A critical piece in the translation of preclinical studies to clinical trials is the determination of dosing regimens which allow maximum therapeutic benefit with minimum toxicity. The preclinical pharmacokinetic/pharmacodynamic (PK/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 target modulation and PK/PD modeling 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 of 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 (Cave50) of about 100 nM. Tofacitinib potency (ED50) in clinical studies was approximately 3.5 mg BID (90% confidence interval: 2.3, 5.5) or total Cave50 of about 40 nM, derived using disease activity scores from patients with RA. The collective clinical and preclinical data indicated the importance of Cave as a driver of efficacy, rather than maximum or minimum plasma concentration (Cmax or Cmin), where Cave50 values were within approximately 2-fold of each other.
- The American Society for Pharmacology and Experimental Therapeutics