Friday, 11 July 2014

Gilenya me-too. How much depletion do we need

Krause A, Brossard P, D'Ambrosio D, Dingemanse J. Population pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator.J Pharmacokinet Pharmacodyn. 2014 Jun 15. [Epub ahead of print]

Ponesimod (ACT-128800), a reversible, orally active, selective S1P1 receptor modulator, prevents the egress of lymphocytes from the lymph node into the systemic circulation. It is currently in clinical development for the treatment of relapsing multiple sclerosis. Modulation of circulating lymphocytes serves as biomarker of efficacy and safety, such that the quantitative characterization of the pharmacokinetic/pharmacodynamic (PK/PD) relationship guides the clinical development of the compound. The was a daily variation of 9 % and a maximum inhibition of 86 % of total lymphocyte count with high doses at steady state. It was instrumental for the selection of doses for subsequent studies that confirmed the effect plateau in total lymphocyte count at approximately 500,000,000 counts/L.

So this study looks at Gilenya me too. This shows that it can deplete white blood cells. The question is how much depletion do you need?  This is important because depletion of white blood cells can leave you open to problems with infection. Based on studies in animals it is clear that the mechanisms of action of some agents is depletion of white blood cells but it is also clear that emergence of disease may not be absolutely dependent on total number of white blood cells.  So with Alemtuzumab and other drugs the action is clearly dependent on white blood cell depletion but when relapse occurs this does not appear to correlate with absolute white cell numbers. This is because we cannot see the trees because we are looking at a wood an it is the number of disease-causing cells that we need to know. So if we look at cladribine, alemtuzumab and anti-CD20 the effects on level of depletion are very varied. All stop relapse and all substantially deplete B cells, but they have very different actions on the level of T cell depletion, some by >95% others by  60%  or less. What is enough depletion with anti CD4 monoclonal antibodies depletion of CD4 cells by 60% was not enough, so how do cladribine and anti-CD20 work. Is it because B cells are the most important cell to deplete?

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