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ABSTRACT: Topotecan is a chemotherapeutic agent of choice for the second-line treatment of recurrent ovarian cancer. In this article, we have developed a physiologically based pharmacokinetic model to characterize and predict topotecan concentrations in mouse plasma and tissues. Single intravenous (IV) doses (5, 10 and 30 mg/kg) of topotecan were administered to male Swiss Webster mice, with plasma and tissue samples collected over 24 h, and with sample analysis by high performance liquid chromatography. Topotecan disposition in the lungs, heart, muscle, skin, spleen, gut, liver, brain and adipose was described by perfusion rate-limited compartments, whereas the testes and intraperitoneal (IP) fluid were described with permeability rate-limited compartments. The kidneys were modeled as a permeability rate-limited compartment with nonlinear efflux. The model included enterohepatic recycling of topotecan, with re-absorption of drug secreted in the bile and nonlinear bioavailability. Topotecan demonstrated dose-dependent, nonlinear pharmacokinetics and its elimination was described by nonlinear clearance from the liver and a parallel nonlinear and linear clearance from the kidneys. Mean tissue-to-plasma partition coefficients ranged from 0.123 (brain) to 55.3 (kidney). The model adequately characterized topotecan pharmacokinetics in plasma and tissue for all three doses. Additionally, the model provided good prediction of topotecan pharmacokinetics from several external data sets, including prediction of topotecan tissue pharmacokinetics following administration of 1 or 20 mg/kg IV, and prediction of plasma pharmacokinetics following doses of 1, 1.25, 15, 20 and 80 mg/kg IV and 20 mg/kg IP.
Journal of Pharmacokinetics and Biopharmaceutics 02/2011; 38(1):121-42. · 2.06 Impact Factor
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ABSTRACT: To evaluate the pharmacokinetics of bevacizumab following IP and IV administration, and to investigate combined bevacizumab therapy (IP or IV) with IP paclitaxel or carboplatin in a mouse model of ovarian cancer.
Bevacizumab pharmacokinetics were investigated following IV or IP dosing, and mice bearing peritoneal A2780 xenografts were treated with vehicle, IV or IP bevacizumab, IP paclitaxel, IP paclitaxel with co-administration of IV or IP bevacizumab, IP carboplatin, and IP carboplatin with co-administration of IV or IP bevacizumab. Survival time was defined as the time to death or the time to reach 120% of baseline body weight.
Following IP administration, bevacizumab was rapidly absorbed and bioavailability was 92.8%. Median survival time, which was 33 days for control mice, was increased by 24% with IP paclitaxel. IP carboplatin failed to increase survival time when administered alone. IV and IP bevacizumab increased survival time by 42 and 33%. Combined bevacizumab and IP paclitaxel was superior to paclitaxel alone (P = 0.01 for IV and P = 0.04 for IP bevacizumab), and combined bevacizumab and IP carboplatin was superior to carboplatin alone (P = 0.002 for IV and P = 0.02 for IP bevacizumab). There were no significant differences in survival between groups receiving bevacizumab IV or IP, either alone (P = 0.586), in combination with paclitaxel (P = 0.467), or in combination with carboplatin (P = 0.149).
Following IP administration to mice, bevacizumab demonstrates rapid and near complete absorption. Bevacizumab therapy, initiated prior to IP carboplatin or paclitaxel administration, increased survival time significantly in mice, and results were not dependent on the route of bevacizumab administration (IV vs. IP).
Cancer Chemotherapy and Pharmacology 02/2011; 68(4):951-8. · 2.83 Impact Factor
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ABSTRACT: The objectives of this study were to develop physiologically based models for the pharmacokinetics (PK) and organ distribution of apicidin in rats and mice and to predict human PK in blood and organs.
The PK of apicidin was characterized in rats and mice after i.v. bolus injection, and distribution to various tissues was determined in rats following i.v. infusions at steady state. The developed models were prospectively validated within rat and within mouse and by scaling from rat to mouse using data after multiple i.v. injections. Human PK was predicted by the physiologically based modeling using intrinsic clearance data for humans from in vitro experiments.
