Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug Exposure and Support Dosing Recommendations for Potential Drug-Drug Interactions or in Special Populations: An Example Using Tofacitinib.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. It is eliminated via multiple pathways including oxidative metabolism (∼70%) and renal excretion (29%). This study aimed to predict the impact of drug-drug interactions and renal or hepatic impairment on tofacitinib pharmacokinetics using a physiologically based pharmacokinetic (PBPK) model. The model was developed using Simcyp based on the physicochemical properties and in vitro and in vivo pharmacokinetics data for tofacitinib. The model was verified by comparing the predicted pharmacokinetic profiles with those observed in available clinical studies after single or multiple doses of tofacitinib, as well as with tofacitinib as a victim of drug-drug interactions (because of inhibition of cytochrome P450 [CYP450] 3A4, CYP450 2C19, or CYP450 induction). In general, good agreement was observed between Simcyp predictions and clinical data. The results from this study provide confidence in using the PBPK modeling and simulation approach to predict the pharmacokinetics of tofacitinib under intrinsic (eg, renal or hepatic impairment) or extrinsic (eg, inhibition of CYP450 enzymes and/or renal transporters) conditions. This approach may also be useful in predicting pharmacokinetics under untested or complex situations (eg, when a combination of intrinsic and extrinsic factors may impact pharmacokinetics) when conducting clinical studies may be difficult, in response to health authority questions regarding dosing in special populations, or for labeling discussions.

Model-Based Comparison of Dose-Response Profiles of Tofacitinib in Japanese Versus Western Rheumatoid Arthritis Patients.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this analysis was to characterize the relationship between tofacitinib dose and efficacy, as measured by American College of Rheumatology (ACR) response rates, and to compare this between Japanese and Western patients with RA. Efficacy data were pooled from 2 double-blind, dose-ranging phase 2 studies of tofacitinib monotherapy 1-15 mg twice daily in patients with RA with an inadequate response to disease-modifying antirheumatic drugs (DMARDs). NCT00550446 was carried out in mostly Western patients and NCT00687193 in Japanese patients. ACR20, ACR50, and ACR70 response rates in week 12 were analyzed using maximum drug effect (Emax ) models on the logit domain. Both studies showed a dose-response for each end point, supporting the efficacy of tofacitinib in patients with inadequate response to DMARDs. Study-specific differences in Emax were noted, whereas potency (dose providing half the maximum effect [ED50 ]) was similar across studies. After adjustment for study differences in Emax by calculating the fractions of the maximum placebo-adjusted proportion of ACR responses, the estimated locations for the 5- and 10-mg twice-daily doses on the dose-response curves were similar for the 2 patient populations: ACR20, ACR50, andACR70 mean fractional responses for 5 and 10 mg twice daily were 0.78, 0.43, 0.32 and 0.90, 0.69, and 0.56, respectively, for the Japanese study and 0.54, 0.41, and 0.22 and 0.73, 0.61, and 0.40, respectively, for the Western study. This analysis therefore supports the rationale for the same dosing regimen in Japanese patients as in Western patients from an efficacy perspective.

Phase 1 Dose-Escalation Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Tofacitinib in Japanese Healthy Volunteers.

The aim of the study was to characterize the pharmacokinetics, safety, and tolerability of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis in healthy Japanese volunteers, and to compare these outcomes with those of healthy Western volunteers. Twenty-five volunteers (Japanese, n = 16; Western [white], n = 9) were randomized to receive either 3 escalating single doses of tofacitinib (1, 5, and 30 mg), single-dose tofacitinib (15 mg) followed by multiple doses (15 mg twice daily for 5 days), or placebo. No significant differences in systemic exposure to tofacitinib were detected between the 2 ethnicities. Following single tofacitinib 1, 5, and 30 mg doses, mean area under the plasma concentration-time curve from time zero to infinity ratio (Japanese/Western) values were 96.6%, 93.5%, and 95.6%, respectively. Similarly, mean maximum observed plasma concentration ratio values were 99.5%, 118%, and 119%, respectively. Mean renal clearance was also similar, ranging across doses from 134 mL/min (5 mg) to 162 mL/min (1 mg) in Japanese volunteers, and 124 mL/min (30 mg) to 160 mL/min (1 mg) in Western volunteers. In both ethnicities, most adverse events were mild. No serious adverse events or deaths were reported. The pharmacokinetics of tofacitinib were well characterized in healthy Japanese volunteers and were similar to those in Western volunteers.

Toward Progress in Quantitative Translational Medicine: A Call to Action.

Quantitative translational medicine (QTM) is envisioned as a multifaceted discipline that will galvanize the path from idea to medicine through quantitative translation across the discovery, development, regulatory, and utilization spectrum. Here, we summarize results of an American Society for Clinical Pharmacology and Therapeutics (ASCPT) survey on barriers relevant to the advancement of QTM and propose opportunities for its deployment. Importantly, we offer a call to action to break down these barriers through patient-centered stewardship, effective communication, cross-sector collaboration, and a modernized educational curriculum.

