Modeling Combined Anti-Inflammatory Effects of Dexamethasone and Tofacitinib in Arthritic Rats

Abstract

Tofacitinib (TOF), a Janus kinase (JAK) inhibitor, which was approved in 2012, has been recommended for the treatment of clinically active rheumatoid arthritis (RA). Dexamethasone (DEX), a potent corticosteroid, is also used in RA therapy but with limited usefulness due to dose- and time-dependent adverse effects. This pilot study examines the single and combined effects of DEX and TOF in order to explore the steroid-sparing potential of TOF. Collagen-induced arthritic (CIA) rats were subcutaneously (SC) dosed with vehicle, 1.5 mg/kg TOF, 5 mg/kg TOF, 0.225 mg/kg DEX, or a combination of 1.5 mg/kg TOF and 0.225 mg/kg DEX. Paw sizes were measured as an index of disease and drug efficacy and dynamically depicted using a logistic function for natural paw growth, a turnover model for disease progression, an indirect response model for inhibitory effects of TOF and DEX and a non-competitive interaction model for the combined effect of DEX and TOF. TOF alone exerted only a slight inhibitory effect on RA paw edema compared to DEX, which reduced edema by 40%. In combination, TOF and DEX had additive effects with an interaction factor of 0.76. Using model simulations, a single SC dose of TOF does not have a visible steroid-sparing potential, although BID oral dosing has such potential. The current study suggests an additive effect of TOF and DEX and simulations indicate that further exploration of TOF and DEX administration timing may produce desirable drug efficacy with lower DEX doses.

Keywords: anti-inflammatory; collagen-induced arthritis; dexamethasone; steroid-sparing; tofacitinib.

Fig. 1.

Schematic of the PK/PD/DIS progression model for effects of DEX and/or TOF on paw edema in CIA rats. Symbols are defined in Table I and II

Fig. 2.

Digitized mean TOF concentration-time data following the indicated doses in healthy rats, mice, and humans and their jointly fitting profiles across species based on the mPBPK model (Fig. I). Parameters utilized and estimates are listed in Table I

Fig. 3.

Simulated TOF concentration of blood, rapidly and slowly perfused tissue compartments after 1.5 and 5.0 mg/kg SC dosing in male rats

Fig. 4.

The paw size versus time profiles of healthy and arthritic rats treated with vehicle and the indicated drug doses. Symbols are measured values and lines are model fittings

Fig. 5.

Model-simulated paw size versus time profiles after 0.225 and 2.25 mg/kg single SC doses of DEX and combined of 0.225 mg/kg SC DEX and 2.5 mg/kg BID oral TOF doses in CIA rats (ψ = 0.76). The arrows indicate the time of DEX dosing at 504 h and that of dual TOF dosing at 522 and 526 h