The Cl(s) predicted for human (9.8 ml/min/kg) was lower than those found in mice (116.9 ml/min/kg) and rats (61.6 ml/min/kg), and the V(ss) predicted for human (1.9 l/kg) was less than in mice (2.0 l/kg) and rats (2.5 l/kg). Consequently, the predicted t (1/2) was longer in human (2.3 h) than in mice and rats (0.4 and 0.9 h, respectively). The highest concentrations of apicidin were predicted in liver followed by adipose tissue, kidney, lung, spleen, heart, arterial blood, venous blood, small intestine, stomach, muscle, testis, and brain.
The developed models adequately described the PK of apicidin in rats and mice and were applied to predict human PK. These models may be useful in predicting human blood and tissue concentrations of apicidin under different exposure conditions.
Cancer Chemotherapy and Pharmacology 11/2010; 68(2):465-75. · 2.83 Impact Factor
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03/2010; , ISBN: 9780470571224
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ABSTRACT: T84.66 is a monoclonal antibody with high affinity and specificity for tumor-associated carcinoembryonic antigen (CEA). In this work, we have developed an enzyme linked immunosorbent assay to determine T84.66 concentrations in mouse plasma. The assay was validated with respect to precision and accuracy by evaluating the recovery of T84.66 from mouse plasma. The working range of the assay is 25-200 ng/mL, and the limit of quantification is 2.5 microg/mL. Intra-assay recoveries ranged from 90.6 to 97.4%, and intra-assay precision reported as the percent coefficient of variation (CV%), ranged from 4.58 to 12.6%. Inter-assay recoveries were between 92.6 to 98.1% and the CV% ranged from 4.9-6.5%. The assay was tested for possible interference from soluble CEA. Soluble CEA, at concentrations up to 5 ng/mL, did not influence the recovery of T84.66. The assay was applied to study the pharmacokinetics of T84.66 in athymic Fox(nu) mice.
Journal of Immunoassay and Immunochemistry 01/2010; 31(1):1-9. · 0.69 Impact Factor
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ABSTRACT: Antibodies directed against tumor associated antigens are being increasingly used for detection and treatment of cancers; however, there is an incomplete understanding of the physiological determinants of antibody pharmacokinetics and tumor distribution. The purpose of this study is to (a) compare the plasma pharmacokinetics of T84.66, a monoclonal anti-CEA antibody directed against tumor associated carcinoembryonic antigen (CEA), in control and CEA expressing LS174T xenograft bearing mice, and (b) to develop a physiologically based pharmacokinetic (PBPK) model capable of integrating the influence of CEA and the IgG salvage receptor, FcRn, on T84.66 disposition. T84.66 pharmacokinetics were studied following i.v. administration (1, 10, 25 mg/kg) in control and xenograft bearing mice. In control mice, no significant differences in clearance were observed across the dose range studied. In mice bearing xenograft tumors, clearance was increased by four- to sevenfold, suggesting the presence of a "target mediated" elimination pathway. T84.66 plasma disposition was characterized with a PBPK model, and the model was applied to successfully predict antibody concentrations in tumor tissue. The PBPK model will be used to assist in the development of antibody-based targeting strategies for CEA-positive tumors.
Journal of Pharmaceutical Sciences 09/2009; 99(3):1582-600. · 3.06 Impact Factor
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ABSTRACT: The efficacy of intraperitoneal chemotherapy for ovarian cancers is limited by poor penetration of drug into peritoneal tumors. Based on pharmacokinetic theory that suggests that penetration depth is primarily determined by the rate of drug removal via tumor capillaries, we have hypothesized that co-administration of antiangiogenic therapy will allow for decreased drug removal, increased drug concentrations in tumor, and increased efficacy of intraperitoneal chemotherapy. Pharmacokinetic modeling was conducted to simulate the effect of tumor blood flow on tumor concentrations of topotecan. Simulations predicted that tumor blood flow reductions, as potentially achieved by antiangiogenic therapy, would lead to substantial increases in tumor concentrations after intraperitoneal chemotherapy but would lead to a slight decrease after systemic chemotherapy. Pharmacokinetic studies performed using the A2780 xenograft tumor model showed that animals receiving combined intraperitoneal topotecan and an anti-vascular endothelial growth factor (VEGF) monoclonal antibody had approximately 6.5-fold higher (p = 0.0015) tumor topotecan concentrations compared with animals receiving intraperitoneal topotecan alone, whereas there was no significant (p = 0.16) difference for systemic topotecan. Therapeutic studies conducted with two different drugs, topotecan and cisplatin, showed that animals receiving combined intraperitoneal chemotherapy and anti-VEGF therapy displayed superior survival relative to animals treated with chemotherapy alone (i.e., cisplatin or topotecan), anti-VEGF alone, or intravenous chemotherapy with concomitant anti-VEGF therapy. Combined intraperitoneal topotecan and anti-VEGF resulted in the complete cure of four of 11 mice. The proposed combination of antiangiogenic therapy and intraperitoneal chemotherapy, which was predicted to be beneficial by pharmacokinetic simulations, may provide substantial benefit to patients with peritoneal malignancies.
Journal of Pharmacology and Experimental Therapeutics 03/2009; 329(2):580-91. · 3.83 Impact Factor
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ABSTRACT: This study reports a rapid screening method for the prediction of oral drug bioavailability in humans based on combined immobilized artificial membrane (IAM) chromatographic capacity factor (k(IAM)) and in vitro stability in hepatic microsomes. The fraction of drug absorbed (F(a)) in humans was predicted for a set of 15 structurally diverse commercial drugs based on k(IAM) values using a mobile phase consisting of acetonitrile: Dulbecco's phosphate-buffered saline. The hepatic intrinsic clearance (CL'(int)) was calculated from in vitro disappearance half-life, and the oral bioavailability was predicted using in vitro hepatic clearance (CL(h)) and F(a). Significant correlations were observed for the relationships between predicted hepatic extraction ratios (ER(h)) and actual presystemic metabolism (r = 0.854) and between predicted and observed oral bioavailabilities (r = 0.805; p < 0.01). The IAM capacity factor together with the hepatic microsomal disappearance half-life may be useful in identifying compounds with high oral absorption potential in early drug discovery processes.
Biomedical Chromatography 03/2009; 23(7):764-9. · 1.97 Impact Factor
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ABSTRACT: A sensitive high performance liquid chromatography method (HPLC) has been developed for the quantification of doxorubicin in mouse plasma and tissues. Samples of serum or tissue homogenates, 20 microl, were analyzed following a single step protein precipitation using perchloric acid (35%, v/v). Doxorubicin was separated from the internal standard, daunorubicin, on a Zorbax 300SB C(18) column at 35 degrees C. Mobile phase was comprised of acetonitrile and water (25:75) containing 0.1% triethylamine, and was adjusted to pH 3 with phosphoric acid. Peaks eluting from the column were detected with a fluorescence detector with excitation and emission wavelengths of 480 and 560 nm, respectively. Standard curves were linear in the range 5-1000 ng/ml, and correlation coefficients were typically greater than 0.999. Intra-assay recoveries ranged from 94.7 to 99.9%, and inter-assay recoveries were in the range of 95.2-101%. The associated coefficient of variation (CV) was less than 10% in all cases. The method was successfully applied to investigate doxorubicin plasma pharmacokinetics and tissue distribution in athymic Fox(nu) mice.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 03/2009; 877(8-9):837-41. · 2.78 Impact Factor
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ABSTRACT: Carcinoembryonic antigen (CEA) is a tumor associated antigen that is over-expressed in colorectal cancer and several other cancers of the gastrointestinal system. An enzyme linked immunosorbent assay was developed to determine CEA concentrations in mouse plasma. The assay was validated over the standard curve range of 1-20 ng/mL. The intra-assay recoveries ranged from 93-104% with associated percent coefficients of variation (CV%) ranging between 2.5-12.8%. The inter-assay recoveries were in the range of 98.4-105% and their CV% values were between 4.77-10.1%. The assay was used to detect the presence of circulating CEA in the LS174T adenocarcinoma xenograft model and to study the pharmacokinetics of recombinant CEA in athymic mice.
Journal of Immunoassay and Immunochemistry 02/2009; 30(4):418-27. · 0.69 Impact Factor
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ABSTRACT: The objective of this study was to investigate the pharmacokinetics and toxicodynamics of topotecan (TPT) in mice and to develop an integrated pharmacokinetic/toxicodynamic (PK/TD) model to characterize the relationship between the time course of TPT disposition and the time course of TPT-induced toxicity. TPT was administered to groups of 3-5 mice via i.v. bolus injection, i.p. bolus injection, and by i.p. infusion over 24, 72 and 168 h. Body weight was monitored to assess TPT-induced toxicity, and serial blood samples were collected and analyzed via HPLC to assess TPT pharmacokinetics. We found that TPT-induced toxicity increased dose-dependently for each mode of dosing investigated. The time course of topotecan-induced body weight-loss was delayed relative to the time course of topotecan disposition; nadir body weight was observed as late as 6 days following i.p. bolus dosing, and 3-5 days following termination of i.p. infusion. TPT exhibited non-linear disposition, which was well-characterized through the use of a two-compartment model with saturable elimination from the central compartment. Toxicodynamic data were characterized with an integrated PK/TD model that incorporated an indirect-effect model and four transit compartments to describe transduction events associated with TPT-induced toxicity. This model will be used to support the development of an inverse-targeting strategy that aims to enhance topotecan safety and efficacy.
Journal of Pharmacokinetics and Pharmacodynamics 01/2008; 34(6):829-47. · 2.06 Impact Factor
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ABSTRACT: Although it is known that FcRn, the neonatal Fc-receptor, functions to protect immune gamma globulin (IgG) from elimination, the influence of FcRn on the tissue distribution of IgG has not been quantified. In the present work, a physiologically-based pharmacokinetic (PBPK) model has been developed to characterize and predict IgG disposition in plasma and in tissues. The model includes nine major compartments, connected in an anatomical manner, to represent tissues known to play a significant role in IgG disposition. Each tissue compartment was subdivided into vascular, endosomal and interstitial spaces. IgG transport between the blood and interstitial compartments may proceed by convection through paracellular pores in the vascular endothelium, or via FcRn-mediated transcytosis across vascular endosomal cells. The model was utilized to characterize plasma concentration-time data for 7E3, a monoclonal antiplatelet IgG1 antibody, in control and FcRn-knockout (KO) mice. These data showed that high dose intravenous immunoglobulin (IVIG), 1g/kg, increased 7E3 clearance in control mice from 5.2 +/- 0.3 to 14.4 +/- 1.4 ml/d/kg; however, IVIG failed to increase the clearance of 7E3 in KO mice (72.5 +/- 4.0 vs. 61.0 +/- 3.6 ml/d/kg). Based on model fitting to the 7E3 plasma concentration data, simulations were conducted to predict tissue concentrations of IgG in control and in KO mice, and the predictions were then tested by assessing 7E3 tissue distribution in KO mice and control mice. 7E3 was radiolabeled with Iodine-125 using chloramine T method, and (125)I-7E3 IgG was administered at a dose of 8 mg/kg to control and KO mice. At various time points, sub-groups of 3 mice were sacrificed, blood and tissue samples were collected, and radioactivity assessed by gamma counting. PBPK model performance was assessed by comparing model predictions with the observed data. The model accurately predicted 7E3 tissue concentrations, with mean predicted vs. observed AUC ratios of 1.04 +/- 0.2 and 0.86 +/- 0.3 in control and FcRn-KO mice. The PBPK model, which incorporates the influence of FcRn on IgG clearance and disposition, was found to provide accurate predictions of IgG tissue kinetics in control and FcRn-knockout mice.
Journal of Pharmacokinetics and Pharmacodynamics 11/2007; 34(5):687-709. · 2.06 Impact Factor
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ABSTRACT: IVIG may achieve its beneficial effects in immune thrombocytopenia (ITP) patients via several mechanisms; however, little is known of the relative importance of various mechanisms associated with IVIG action in ITP. The purposes of this study were to develop a pharmacokinetic/pharmacodynamic (PK/PD) model relating an anti-platelet antibody, MWReg30, to platelet counts in a mouse model of sustained ITP, to use modeling to characterize effects of IVIG on MWReg30 elimination, and to use PK/PD modeling to assess the contribution of IVIG effects on MWReg30 disposition to the effects of IVIG on MWReg30-induced thrombocytopenia in mice. A pharmacokinetic model, based on the competitive occupancy of protective FcRn receptors, was used to characterize the effects of IVIG on MWReg30 pharmacokinetics. The relationships between MWReg30 plasma concentrations to MWReg30-induced thrombocytopenia, in the presence and absence of IVIG treatment, were characterized using an indirect response model. The pharmacokinetic model well-captured MWReg30 plasma concentration-time profiles, with and without administration of IVIG. The indirect response model accurately characterized the effects of IVIG on MWReg30-induced thrombocytopenia in mice. Using these models, it was estimated that 43 +/- 5% of overall effects of IVIG on MWReg30-induced thrombocytopenia in mice could be accounted for by the IVIG-mediated increases in MWReg30 clearance.
Journal of Pharmaceutical Sciences 07/2007; 96(6):1625-37. · 3.06 Impact Factor
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ABSTRACT: The present work evaluated antibody-coated liposomes as a new treatment strategy for immune thrombocytopenic purpura (ITP) through the use of a mouse model of the disease. Effects of antimethotrexate antibody (AMI)-coated liposomes and intravenous immunoglobulin (IVIG)-coated liposomes (15, 30, 60 micromol lipid/kg) were compared with the effects of IVIG (0.4, 1, 2 g/kg) and anti-red blood cell (anti-RBC) monoclonal antibody immunotherapy (TER119, 5, 15, 25, and 50 microg/mouse) on MWReg30-induced thrombocytopenia. Each treatment was found to attenuate thrombocytopenia in a dose-dependent manner and, consistent with previous work, IVIG was found to increase antiplatelet antibody clearance in a dose-dependent manner. TER119 demonstrated greater effects on thrombocytopenia relative to other therapies (peak platelet counts: 224% +/- 34% of initial platelet counts for 50 microg TER119/mouse versus 160% +/- 34% for 2 g/kg IVIG, 88% +/- 36% for 60 micromol lipid/kg AMI-coated liposomes, and 80% +/- 25% for 60 micromol lipid/kg IVIG-coated liposomes). However, the effects of TER119 were associated with severe hemolysis, as TER119 decreased RBC counts by approximately 50%. The present work demonstrated that antibody-coated liposomes attenuated thrombocytopenia in this model at a much lower immunoglobulin dose than that required for IVIG effects and, in contrast with TER119, antibody-coated liposomes increased platelet counts without altering RBC counts.
Blood 04/2007; 109(6):2470-6. · 9.90 Impact Factor
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ABSTRACT: A rapid and sensitive liquid chromatography/mass spectrometry (LC/MS) method was developed and validated for the determination of roxatidine in human plasma. Roxatidine was extracted by single liquid-liquid extraction with tert-butyl methyl ether, and the chromatographic separation was performed on a C8 column. The total analytical run time was relatively short (5 min), and the limit of assay quantification was 2 ng/mL using 0.1 mL of human plasma. Roxatidine and the internal standard, propranolol, were monitored in selected ion monitoring (SIM) mode at m/z 307.3 and 260.3, respectively. The standard curve was linear over a concentration range from 2-500 ng/mL, and the correlation coefficients were >0.999. The mean intra- and inter-day assay accuracy ranged from 103.4-108.8% and 102.3-110.0%, respectively, and the mean intra- and inter-day precision was between 3.3-8.8% and 5.3-6.2%, respectively. The developed assay method was successfully applied to a pharmacokinetic study in human volunteers after oral administration of roxatidine acetate hydrochloride at a dose of 75 mg.
Rapid Communications in Mass Spectrometry 02/2007; 21(3):329-35. · 2.79 Impact Factor
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08/2006: pages 835 - 850; , ISBN: 9780470117118
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ABSTRACT: Heparin employed in extracorporeal blood circulation (ECBC) procedures (e.g. open heart operations) often leads to a high incidence of bleeding complications. Protamine employed in heparin neutralization, on the other hand, can cause severe adverse reactions. We previously developed an approach that could prevent both heparin- and protamine-induced toxic side effects concomitantly. This approach consisted of placing a hollow fiber-based bioreactor device containing immobilized protamine (termed a "protamine bioreactor") at the distal end of the ECBC procedure. This protamine bioreactor would remove heparin after heparin served its anticoagulant purpose in the ECBC device, thereby eliminating heparin-induced bleeding risks. In addition, this protamine bioreactor would prevent protamine from entering the patients, thereby aborting any protamine-induced toxic effects. Both in vitro and in vivo studies have successfully demonstrated the feasibility of this approach. Despite promises, early findings also revealed two shortcomings that must be overcome for the protamine bioreactor to be applied clinically. The first drawback was that the cyanate ester linkages, involved in conjugating protamine to the bioreactor device, were unstable and prone to hydrolysis, resulting in the leakage of a significant amount of protamine into circulation during application of the protamine bioreactor. The second deficiency was that the capacity of the protamine bioreactor in heparin removal was rather low, owing to the limited surface area of the hollow fibers for protamine immobilization and subsequently heparin adsorption. In this paper, we present novel strategies to overcome these two limitations. A new conjugation method based on the use of 4-(oxyacetyl)phenoxyacetic acid (OAPA) as the activating reagent was employed to yield stable linkages, via the abundant arginine residues of protamine, onto the hollow fibers. Results showed that while the amount of protamine immobilized on each gram of fibers was relatively comparable between the OAPA and the previous CNBr activation methods (7.45 mg/g versus 7.69 mg/g fibers), there was virtually no detectable leaching of immobilized protamine from the bioreactor by the OAPA method, comparing to 35% leaching of protamine by the previous CNBr method following 72 h of storage of the bioreactor in PBS buffer at 37 degrees C. To improve the capacity and functionality of the protamine bioreactor, two novel approaches were adopted. Long chain and high molecular weight poly-lysine was linked to the hollow fibers, prior to protamine coupling, to create multiple layers of immobilized protamine for subsequent heparin adsorption. In addition, a poly(ethylene glycol) (PEG) chain was inserted between protamine and the hollow fibers to yield a three-dimensional, free dynamic motion for immobilized protamine. Preliminary observations indicated that a four- to five-fold enhancement in heparin adsorption was attained by utilizing each of these new approaches. Aside from their current use, these new strategies can also be employed generically to improve the functionality of any affinity-type bioreactor. Indeed, efforts have been made recently in utilizing these approaches to develop a clinically usable GPIIb/IIIa bioreactor for the treatment of immune thrombocytopenic purpura (ITP)-an autoimmune disease.
International Journal of Pharmaceutics 01/2006; 306(1-2):132-41. · 3.35 Impact Factor
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ABSTRACT: Immune thrombocytopenic purpura (ITP) is an autoimmune disease that affects thousands of Americans each year. The resulting thrombocytopenia, which develops from destruction of platelets (PLT) by anti-PLT autoantibodies (APAb), is often associated with hemorrhagic complications. Existing therapies are not effective and are associated with significant morbidity. Recently, a new treatment modality using plasmapheresis with a Protein-A column has shown some clinical promise. Yet, although this method would remove the pathogenic APAb, it would also deplete protective antibodies, thereby weakening the body's self-defense system. Because about 80% of patients with ITP develop APAb against the GPIIb/IIIa antigens on PLT, a novel approach of attaching a GPIIb/IIIa-linked bioreactor with an extracorporeal circuit is suggested herein to achieve highly effective/specific APAb removal and overcome shortcomings of plasmapheresis in treating ITP. A hollow fiber-based bioreactor device was fabricated, and GPIIb/IIIa antigens were immobilized onto the inner lumens of the hollow fibers by using the epichlorohydrin activation method. An optimized bioreactor containing a loading of 1.63 mg GPIIb/IIIa/g fibers and adsorption capacity of 1.9 mg 7E3/g fibers was developed. Preliminary proof-of-concept investigation using a 7E3-induced thrombocytopenic rat model (which mimicked clinical ITP) was carried out. A complete (100%) return of PLT counts to their initial levels was observed in rats within 6 h after the GPIIb/IIIa bioreactor treatment. In addition, a rapid restoration of WBC counts in the treated rats was also found. These preliminary findings shed light of promise of using the GPIIb/IIIa bioreactor approach in achieving highly improved ITP therapy.
Journal of Biomedical Materials Research Part A 01/2006; 75(3):648-55. · 2.63 Impact Factor
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ABSTRACT: Immune thrombocytopenia (ITP) is an autoimmune disease that is mediated by anti-platelet antibodies. It is believed that anti-platelet antibody-opsonized platelets are eliminated through Fcgamma receptor-mediated and complement-mediated phagocytosis by macrophages of the reticuloendothelial system (RES). Polyclonal pooled immunoglobulin with high titer for the D-antigen of erythrocytes (i.e., anti-D) has been successfully used to ameliorate ITP. Based on the pathogenesis of ITP and based on the successful application of anti-D for the treatment of ITP, we hypothesized that antibody-coated liposomes may be used to inhibit Fcgamma receptor-mediated and complement-mediated phagocytosis, thereby increasing platelet counts in ITP. To test this hypothesis, we have developed a liposome preparation that is coated with a model monoclonal IgG1 antibody. Antibody-coated liposomes were found to inhibit complement deposition and macrophage phagocytosis in vitro. Furthermore, antibody-coated liposomes were also found to attenuate thrombocytopenia in a rat model of ITP, in a dose-dependent manner. The results suggest that antibody-coated liposomes may be used as 'decoy particles' to competitively inhibit the destruction of antibody-coated platelets; thus, antibody-coated liposomes may have value in the treatment of ITP.
International Journal of Pharmaceutics 12/2005; 304(1-2):51-62. · 3.35 Impact Factor
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ABSTRACT: Anti-drug antibodies may be used to impart regio-specific alterations in drug disposition, potentially enhancing the therapeutic selectivity of intracavitary chemotherapy. In the present study, we tested the hypotheses that systemic therapy with anti-methotrexate antibodies would allow increases in the maximum tolerated dose of intraperitoneal methotrexate (MTX) and allow increases in the therapeutic efficacy of intraperitoneal MTX in a murine model of peritoneal cancer. Monoclonal anti-MTX Fab antibody fragments (AMF) were produced, purified, and characterized. AMF pharmacokinetics were determined following i.v. bolus injection (0.4 g/kg) and s.c. bolus injection (0.4, 0.8, 2.2 g/kg). MTX efficacy was investigated in mice bearing peritoneal sarcoma 180 tumors, following administration of MTX via 72 h i.p. infusion at 1.9, 2.8, 3.8 mg/kg, and following combination therapy of 7.5 or 10 mg/kg i.p. MTX (72 h infusion) and 4.2 g/kg s.c. AMF. The mean terminal half-life of AMF was found to be 10.9 +/- 3.3 h and was not dose-dependent, and s.c. bioavailability was 28% +/- 7% at 2.2 g/kg. In mice bearing peritoneal tumors, the maximally tolerated dose of i.p. MTX increased from 1.9 mg/kg (following i.p. MTX alone) to 10 mg/kg (with co-administration of s.c. AMF). Median survival times for saline-treated control animals and animals receiving i.p. MTX (1.9, 2.8, 3.8 mg/kg) were 9, 12, 10, and 7 days, respectively. However, for animals receiving combination therapy with i.p. MTX 7.5 or 10 mg/kg and 4.2 g/kg s.c. AMF, median survival time increased to 17 and 14 days, respectively. As such, the present data suggest that systemic administration of AMF may allow increases in the maximally tolerated dose of i.p. MTX, and allow increases in the therapeutic efficacy of i.p. MTX chemotherapy of peritoneal tumors.
Journal of Pharmaceutical Sciences 10/2005; 94(9):1957-64. · 3.06 Impact Factor
