Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.

Evaluation of Safety, Pharmacokinetics and Pharmacodynamics of a Selective Glucocorticoid Receptor Modulator (SGRM) in Healthy Volunteers

Stock1,  Thomas, Fleishaker1,  Dona, Mukherjee2,  Arnab, Le2,  Vu, Xu2,  Jian, Zeiher2,  Bernhardt

Pfizer, Inc., Chesterfield, MO
Pfizer, Inc., New London, CT


SGRMs were identified preclinically using in vitro and in vivo assays. Compounds that displayed anti-inflammatory activity similar to glucocorticoids (e.g., prednisone) but lesser inhibition of bone formation in animal models were further evaluated in humans. PF-00251802 (C-A), and its phosphate ester pro-drug, PF-04171327 (C-B), were evaluated in separate Phase 1 single-dose studies in healthy volunteers to characterize safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of glucorticoid receptor (GR) agonism.


Single C-A doses (0.3 to 300 mg), and single C-B doses (1 to 300 mg) were evaluated in separate randomized, placebo-controlled, investigator- and subject-blinded clinical studies in 27 and 18 subjects, respectively, using partial cross-over designs. A washout period of 14 days was allowed between dosing. Serial blood samples and safety parameters were collected up to 7 days post-dose for PK, biomarker and safety assessments. C-A plasma concentration, complete blood count with differential, plasma osteocalcin (OC), plasma cortisol, and urinary N-terminal cross-linking telopeptide of type-1 collagen (uNTX-1) were measured. C-A plasma concentrations were linked to biomarker responses using PK-PD models for estimation of potency (IC50) and maximal effect (Imax). Selectivity of C-A was assessed by model-based comparison to biomarker effects of prednisolone (P), the active metabolite of prednisone, from a previous study.


C-A plasma concentrations increased proportionately with increasing doses of C-A and C-B. C-A PK was similar following equivalent doses of C-A and its pro-drug, C-B, which was not absorbed systemically. Dose-dependent biomarker effects consistent with GR-mediated pharmacology were observed, including cortisol and OC suppression, lymphopenia, eosinopenia, and neutrophilia. The duration of effect was substantially longer than that of P, likely due to the longer elimination half-life and GR binding affinity (Kd) of C-A (24 hr and 0.061 nM, respectively) compared to P (3 hr and 1.3 nM, respectively). The relative potency of C-A for OC suppression versus effects on other markers (cortisol suppression, neutrophilia) was lower compared to P. The Imax for C-A effect on OC was half that of P, but Imax on cortisol and neutrophils was similar to P. PK-PD model-based evaluations indicated that C-A doses up to 10 mg QD would provide OC suppression less than or equal to that of 5 mg QD prednisone, and cortisol suppression and neutrophilia similar to or greater than that of 20 mg QD prednisone. Both compounds were generally well tolerated, with dose limiting nausea and emesis occurring in some subjects at doses greater than 150 and 300 mg for C-A and C-B, respectively. There were no serious or severe adverse events.


Compared to prednisone, C-A was shown to have less impact on OC, a biomarker of adverse effects on bone, with similar effects on other biomarkers of glucocorticoid activity.

To cite this abstract, please use the following information:
Stock, Thomas, Fleishaker, Dona, Mukherjee, Arnab, Le, Vu, Xu, Jian, Zeiher, Bernhardt; Evaluation of Safety, Pharmacokinetics and Pharmacodynamics of a Selective Glucocorticoid Receptor Modulator (SGRM) in Healthy Volunteers [abstract]. Arthritis Rheum 2009;60 Suppl 10 :420
DOI: 10.1002/art.25503

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