Preclinical to clinical translation of tofacitinib, a Janus kinase inhibitor, in rheumatoid arthritis.

Abstract

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 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 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 (Cave50) of ~100 nM. Tofacitinib potency (ED50) in clinical studies was ~3.5 mg BID (90% confidence interval: 2.3, 5.5) or total Cave50 of ~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 ~2-fold of each other.

• Authors: Martin E Dowty, Michael I Jesson, Sarbani Ghosh, Jamie Lee, Debra M Meyer, Sriram Krishnaswami, Nandini Kishore
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 348 Issue 1 Pg. 165-73 (Jan 2014) ISSN: 1521-0103 [Electronic] United States
• PMID: 24218541 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Piperidines
• Protein Kinase Inhibitors
• Pyrimidines
• Pyrroles
• tofacitinib
• Jak1 protein, mouse
• Janus Kinase 1
• Janus Kinase 3

Topics

• Animals
• Arthritis, Experimental (drug therapy, enzymology)
• Double-Blind Method
• Drug Evaluation, Preclinical (methods)
• Humans
• Janus Kinase 1 (antagonists & inhibitors, metabolism)
• Janus Kinase 3 (antagonists & inhibitors, physiology)
• Male
• Mice
• Mice, Inbred DBA
• Piperidines (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Pyrroles (pharmacology, therapeutic use)