CPSA Shanghai 2011
Changing Paradigm in Drug Discovery & Development:
East Meets West
April 13 - 16, 2011
Renaissance Shanghai Pudong Hotel
Shanghai, China
Abstract
Friday PM - Parallel Session III
The PK/PD Relationship of an S1P1 Agonist in Rats as a Tool to Guide FIH Dose Selections
Ellen Rohde, Cheryl Black, Ivan Nestorov, Qin Wang, Lawrence Gan; Preclinical Development Sciences, Biogen Idec
Agonists of the S1P1 receptor decrease circulating lymphocytes by blocking their egress from peripheral lymphoid tissues, thereby limiting their access to sites of inflammation in the body. Hence, S1P1 agonists have been used in preclinical models of autoimmune diseases, transplant rejection and at least one molecule, FTY720, has shown efficacy in patients with multiple sclerosis. The lowered number of lymphocytes in circulation is used widely as a pharmacodynamic (PD) marker for the efficacy of the receptor interaction and disease outcome but poses also a potential risk for opportunistic infections due to immunosupression. Mathematical modeling of the exposure-response relationship may be able to correlate dose levels that show efficacy with lymphocyte levels that provide optimal safety in chronic use against autoimmune diseases.
Compound A (Cpd A) is selectively phosphorylated in vivo by sphingosine kinase 2 to yield metabolite 1 (M1) that acts as a potent S1P1 agonist (in vitro EC50 of 8nM). We describe the start of an iterative process of pharmacokinetic (PK) and pharmacodynamic (PD) response modeling in preclinical species with the goal to guide early decisions in clinical development. In a SAD study male Sprague-Dawley rats received a single oral bolus dose at 7 dose levels from 0.01mg/kg to 10mg/kg. Whole blood samples were collected up to 336h and absolute lymphocyte counts were measured in an aliquot of each. The rest of the samples were used to analyze for CpdA and M1 by LC-MS. The exposure to M1 was modeled with a 2-compartment model with first order absorption and elimination. Since M1 is thought to cause the inhibition of lymphocyte re-entry into the circulation the correlation between M1 concentration and absolute lymphocyte counts was modeled with an indirect response model. Assuming Imax=1 the response curves were fitted for all dose levels and an IC50 of 3ng/ml (6nM) was determined. Using the model we simulated differential lymphocyte levels and corresponding dose levels for a MAD study in rats. Results from this study will be compared with the prediction to create a data set that supports a comparable iterative modeling approach to studies in higher preclinical species and man.