Received for publication March 27, 2007.
Revised July 23, 2007.
Accepted for publication July 23, 2007.

Pharmacokinetics and Pharmacodynamics of DPC 333, a Potent and Selective Inhibitor of Tumor Necrosis Factor- Converting Enzyme in Rodents, Dogs, Chimpanzees and Humans

Abstract

DPC 333 is a potent and selective inhibitor of tumor necrosis factor TNF- converting enzyme (TACE). It significantly inhibits lipopolysaccharide (LPS) induced soluble TNF- production in blood from rodents, chimpanzee and human, with IC₅₀ values ranging from 17 to 100 nM. In rodent models of endotoxemia, DPC 333 dose-dependently inhibited the production of TNF-, with an oral ED50 ranging from 1.1 to 6.1 mg/kg. Oral dosing of DPC 333 at 5.5 mg/kg daily for 2 weeks in a rat collagen antibody-induced arthritis (CIA) model suppressed the maximal response by approximately 50%. DPC 333 was distributed widely to tissues including the synovium, the site of action for anti-arthritic drugs. Pharmacokinetic and pharmacodynamic studies in chimpanzee revealed a systemic clearance of 0.4L/h/kg, a Vss of 0.6L/kg, an oral bioavailability of 17% and an ex vivo IC50 for the suppression of TNF- production of 55 nM (n=1). In a Phase I clinical trial with male volunteers following single escalating doses of oral DPC 333, the terminal half-life was between 3-6 h and the ex vivo IC₅₀ for suppressing TNF- production was 113 nM. Measurement of the suppression of TNF- production ex vivo may serve as a good biomarker in evaluating the therapeutic efficacy of TACE inhibitors. Overall, the pharmacological profiles of DPC 333 support the notion that suppression of TNF- with TACE inhibitors like DPC 333 may provide a novel approach in the treatment of various inflammatory diseases including RA, via control of excessive TNF-production.

Key words: anti-inflammatory drugs, bioavailability, clinical pharmacology, cytokines, drug development, drug disposition, drug distribution, oral absorption, pharmacokinetic/pharmacodynamic modeling, plasma protein binding

This article has been cited by other articles:

				H. P. Jia, D. C. Look, P. Tan, L. Shi, M. Hickey, L. Gakhar, M. C. Chappell, C. Wohlford-Lenane, and P. B. McCray Jr Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia Am J Physiol Lung Cell Mol Physiol, July 1, 2009; 297(1): L84 - L96. [Abstract] [Full Text] [PDF]

				X. Deng, J. Lu, L. D. Lehman-McKeeman, E. Malle, D. L. Crandall, P. E. Ganey, and R. A. Roth p38 Mitogen-Activated Protein Kinase-Dependent Tumor Necrosis Factor-{alpha}-Converting Enzyme Is Important for Liver Injury in Hepatotoxic Interaction between Lipopolysaccharide and Ranitidine J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 144 - 152. [Abstract] [Full Text] [PDF]

				C. E. Garner, E. Solon, C.-M. Lai, J. Lin, G. Luo, K. Jones, J. Duan, C. P. Decicco, T. Maduskuie, S. E. Mercer, et al. Role of P-Glycoprotein and the Intestine in the Excretion of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] in Rodents Drug Metab. Dispos., June 1, 2008; 36(6): 1102 - 1110. [Abstract] [Full Text] [PDF]