Received for publication October 12, 2004.
Revised January 4, 2005.
Accepted for publication January 12, 2005.

Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV

Abstract

UK-427,857 is a novel CCR5 antagonist undergoing investigation for use in the treatment of HIV infection. Pharmacokinetic and metabolism studies have been performed in mouse, rat, dog and human after single and multiple administration by oral and intravenous routes. The compound has physicochemical properties that are borderline for good pharmacokinetics, being moderately lipophilic (log D_7.4 2.1) and basic (pKa 7.3), possessing a number of H-bonding functionalities and molecular weight of 514Da. The compound was incompletely absorbed in rat (20 - 30%) but well absorbed in dog (>70%). Based on in vitro studies in Caco-2 cells, UK-427,857 has relatively poor membrane permeability and transcellular flux is enhanced in the presence of inhibitors of P-glycoprotein. Further evidence for the involvement of P-glycoprotein in restricting the oral absorption of UK-427,857 was obtained in P-glycoprotein null mice (mdr1a/mdr1b knockout). In these animals AUC after oral administration was 3-fold higher than in control animals. In oral dose escalation studies in man, the compound demonstrated non-linear pharmacokinetics, with increased dose normalised exposure with increased dose size, consistent with saturation of P-glycoprotein. The oral dose-exposure relationship of UK-427,857 in man was not reflected in either rat or dog. In animal species and man, UK-427,857 undergoes some metabolism, with parent compound the major component present in the systemic circulation and excreta. Elimination of radioactive dose was primarily via the faeces. In rat, parent compound was secreted via bile and directly into the gastrointestinal tract. Metabolites were products of oxidative metabolism and showed a high degree of structural consistency across species.

Key words: antivirals, drug development, human pharmacokinetics, in vitro-in vivo prediction, mass spectrometry, oral absorption, p-glycoprotein, pharmacokinetics, protein binding, toxicokinetics

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