4.5 Article

Preclinical to Clinical Translation of Tofacitinib, a Janus Kinase Inhibitor, in Rheumatoid Arthritis

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AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.113.209304

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  1. Pfizer Inc (New London, CT)

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A critical piece in the translation of preclinical studies to clinical trials is the determination of dosing regimens that allow maximum therapeutic benefit with minimum toxicity. The preclinical pharmacokinetic (PK)/pharmacodynamic (PD) profile of tofacitinib, an oral Janus kinase (JAK) inhibitor, in a mouse collagen-induced arthritis (mCIA) model was compared with clinical PK/PD data from patients with rheumatoid arthritis (RA). Preclinical evaluations included targetmodulation and PK/PDmodeling based on continuous subcutaneous infusion or oral once-or twice-daily (BID) dosing paradigms in mice. The human PK/PD profile was obtained from pooled data from four phase 2 studies in patients with RA, and maximal effect models were used to evaluate efficacy after 12 weeks of tofacitinib treatment (1-15 mg BID). In mCIA, the main driver of efficacy was inhibition of cytokine receptor signaling mediated by JAK1 heterodimers, but not JAK2 homodimers, and continuous daily inhibition was not required to maintain efficacy. Projected efficacy could be predicted from total daily exposure irrespective of the oral dosing paradigm, with a total steady-state plasma concentration achieving 50% of the maximal response (C-ave50) of similar to 100 nM. Tofacitinib potency (ED50) in clinical studies was similar to 3.5 mg BID (90% confidence interval: 2.3, 5.5) or total C-ave50 of similar to 40 nM, derived using Disease Activity Scores from patients with RA. The collective clinical and preclinical data indicated the importance of C-ave as a driver of efficacy, rather than maximum or minimum plasma concentration (C-max or C-min), where Cave50 values were within similar to 2-fold of each other.

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