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

• Published in: Journal of pharmaceutical sciences Vol. 92; no. 8; pp. 1665 - 1676
• Main Authors: Lobo, Evelyn D., Soda, David M., Balthasar, Joseph P.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.08.2003; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: agonistic effect; Animals; antagonistic effect; anti-drug antibodies; Antibodies, Monoclonal - biosynthesis; Antibodies, Monoclonal - isolation & purification; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - pharmacology; Antineoplastic agents; Biological and medical sciences; Computer Simulation; General aspects; Hybridomas; Male; Medical sciences; methotrexate; Methotrexate - administration & dosage; Methotrexate - agonists; Methotrexate - immunology; Mice; Models, Biological; Models, Chemical; Pharmacology. Drug treatments; Predictive Value of Tests; Weight Loss - immunology; anti-drug antibodies; methotrexate; agonistic effect; antagonistic effect; Antineoplastic agent; Agonist; Intraperitoneal administration; Intravenous administration; Toxicity; Rodentia; Prediction; Monoclonal antibody; Biological activity; Prevention; Vertebrata; Mammalia; Simulation; Mouse; Animal; Antagonist; Mathematical model; Methotrexate; Pharmacokinetics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.10432

We have shown that intravenous (iv) administration of anti-methotrexate (MTX) antibodies (AMAb) reduces the systemic exposure of intraperitoneal (ip) MTX therapy, and we have proposed that AMAb effects on MTX systemic exposure would allow a reduction in MTX-induced systemic toxicity (i.e., producing a desirable antagonistic effect). However, many literature reports have shown that anti-toxin antibodies occasionally demonstrate unexpected agonist-like activity, increasing the extent of toxicity induced by their ligand. In this report, we have utilized a pharmacokinetic–pharmacodynamic (PKPD) model to predict the potential of AMAb to increase or decrease the magnitude of MTX-induced body weight loss in mice. Simulations predicted that both anti-MTX immunoglobulin G (AMI) and anti-MTX Fab fragments (AMF) would lead to increases or decreases in MTX toxicity, with effects dependent on the dosing protocol used. Based on the computer simulations, two protocols were selected for in vivo evaluation of predicted agonistic or antagonistic effects. Murine monoclonal AMI and AMF were produced, purified, and characterized. Agonistic effects were tested after 24-h infusion of ip MTX (10mg/kg) and iv administration of an equimolar dose of AMI. Antagonistic effects were tested after 72-h infusion of ip MTX (5mg/kg) and iv infusion of an equimolar dose of AMF. Consistent with model predictions of agonist-like activity, the 24-h AMI protocol led to significantly increased animal mortality (all animals died, p<0.005) and mean nadir weight loss (p<0.005). Also consistent with the predictions of the PKPD model, the 72-h AMF protocol significantly decreased animal mortality and mean nadir body weight loss (p<0.01). Thus, these studies demonstrate that agonistic and antagonistic effects of anti-toxin antibodies may be predicted through the use of an integrated PKPD model. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association