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 collageninduced 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 (C ave50 ) of~100 nM. Tofacitinib potency (ED 50 ) in clinical studies was ∼3.5 mg BID (90% confidence interval: 2.3, 5.5) or total C ave50 of ∼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 C ave50 values were within ∼2-fold of each other.

JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

“…In a cellular setting, tofacitinib demonstrates preferential inhibition of signaling pathways associated with JAK1 and/or JAK3 (43). With tofacitinib 5 mg twice daily (bid), average inhibition of preferentially inhibited cytokines is 50 -60%, declining to 10 -30% at trough concentration during each dosing period (12). Reversibility of pharmacodynamic effects is generally seen within 14 days of tofacitinib discontinuation (19).…”

Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Antipruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis

“…The JAK inhibitors (tofacitinib or oclacitinib) were administered orally or topically 30 minutes before and 4 hours after TDI challenge because the absorption of tofacitinib and oclacitinib was rapid, with plasma concentrations for both tofacitinib and oclacitinib peaking at around 1 hour after oral or intravenous administration. Tofacitinib and oclacitinib both have a short half-life of 2 and 4 hours after administration, respectively (Collard et al, 2014;Dowty et al, 2014). Each drug was diluted in a 0.5% methylcellulose/0.25% Tween 20 solution for oral administration, and a 7:1 acetone:DMSO solution for topical application to concentrations described subsequently.…”

Molecular targets in arthritis and recent trends in nanotherapy

“…3 It has been reported that tofacitinib involves serious infections (cellulitis [5-mg group] and liver abscess, bronchitis, tuberculous pleural effusion, and pyelonephritis [10-mg group]). 4 Tofacitinib is administered orally at 50 mg/kg 5 or using osmotic minipump infusion at doses of 1.5, 5, and 15 mg/kg. 6 Competitive inhibition of dihydrofolate reductase that plays an important role in tetrahydrofolate synthesis can be achieved by MTX.…”

“…15 Tofacitinib has been proven to be functionally, clinically, and radiographically more effective than MTX in treating patients with RA. 5 Leflunomide (brand names: Arabloc, Arava, Lunava, Repso) is an immunosuppressive disease-modifying antirheumatic drug. 16 Inhibition of mitochondrial enzyme named dihydroorotate dehydrogenase that is involved in de novo pyrimidine synthesis is the primary mode by which leflunomide acts as an immunomodulatory drug.…”