Modeling Sex Differences in Anti-inflammatory Effects of Dexamethasone in Arthritic Rats

Purpose: Collagen-induced arthritic (CIA) rats are used commonly for preclinical pharmacologic research into rheumatoid arthritis (RA). Dexamethasone (DEX), a potent corticosteroid (CS), remains an important component in combination therapy for RA. Although sex differences in RA and CS pharmacokinetics/pharmacodynamics (PK/PD) have been documented in humans, there has been no such comprehensive evaluation of sex differences in CIA rats. Methods: Paw size measurements were obtained for males and females from four groups of animals: healthy controls, non-drug treated arthritic animals, and both 0.225 and 2.25 mg/kg DEX-treated arthritic animals. A turnover model for disease progression, minimal PBPK model for drug concentrations, and inhibitory indirect response model were applied using population PK/PD modeling. Results: The clearances of DEX were 43% greater in males, but other PK parameters were similar. The temporal profiles of paw swelling exhibited earlier progression, peak edema times, and disease remission in females. DEX suppressed paw edema well in both males and females with similar capacity (I_max) values (=1.0), but DEX potency was less in females with higher IC₅₀ values (0.101 versus 0.015 ng/mL). Conclusions: The pharmacology of DEX was well characterized in CIA rats. This study addresses knowledge gaps about sex differences and can be a guide for more mechanistic assessment of sex, drug, and disease differences in RA.