RT Journal Article
SR Electronic
T1 Preclinical to Clinical Translation of Tofacitinib, a Janus Kinase Inhibitor, in Rheumatoid Arthritis
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 165
OP 173
DO 10.1124/jpet.113.209304
VO 348
IS 1
A1 Martin E. Dowty
A1 Michael I. Jesson
A1 Sarbani Ghosh
A1 Jamie Lee
A1 Debra M. Meyer
A1 Sriram Krishnaswami
A1 Nandini Kishore
YR 2014
UL http://jpet.aspetjournals.org/content/348/1/165.abstract
AB 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.