Exposure–response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from a dose‐ranging phase 2 trial

Abstract

AimsTofacitinib is an oral, small molecule JAK inhibitor being investigated for ulcerative colitis (UC). In a phase 2 dose‐ranging study, tofacitinib demonstrated efficacy vs. placebo as UC induction therapy. In this posthoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC.MethodsOne‐ and two‐compartment pharmacokinetic models, with first‐order absorption and elimination, were evaluated to describe plasma tofacitinib concentration‐time data at baseline and week 8. Relationships between tofacitinib exposure (dose, average plasma drug concentration during a dosing interval at steady state [Cav,ss] and trough plasma concentration at steady state [Ctrough,ss]) and week 8 efficacy endpoints were characterized using logistic regression analysis. Baseline disease, demographics, prior and concurrent UC treatment were evaluated as covariates.ResultsPlasma tofacitinib concentrations increased proportionately with dose and estimated oral clearance, and Cav,ss values were not significantly different between baseline and week 8. Dose, Cav,ss and Ctrough,ss performed similarly as predictors of efficacy based on statistical criteria for model fit and comparison of model predictions for each endpoint. Individual Cav,ss values were similar between clinical remitters and nonremitters at predicted efficacious doses (10 and 15 mg twice daily). Baseline Mayo score was a significant determinant of efficacy. Predicted differences from placebo in clinical remission at 10 mg twice daily for patients with baseline Mayo score >8 and ≤8 were 39% (95% CI: 7–70) and 21% (–2–50), respectively.ConclusionsExposure–response characterization demonstrated the potential of tofacitinib 10 and 15 mg twice daily as induction therapy for UC without monitoring of plasma drug concentrations for dose optimization.

Efficacy and safety of tofacitinib dose de‐escalation and dose escalation for patients with ulcerative colitis: results from OCTAVE Open

“…As a small molecule, tofacitinib is not expected to elicit the neutralising anti‐drug antibodies seen with biologic therapies, which can occur with or without dose de‐escalation, but are more likely to occur with lower drug exposure as a complication of dose de‐escalation . Secondary loss of response with biologic therapies may occur in patients treated with tumour necrosis factor inhibitor therapies, with loss of response often related to the formation of such neutralising anti‐drug antibodies .…”

Efficacy of JAK inhibitors in Ulcerative Colitis

“… 4 , 26 Interestingly, the dose and exposure [plasma concentrations] of tofacitinib were both linked to the observed outcomes. 44 Patients who do not respond to the induction phase [8 weeks] of tofacitinib may benefit from an extended induction period [another 8 weeks]. However, the rates of adverse events are also observed to be dose-dependent, 45 precluding the widespread use of higher doses of tofacitinib and extended induction periods.…”

Clinical Pharmacology of Janus Kinase Inhibitors in Inflammatory Bowel Disease

“… 35 , 36 Tofacitinib has a linear and dose-proportional pharmacokinetic [PK] profile with a functional half-life of ~3 h in healthy subjects 35 and patients with UC. 26 Tofacitinib clearance is mediated by hepatic cytochrome P450 [CYP]-mediated metabolism [65%]. 35 Primary and secondary hepatic metabolism occurs through CYP3A4 and CYP2C19, respectively, and results in fewer than 10% circulating metabolites.…”

“…A population PK analysis of tofacitinib IR was conducted in patients with UC and administered 0.5, 3, 10, or 15 mg of tofacitinib BID for 8 weeks, in a dose-ranging phase 2 trial. 26 The pharmacokinetic profile of tofacitinib was described by a one-compartment model with first-order absorption and elimination. Oral clearance, oral volume of distribution [V/F], and first order absorption rate constant [Ka] population parameters were estimated to be 22.4 ± 0.95 L.h -1 , 94.2 ± 2.35 L, and 2.83 ± 0.46 h -1 (mean ± standard error [SD]), respectively, with an absorption lag time of 0.16 h. Estimated interpatient variability [%CV] was 31.4% for CL/F and 87.5% for Ka.…”

“…The PK profile of TD-1473 was also investigated in patients with moderate- to- severe active UC who received QD doses ranging from 20 to 270 mg. 70 Plasma exposure was low [C trough ranged from 0.20 to 1.074 nM with ascending doses], specifically when compared with systemic tofacitinib exposure measured in patients with UC who received BID doses ranging from 0.5 to 15 mg [C trough ranged from 0 to 20 ng/mL or 0 to 64 nM]. 26 Colonic tissue concentrations of TD-1473 were expectedly higher than plasma [range from 10 to 160 nM with ascending doses] and were in the necessary range for JAK inhibition [IC 50 = 32–158 nM for TD-1473-induced JAK1/JAK3 inhibition]. 68 …”