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.

• Authors: Ruihong Yu, Dawei Song, Debra C DuBois, Richard R Almon, William J Jusko
• Journal: The AAPS journal (AAPS J) Vol. 21 Issue 5 Pg. 93 (07 24 2019) ISSN: 1550-7416 [Electronic] United States
• PMID: 31342216 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Piperidines
• Protein Kinase Inhibitors
• Pyrimidines
• Pyrroles
• Dexamethasone
• tofacitinib

Topics

• Animals
• Anti-Inflammatory Agents (administration & dosage, pharmacology)
• Arthritis, Experimental (drug therapy, physiopathology)
• Arthritis, Rheumatoid (drug therapy, physiopathology)
• Dexamethasone (administration & dosage, pharmacology)
• Disease Progression
• Dose-Response Relationship, Drug
• Drug Therapy, Combination
• Edema (drug therapy, pathology)
• Male
• Pilot Projects
• Piperidines (administration & dosage, pharmacology)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Pyrimidines (administration & dosage, pharmacology)
• Pyrroles (administration & dosage, pharmacology)
• Rats
• Rats, Inbred Lew