Temporal pharmacokinetic/pharmacodynamic interaction between human CD3ε antigen-targeted monoclonal antibody otelixizumab and CD3ε binding and expression in human peripheral blood mononuclear cell static culture.

Otelixizumab is a monoclonal antibody (mAb) directed to human CD3ε, a protein forming part of the CD3/T-cell receptor (TCR) complex on T lymphocytes. This study investigated the temporal interaction between varying concentrations of otelixizumab, binding to human CD3 antigen, and expression of CD3/TCR complexes on lymphocytes in vitro, free from the confounding influence of changing lymphocyte frequencies observed in vivo. A static in vitro culture system was established in which primary human peripheral blood mononuclear cells (PBMCs) were incubated over an extended time course with titrated concentrations of otelixizumab. At each time point, free, bound, and total CD3/TCR expression on both CD4+ and CD8+ T cells and the amount of free otelixizumab antibody in the supernatant were measured. The pharmacokinetics of free otelixizumab in the culture supernatants was saturable, with a shorter apparent half-life at low concentration. Correspondingly, a rapid, otelixizumab concentration-, and time-dependent reduction in CD3/TCR expression was observed. These combined observations were consistent with the phenomenon known as target-mediated drug disposition (TMDD). A mechanistic, mathematical pharmacokinetic/pharmacodynamic (PK/PD) model was then used to characterize the free otelixizumab-CD3 expression-time relationship. CD3/TCR modulation induced by otelixizumab was found to be relatively fast compared with the re-expression rate of CD3/TCR complexes following otelixizumab removal from supernatants. In summary, the CD3/TCR receptor has been shown to have a major role in determining otelixizumab disposition. A mechanistic PK/PD model successfully captured the PK and PD in vitro data, confirming TMDD by otelixizumab.

SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Receptor antagonists that block the binding of chemokines such as CXCL8 (IL-8) are effective in animals models of neutrophil-mediated inflammation. It has been hypothesized that selective inhibition of neutrophil trafficking and activation may be a useful adjunct for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease or cystic fibrosis. A CXCR1/2 receptor antagonist has shown activity in an ozone challenge model in humans. WHAT THIS STUDY ADDS: SB-656933, a selective CXCR2 antagonist, is safe and well-tolerated at single doses and is shown to inhibit agonist (CXCL1)-mediated expression of the CD11b on peripheral blood neutrophils as well as ozone-induced airway neutrophilia in healthy subjects. AIMS: To determine the safety and tolerability of a novel selective CXCR2 antagonist and assess its pharmacodynamic effects using measures of neutrophil activation and function, including CD11b expression in whole blood and ozone-induced airway inflammation in healthy subjects. METHODS: Flow cytometric determination of ex vivo CXCL1-induced CD11b expression on peripheral blood neutrophils was performed following single dose oral administration of SB-656933 (dose range 2-1100 mg). A subsequent randomized study (placebo, 50 mg and 150 mg) was performed to explore the dose-response for ozone-induced airway inflammation, as measured by sputum biomarkers. RESULTS: Oral administration of SB-656933 resulted in significant inhibition of CXCL1-induced CD11b expression on peripheral blood neutrophils at single doses greater than or equal to 50 mg. Maximum inhibition (70%) relative to placebo was observed following administration of SB-656933 400 mg (95% CI 60%, 77%). This was sustained up to a dose of 1100 mg. Single doses of SB-656933 reduced ozone-induced airway inflammation in a dose-dependent manner. Relative to placebo, there were 55% (95% CI 20%, 75%) and 74% (95% CI 55%, 85%) fewer neutrophils in the sputum of subjects after a single dose of 50 mg or 150 mg, respectively. There was a corresponding reduction in myeloperoxidase concentrations in the sputum supernatant of 32.8% (95% CI 9.2, 50.3) and 50.5% (95% CI 33.3, 63.3). SB-656933 was safe and well-tolerated at all doses. CONCLUSIONS: SB-656933 is a CXCR2 antagonist that demonstrates dose-dependent effects on neutrophil activation and recruitment within a well-tolerated dose range. These data suggest that SB-656933 may be an effective agent in neutrophil-predominant diseases.

Abnormally tender muscle regions and associated painful movements.

The location, signs, aetiology, clinical importance and treatment of abnormally tender muscle regions are discussed. Impaired movements associated with one affected muscle in any joint region are investigated in 10 patients; all 10 present with the same pattern of pain-producing movements (i.e. any movement or manoeuvre that increases either the length or the isometric tension within the affected muscle).