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Int J Pharm. 2014 Apr 25;465(1-2):228-38. doi: 10.1016/j.ijpharm.2014.01.038. Epub 2014 Feb 6.

PK/TD modeling for prediction of the effects of 8C2, an anti-topotecan mAb, on topotecan-induced toxicity in mice.

Author information

1
Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States.
2
Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States. Electronic address: jb@acsu.buffalo.edu.

Abstract

To facilitate the development of an inverse targeting strategy, where anti-topotecan antibodies are administered to prevent systemic toxicity following intraperitoneal topotecan, a pharmacokinetic/toxicodynamic (PK/TD) model was developed and evaluated. The pharmacokinetics of 8C2, a monoclonal anti-topotecan antibody, were assessed following IV and SC administration, and the data were characterized using a two compartmental model with nonlinear absorption and elimination. A hybrid PK model was constructed by combining a PBPK model for topotecan with the two-compartment model for 8C2, and the model was employed to predict the disposition of topotecan, 8C2, and the topotecan-8C2 complex. The model was linked to a toxicodynamic model for topotecan-induced weight-loss, and simulations were conducted to predict the effects of 8C2 on the toxicity of topotecan in mice. Increasing the molar dose ratio of 8C2 to topotecan resulted in a dose-dependent decrease in the unbound (i.e., not bound to 8C2) topotecan exposure in plasma (AUCf) and a decrease in the extent of topotecan-induced weight-loss. Consistent with model predictions, toxicodynamic experiments showed substantial reduction in the percent nadir weight loss observed with 30 mg/kg IP topotecan after co-administration of 8C2 (20 ± 8% vs. 10 ± 8%). The investigation supports the use of anti-topotecan mAb to reduce the systemic toxicity of IP topotecan chemotherapy.

KEYWORDS:

8C2; Enzyme linked immunosorbent assay; Immunotoxicotherapy; Intraperitoneal chemotherapy; Inverse targeting; Monoclonal antibody; Pharmacokinetic/toxicodynamic model; Subcutaneous bioavailability; Surface plasmon resonance; Topotecan

PMID:
24508555
PMCID:
PMC4096764
DOI:
10.1016/j.ijpharm.2014.01.038
[Indexed for MEDLINE]
Free PMC Article

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