor oil. Pharmacokinetics were linear over the dose range studied. Antitumor responses occurred in patients previously treated with paclitaxel containing polyoxyethylated castor oil.
Journal of Clinical Oncology 12/2005; 23(31):7785-93. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: ABI-007, the first biologically interactive albumin-bound paclitaxel in a nanameter particle, free of solvents, was compared with polyethylated castor oil-based standard paclitaxel in patients with metastatic breast cancer (MBC). This phase III study was performed to confirm preclinical studies demonstrating superior efficacy and reduced toxicity of ABI-007 compared with standard paclitaxel.
Patients were randomly assigned to 3-week cycles of either ABI-007 260 mg/m(2) intravenously without premedication (n = 229) or standard paclitaxel 175 mg/m(2) intravenously with premedication (n = 225).
ABI-007 demonstrated significantly higher response rates compared with standard paclitaxel (33% v 19%, respectively; P = .001) and significantly longer time to tumor progression (23.0 v 16.9 weeks, respectively; hazard ratio = 0.75; P = .006). The incidence of grade 4 neutropenia was significantly lower for ABI-007 compared with standard paclitaxel (9% v 22%, respectively; P < .001) despite a 49% higher paclitaxel dose. Febrile neutropenia was uncommon (< 2%), and the incidence did not differ between the two study arms. Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard paclitaxel arm (10% v 2%, respectively; P < .001) but was easily managed and improved rapidly (median, 22 days). No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time.
ABI-007 demonstrated greater efficacy and a favorable safety profile compared with standard paclitaxel in this patient population. The improved therapeutic index and elimination of corticosteroid premedication required for solvent-based taxanes make the novel albumin-bound paclitaxel ABI-007 an important advance in the treatment of MBC.
Journal of Clinical Oncology 11/2005; 23(31):7794-803. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: ABI-007 is a novel nanoparticle, albumin-bound paclitaxel that is free of solvents. This multicenter phase II study was designed to evaluate the efficacy and safety of ABI-007 for the treatment of metastatic breast cancer (MBC).
Sixty-three women with histologically confirmed and measurable MBC received 300 mg/m2 ABI-007 by intravenous infusion over 30 minutes every 3 weeks without premedication. Forty-eight patients received prior chemotherapy; 39 patients received no prior treatment for metastatic disease.
Overall response rates (complete or partial responses) were 48% (95% CI, 35.3% to 60.0%) for all patients. For patients who received ABI-007 as first-line and greater than first-line therapy for their metastatic disease, the respective response rates were 64% (95% CI, 49.0% to 79.2%) and 21% (95% CI, 7.1% to 42.1%). Median time to disease progression was 26.6 weeks, and median survival was 63.6 weeks. No severe hypersensitivity reactions were reported despite the lack of premedication. Toxicities observed were typical of paclitaxel and included grade 4 neutropenia (24%), grade 3 sensory neuropathy (11%), and grade 4 febrile neutropenia (5%). Patients received a median of six treatment cycles; 16 patients had 25% dose reductions because of toxicities, and two of these patients had subsequent dose reductions.
ABI-007, the first biologically interactive albumin-bound form of paclitaxel in the nanoparticle state, uses the natural carrier albumin rather than synthetic solvents to deliver paclitaxel and allows for safe administration of high paclitaxel doses without premedication, resulting in significant antitumor activity in patients with MBC, including those receiving the drug as first-line therapy.
Journal of Clinical Oncology 10/2005; 23(25):6019-26. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response is extensive, and largely unexplained. We hypothesized that this is due to affinity of taxanes for an uptake transporter that indirectly regulates elimination pathways. Here, we studied accumulation of [3H]docetaxel and [3H]paclitaxel in Xenopus laevis oocytes injected with cRNA of the liver-specific organic anion transporting polypeptide (OATP) family members OATP1B1 (OATP2) or OATP1B3 (OATP8). Taxane transport by OATP1B1 expressing oocytes was not significantly different from that by water-injected controls, whereas uptake by OATP1B3 was 2.2-fold higher for docetaxel (p = 0.0007) and 3.3-fold higher for paclitaxel (p < 0.0001). OATP1B3-mediated paclitaxel transport was saturable (Michaelis-Menten constant, 6.79 microM), time-dependent, and highly sensitive to chemical inhibition. Paclitaxel uptake was not inhibited by ketoconazole or tariquidar. However, uptake was inhibited by the formulation excipient Cremophor (74.4% inhibition, p < 0.0001), cyclosporin A (25.2%, p = 0.005), glycyrrhizic acid (24.6%, p = 0.012), and hyperforin (28.4%, p = 0.003). Consistent with this finding, Cremophor was found to significantly affect the hepatic uptake of paclitaxel in mice. These data suggest that OATP1B3 is a key regulator of hepatic uptake, and may therefore play a role in the variable response to treatment with taxanes.
Cancer biology & therapy 08/2005; 4(8):815-8. · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: To compare the preclinical and clinical pharmacokinetic properties of paclitaxel formulated as a Cremophor-free, albumin-bound nanoparticle (ABI-007) and formulated in Cremophor-ethanol (Taxol).
ABI-007 and Taxol 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.
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].
Paclitaxel formulated as ABI-007 differs from paclitaxel formulated as Taxol, 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.
Clinical Cancer Research 07/2005; 11(11):4136-43. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Paclitaxel (PXL)-eluting stents in animals cause incomplete healing and, in some instances, a lack of sustained suppression of neointimal growth. The present study tested the efficacy of a novel systemic delivery nanoparticle PXL for reducing in-stent restenosis.
A saline-reconstituted formulation of PXL stabilized by albumin nanoparticles (nPXL) was tested in 38 New Zealand White rabbits receiving bilateral iliac artery stents. Doses of nPXL (1.0 to 5.0 mg/kg) were administered as a 10-minute intra-arterial infusion; control animals received vehicle (0.9% normal saline). In a follow-up chronic experiment, nPXL 5.0 mg/kg was given at stenting with or without an intravenous 3.5-mg/kg repeat nPXL dose at 28 days; these studies were terminated at 3 months. At 28 days, mean neointimal thickness was reduced (P< or =0.02) by doses of nPXL > or =2.5 mg/kg with evidence of delayed healing. The efficacy of a single dose of nPXL 5.0 mg/kg, however, was lost by 90 days. In contrast, a second repeat dose of nPXL 3.5 mg/kg given 28 days after stenting resulted in sustained suppression of neointimal thickness at 90 days (P< or =0.009 versus single dose nPXL 5.0 mg/kg and controls) with nearly complete neointimal healing.
Although systemic nPXL reduces neointimal growth at 28 days, a single repeat dose was required for sustained neointimal suppression. Thus, this novel systemic formulation of PXL may allow adjustment of dose at the stent treatment site and prove to be a useful adjunct for the clinical prevention of in-stent restenosis.