Evaluation of the Short-, Mid-, and Long-Term Effects of Tofacitinib on Lymphocytes in Patients With Rheumatoid Arthritis.

OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Altered lymphocyte cell counts and a potential association with increased infection rates have been reported in RA patients treated with JAK inhibitors. This analysis was undertaken to evaluate the short-, mid-, and long-term effects of tofacitinib on lymphocytes and infection rates in patients with RA. METHODS: In this post hoc analysis, absolute lymphocyte counts (ALCs) were obtained from phase III studies (12-24 months; n = 717-958) and phase I/II/III/long-term extension studies of tofacitinib (≤117 months) (All RA population; n = 7,061); lymphocyte subset counts (LSCs) were from phase II studies (1.5-6 months' exposure; n = 236-486), an ORAL Sequel vaccine substudy (~22 months; n = 198), and an ORAL Sequel lymphocyte substudy (~50 months; n = 55-1,035) of tofacitinib. The reversibility of ALC/LSC changes was evaluated. The relationship of ALC and LSC to infections was analyzed in the All RA population. The value of monitoring ALC alone was assessed by examining correlations between ALCs and LSCs. RESULTS: Tofacitinib treatment resulted in an initial increase in ALC versus pretreatment baseline, which gradually declined to steady state by ~48 months. CD4+ and CD8+ T cell counts decreased over long-term treatment, and ALC and LSC changes were reversible upon treatment cessation. Patients with ALCs of <500 cells/mm3 had an increased risk of serious infections. There was no strong association between CD4+ T cell, CD8+ T cell, B cell, or natural killer cell counts and serious infection incidence rates. ALC and CD4+ or CD8+ T cell counts correlated well (R = 0.65-0.86). CONCLUSION: Our findings indicate that monitoring of ALC alone appears to be adequate to assess infection risk in tofacitinib-treated patients with RA.

Pharmacokinetic Characteristics of Tofacitinib in Adult Patients With Moderate to Severe Chronic Plaque Psoriasis.

Tofacitinib is an oral Janus kinase (JAK) inhibitor. This study characterized the pharmacokinetics of tofacitinib in patients with psoriasis and evaluated the impact of patient factors on disposition. Pooled phase 2/3 data (2981 patients: 9735 concentrations, dose range: 2-15 mg twice daily) up to 56 weeks were used for modeling. A one-compartment model parameterized in terms of apparent oral clearance (CL/F), apparent volume of distribution, zero-order absorption (duration, D), with interindividual variability and inter-occasion variability terms, described tofacitinib pharmacokinetics. A full covariate model incorporated effects for age, sex, race, ethnicity, and baseline variables (body weight, Psoriasis Area Severity Index [PASI], C-reactive protein [CRP], creatinine clearance [CrCl]). The parameter estimates (95%CI) for CL/F, Vd/F, and D in a typical individual (white, male, 86 kg, 46 years, CrCl 121 mL/min, PASI 19.8, and CRP 0.267 mg/dL) were 26.7 (25.9, 27.5) L/h, 125 (120.8, 128.3) liters, and 0.69 (0.646, 0.735) hours, respectively. Only CrCl led to clinically relevant changes in exposure. The analysis suggested no dosing modifications for age, body weight, sex, race, ethnicity, baseline PASI, or CRP based on the magnitude of exposure change. Dosing adjustments for renal impairment were derived from a separate phase 1 study.

Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and a leading cause of childhood disability. The objective of this study was to characterize the PK, safety, and taste acceptability of tofacitinib in patients with JIA. METHODS: This Phase 1, open-label, multiple-dose (twice daily [BID] for 5 days) study of tofacitinib in patients with active (≥ 5 joints) polyarticular course JIA was conducted from March 2013-December 2015. Patients were allocated to one of three age-based cohorts: Cohort 1, 12 to < 18 years; Cohort 2, 6 to < 12 years; and Cohort 3, 2 to < 6 years. Tofacitinib was administered according to age and body weight as tablets or oral solution (grape flavor). PK were assessed on Day 5; safety was assessed at screening, Day 1, and Day 5. Taste acceptability of the oral solution was evaluated. RESULTS: Twenty-six patients (age range 2-17 years) were enrolled: Cohort 1, N = 8; Cohort 2, N = 9; Cohort 3, N = 9; median tofacitinib doses were 5.0, 2.5, and 3.0 mg BID, respectively. The higher median tofacitinib dose in Cohort 3 versus Cohort 2 reflected implementation of an amended dosing scheme following an interim PK analysis after Cohort 2 recruitment. Geometric mean AUC at steady state (AUCtau) was 156.6 ng•h/mL in Cohort 1, 118.8 ng•h/mL in Cohort 2, and 142.5 ng•h/mL in Cohort 3; Cmax (ng/mL) was 47.0, 41.7, and 66.2, respectively. