Application of Pharmacokinetic–Pharmacodynamic Modeling to Predict the Kinetic and Dynamic Effects of Anti-Methotrexate Antibodies in Mice

Lobo, Evelyn D.; Soda, David M.; Balthasar, Joseph P.

doi:10.1002/jps.10432

Cited by 26 publications

(28 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A murine antimethotrexate IgG1 (AMI) monoclonal antibody was generated and purified in our laboratory. 12 IVIG (Gamimune N 10%) was from Bayer (Elkhart, IN). Distearoyl-N-(3-carboxypropionoyl poly (ethylene glycol) succinyl) phosphatidylethanolamine (COOH-PEG 2000 -PE), cholesterol, and dimyristoylphosphatidylcholine (DMPC) were from Avanti (Alabaster, FL).…”

Section: Reagentsmentioning

confidence: 99%

Comparison of the effects of antibody-coated liposomes, IVIG, and anti-RBC immunotherapy in a murine model of passive chronic immune thrombocytopenia

Deng

Balthasar

2006

Blood

Self Cite

View full text Add to dashboard Cite

IntroductionImmune thrombocytopenia (ITP) is classified as an autoimmune disease in which antibody-coated platelets are phagocytosed by macrophages in the reticuloendothelial system (RES) through Fc␥ receptor-mediated or complement-mediated pathways. 1 There are about 33 000 new cases of ITP diagnosed in the United States each year. [2][3][4] Platelets play an important role in blood homeostasis and vascular repair; consequently, thrombocytopenic patients are at risk for the development of purpura, petechiae, or even life-threatening bleeding such as intracranial hemorrhage. Corticosteroids, splenectomy, intravenous immunoglobulin (IVIG), anti-D immunotherapy, and plasmapheresis have been used to acutely increase platelet counts in the treatment of ITP. 2-4 However, the above therapies are associated with troubling side effects and high cost. In addition, some ITP patients do not respond to any of the existing therapies; therefore, there is substantial need for the development of new strategies to treat this disease.In 1981, Imbach et al 5 reported the therapeutic efficacy of high-dose IVIG in ITP patients. Later, Salama et al 6 proposed that IVIG contained anti-red blood cell (anti-RBC) antibodies, which led to the opsonization of RBCs in vivo following IVIG administration. Additionally, Salama et al 6 hypothesized that antibodyopsonized RBCs competed for binding to Fc␥ receptors, effectively inhibiting the Fc␥ receptor-mediated elimination of platelets in ITP patients. Consistent with this hypothesis, anti-D, a polyclonal antibody preparation against the D antigens on the RBC, has been used to treat Rh ϩ ITP successfully. 2,7,8 Although anti-D has been Food and Drug Administration (FDA)-approved to treat ITP, this therapy is rarely associated with intravascular hemolysis, leading to severe anemia and, in very rare cases, death. 9,10 Additionally, anti-D has not demonstrated efficacy in D-negative patients or in splenectomized patients. 7,8 We have proposed that antibody-coated liposomes may be used in place of anti-D to compete for pathways for platelet elimination in ITP. 11 Previous work has shown that antibody-coated liposomes increased platelet counts in a rat model of acute passive ITP. 11 A murine model of chronic passive ITP, which may be more similar to human ITP, was developed here. The effects of antibody-coated liposomes were examined and compared with effects observed following treatment with IVIG or treatment with an anti-RBC monoclonal antibody (TER119). Our data showed that antibodycoated liposomes, IVIG, and TER119 increased platelet counts in this model. Antibody-coated liposomes achieved effects at a much lower immunoglobulin dose than that required for IVIG and, in contrast with TER119, antibody-coated liposomes achieved an increase in platelet counts without altering RBC counts. Materials and methods MiceFemale Balb/c mice (20 g) were obtained from Harlan (Bar Harbor, ME). Mice were kept under a natural light/dark cycle, maintained at 22 Ϯ 4°C, and fed with standard diet and water ad libitu...

show abstract

Section: Reagentsmentioning

confidence: 99%

Comparison of the effects of antibody-coated liposomes, IVIG, and anti-RBC immunotherapy in a murine model of passive chronic immune thrombocytopenia

Deng

Balthasar

2006

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…methotrexate therapy, increasing the ratio of peritoneal to systemic exposure to unbound drug [6]. With this combination therapy, AMF was found to be able to reduce MTX toxicity [7], allow a greater than five-fold increase in the maximum tolerated dose of MTX, and enhance the median survival time of mice bearing peritoneal tumors (Lobo and Balthasar, in preparation).…”

Section: Introductionmentioning

confidence: 97%

High-performance liquid chromatographic assay for the determination of total and free topotecan in the presence and absence of anti-topotecan antibodies in mouse plasma

Jin

Balthasar

2005

Journal of Chromatography B

Self Cite

View full text Add to dashboard Cite

“…BSAmethotrexate (BSA-MTX) was prepared, using the method published previously, in our laboratory. 14 Outdated human platelets were obtained from the American Red Cross (Buffalo, NY).…”

Section: Reagentsmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic effects of high-dose monoclonal antibody therapy in a rat model of immune thrombocytopenia

Jin

Tayab

Balthasar

2005

AAPS J

Self Cite

View full text Add to dashboard Cite

A BSTRACTIntravenous administration of pooled, polyvalent human immunoglobulin (IVIG) has been used for over 20 years as a therapy for immune thrombocytopenia (ITP). IVIG is available in limited quantities, and clinical preparations have been associated with the transfer of human pathogens. We have proposed that high-dose monoclonal antibody may be used in lieu of IVIG to achieve benefi cial effects in the treatment of ITP. The current study investigates the effects of high-dose monoclonal antibody therapy in a rat model of ITP. Hybridoma cells secreting a murine monoclonal antiplatelet antibody (7E3) and murine monoclonal anti-methotrexate IgG (AMI) were grown in serum-free media. Next, 7E3, 8 mg kg -1 , was administered intravenously to rats following pretreatment with saline or AMI (1 g kg -1 IV). AMI and 7E3 plasma concentrations were determined via enzyme-linked immunosorbent assay, and platelet count was determined with a Cell-Dyne hematology analyzer. Severe, transient thrombocytopenia was induced by 7E3. Platelet counts dropped to ~8% of initial values within 1 hour after 7E3 administration. AMI pretreatment dramatically affected 7E3-induced thrombocytopenia, signifi cantly altering the time course of thrombocytopenia ( P < .05) and signifi cantly decreasing the severity of 7E3-induced thrombocytopenia (ie, following AMI pretreatment, nadir platelet count was greater than 8-fold that of the control group, P < .05). In addition, AMI pretreatment induced a 57% increase in 7E3 clearance (1.13 ± 0.13 mL h -1 kg -1 vs 0.72 ± 0.08 mL h -1 kg -1 , P < .05). Consequently, high-dose monoclonal antibody therapy attenuated thrombocytopenia and produced a moderate increase in the clearance of antiplatelet antibodies in a rat model of ITP.

show abstract

Application of Pharmacokinetic–Pharmacodynamic Modeling to Predict the Kinetic and Dynamic Effects of Anti-Methotrexate Antibodies in Mice

Cited by 26 publications

References 20 publications

Comparison of the effects of antibody-coated liposomes, IVIG, and anti-RBC immunotherapy in a murine model of passive chronic immune thrombocytopenia

Comparison of the effects of antibody-coated liposomes, IVIG, and anti-RBC immunotherapy in a murine model of passive chronic immune thrombocytopenia

High-performance liquid chromatographic assay for the determination of total and free topotecan in the presence and absence of anti-topotecan antibodies in mouse plasma

Pharmacokinetic and pharmacodynamic effects of high-dose monoclonal antibody therapy in a rat model of immune thrombocytopenia

Contact Info

Product

Resources

About