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Alex Sparreboom - One of the best experts on this subject based on the ideXlab platform.
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paclitaxel chemotherapy from empiricism to a mechanism based formulation strategy
Therapeutics and Clinical Risk Management, 2005Co-Authors: Charity D Scripture, William D Figg, Alex SparreboomAbstract:Paclitaxel is an anticancer agent effective for the treatment of breast, ovarian, lung, and head and neck cancer. Because of water insolubility, paclitaxel is formulated with the micelle-forming vehicle Cremophor EL to enhance drug solubility. However, the addition of Cremophor EL results in hypersensitivity reactions, neurotoxicity, and altered pharmacokinetics of paclitaxel. To circumvent these unfavorable effects resulting from the addition of Cremophor EL, efforts have been made to develop new delivery systems for paclitaxel administration. For example, ABI-007 is a Cremophor-free, albumin-stabilized, nanoparticle paclitaxel formulation that was found to have significantly less toxicity than Cremophor-containing paclitaxel in mice. Pharmacokinetic studies indicate that in contrast to Cremophor-containing paclitaxel, ABI-007 displays linear pharmacokinetics over the clinically relevant dose range of 135-300 mg/m(2). In a phase III study conducted in patients with metastatic breast cancer, patients treated with ABI-007 achieved a significantly higher objective response rate and time to progression than those treated with Cremophor-containing paclitaxel. Together these findings suggest that nanoparticle albumin-bound paclitaxel may enable clinicians to administer paclitaxel at higher doses with less toxicity than is seen with Cremophor-containing paclitaxel. The role of this novel paclitaxel formulation in combination therapy with other antineoplastic agents needs to be determined.
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comparative preclinical and clinical pharmacokinetics of a Cremophor free nanoparticle albumin bound paclitaxel abi 007 and paclitaxel formulated in Cremophor taxol
Clinical Cancer Research, 2005Co-Authors: Alex Sparreboom, Andrew Yang, Bridget Beals, Charity D Scripture, Vuong Trieu, Paul J Williams, William D Figg, Michael J Hawkins, Neil DesaiAbstract:Purpose: 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). Experimental Design: 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. 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 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.
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pharmacokinetic modeling of paclitaxel encapsulation in Cremophor el micelles
Cancer Chemotherapy and Pharmacology, 2001Co-Authors: Lia Van Zuylen, Mats O Karlsson, Jaap Verweij, Eric Brouwer, Peter De Bruijn, Kees Nooter, Gerrit Stoter, Alex SparreboomAbstract:Nonlinear disposition of paclitaxel (Taxol) in cancer patients has been described in several studies, but the underlying mechanism is still a matter of speculation. Previously, we have shown in vitro that the paclitaxel formulation vehicle, Cremophor EL (CrEL), alters the blood distribution of paclitaxel as a result of entrapment of the compound in circulating CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. Based on these findings, we prospectively re-evaluated the linearity of paclitaxel disposition in patients using whole blood and plasma analysis, and sought to define a new pharmacokinetic model to describe the data. Seven patients with solid tumors were treated with paclitaxel infused over 3 h, each at consecutive 3-weekly dose levels of 225, 175 and 135 mg/m2 (CrEL dose level, 18.8, 14.6, and 11.3 ml/m2, respectively). Patient samples were collected up to 24 h after the start of infusion, and analyzed by high-performance liquid chromatography. Paclitaxel peak levels and areas under the curve in whole blood increased linearly with dose, whereas plasma levels showed substantial deviation from linearity. This was shown to be caused by a CrEL concentration-dependent decrease in paclitaxel uptake in blood cells, as reflected by the blood:plasma concentration ratios which altered significantly from 0.83±0.11 (at 135 mg/m2) to 0.68±0.07 (at 225 mg/m2). It is concluded that the nonlinear disposition of paclitaxel is related to paclitaxel dose-related levels of the formulation vehicle CrEL, leading to a disproportionate drug accumulation in the plasma fraction. The pharmacokinetic model developed accurately described the data, and will help guide future development and refinement of clinical protocols, especially in defining the exposure measure best linked to paclitaxel effects and toxicities.
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quantitation of Cremophor el in human plasma samples using a colorimetric dye binding microassay
Analytical Biochemistry, 1998Co-Authors: Alex Sparreboom, Jaap Verweij, Gerrit Stoter, Walter J Loos, Aad I De Vos, Maria E L Van Der Burg, Kees NooterAbstract:Abstract This paper describes an analytical procedure for the quantitative determination of the pharmaceutical vehicle Cremophor EL in human plasma samples. The procedure is based on rapid binding of Coomassie brilliant blue G-250 to Cremophor EL following plasma protein precipitation with acetonitrile and analyte extraction with n -butylchloride. The binding of the dye to Cremophor EL causes a shift in the absorption maximum from 465 to 624 nm, which is monitored using an automated microplate-absorbance reader. The assay permits estimation of Cremophor EL concentrations in the range 0.05–1.00% (v/v) in 50 μL of human plasma, with percentage deviation and precision of ≤12 and ≤15%, respectively. The assay was subsequently used to measure Cremophor EL concentrations in plasma samples in support of a project to develop a pharmacokinetic model for this compound in patients receiving paclitaxel.
Andrew Yang - One of the best experts on this subject based on the ideXlab platform.
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increased antitumor activity intratumor paclitaxel concentrations and endothelial cell transport of Cremophor free albumin bound paclitaxel abi 007 compared with Cremophor based paclitaxel
Clinical Cancer Research, 2006Co-Authors: Neil Desai, Vuong Trieu, Leslie Louie, Sherry Ci, Andrew Yang, Tapas De, Bridget Beals, Donald J Dykes, Patricia E Noker, Elizabeth LabaoAbstract: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.
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comparative preclinical and clinical pharmacokinetics of a Cremophor free nanoparticle albumin bound paclitaxel abi 007 and paclitaxel formulated in Cremophor taxol
Clinical Cancer Research, 2005Co-Authors: Alex Sparreboom, Andrew Yang, Bridget Beals, Charity D Scripture, Vuong Trieu, Paul J Williams, William D Figg, Michael J Hawkins, Neil DesaiAbstract:Purpose: 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). Experimental Design: 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. 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 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.
Bridget Beals - One of the best experts on this subject based on the ideXlab platform.
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increased antitumor activity intratumor paclitaxel concentrations and endothelial cell transport of Cremophor free albumin bound paclitaxel abi 007 compared with Cremophor based paclitaxel
Clinical Cancer Research, 2006Co-Authors: Neil Desai, Vuong Trieu, Leslie Louie, Sherry Ci, Andrew Yang, Tapas De, Bridget Beals, Donald J Dykes, Patricia E Noker, Elizabeth LabaoAbstract: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.
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comparative preclinical and clinical pharmacokinetics of a Cremophor free nanoparticle albumin bound paclitaxel abi 007 and paclitaxel formulated in Cremophor taxol
Clinical Cancer Research, 2005Co-Authors: Alex Sparreboom, Andrew Yang, Bridget Beals, Charity D Scripture, Vuong Trieu, Paul J Williams, William D Figg, Michael J Hawkins, Neil DesaiAbstract:Purpose: 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). Experimental Design: 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. 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 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.
Elizabeth Labao - One of the best experts on this subject based on the ideXlab platform.
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increased antitumor activity intratumor paclitaxel concentrations and endothelial cell transport of Cremophor free albumin bound paclitaxel abi 007 compared with Cremophor based paclitaxel
Clinical Cancer Research, 2006Co-Authors: Neil Desai, Vuong Trieu, Leslie Louie, Sherry Ci, Andrew Yang, Tapas De, Bridget Beals, Donald J Dykes, Patricia E Noker, Elizabeth LabaoAbstract: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.
Gao Li - One of the best experts on this subject based on the ideXlab platform.
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enhanced intestinal absorption of etoposide by self microemulsifying drug delivery systems roles of p glycoprotein and cytochrome p450 3a inhibition
European Journal of Pharmaceutical Sciences, 2013Co-Authors: Gang Zhao, Jiangeng Huang, Luqin Si, Gao LiAbstract:Abstract Etoposide is recognized as a dual P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) substrate drug with poor water-solubility. To improve its solubility and bioavailability, three novel self-microemulsifying drug delivery systems (SMEDDS) contained the known P-gp and CYP3A inhibitory surfactants, Cremophor RH40, Cremophor EL, or Polysorbate 80, were prepared. This work aims to evaluate the enhanced intestinal absorption of etoposide SMEDDS as well as to explore the roles of P-gp and CYP3A inhibition in the absorption process. Etoposide SMEDDS were orally administered to rats for in vivo bioavailability investigation. In situ single-pass intestinal perfusion with mesenteric vein cannulation was employed to study the drug permeability and intestinal metabolism. In vitro Caco-2 cell models were applied to study the effects of P-gp and CYP3A inhibition by SMEDDS on the cellular accumulation of etoposide. It was found that the bioavailability and in situ intestinal absorption were significantly enhanced by SMEDDS with the order of Polysorbate 80-based SMEDDS > Cremophor EL-based SMEDDS > Cremophor RH40-based SMEDDS. In addition, there was a dramatically high linear correlation between the AUC0–t values and the apparent permeability coefficient values based on the appearance of the drug in mesenteric vein blood. Cellular uptake studies demonstrated that P-gp inhibition by SMEDDS played an important role in etoposide uptake. Moreover, etoposide metabolism was demonstrated to be dramatically inhibited by the three kinds of SMEDDS. These finding may assist in the improvement of the intestinal absorption of P-gp and/or CYP3A substrate drugs.
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enhanced intestinal absorption of etoposide by self microemulsifying drug delivery systems roles of p glycoprotein and cytochrome p450 3a inhibition
European Journal of Pharmaceutical Sciences, 2013Co-Authors: Gang Zhao, Jiangeng Huang, Luqin Si, Gao LiAbstract:Abstract Etoposide is recognized as a dual P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) substrate drug with poor water-solubility. To improve its solubility and bioavailability, three novel self-microemulsifying drug delivery systems (SMEDDS) contained the known P-gp and CYP3A inhibitory surfactants, Cremophor RH40, Cremophor EL, or Polysorbate 80, were prepared. This work aims to evaluate the enhanced intestinal absorption of etoposide SMEDDS as well as to explore the roles of P-gp and CYP3A inhibition in the absorption process. Etoposide SMEDDS were orally administered to rats for in vivo bioavailability investigation. In situ single-pass intestinal perfusion with mesenteric vein cannulation was employed to study the drug permeability and intestinal metabolism. In vitro Caco-2 cell models were applied to study the effects of P-gp and CYP3A inhibition by SMEDDS on the cellular accumulation of etoposide. It was found that the bioavailability and in situ intestinal absorption were significantly enhanced by SMEDDS with the order of Polysorbate 80-based SMEDDS > Cremophor EL-based SMEDDS > Cremophor RH40-based SMEDDS. In addition, there was a dramatically high linear correlation between the AUC0–t values and the apparent permeability coefficient values based on the appearance of the drug in mesenteric vein blood. Cellular uptake studies demonstrated that P-gp inhibition by SMEDDS played an important role in etoposide uptake. Moreover, etoposide metabolism was demonstrated to be dramatically inhibited by the three kinds of SMEDDS. These finding may assist in the improvement of the intestinal absorption of P-gp and/or CYP3A substrate drugs.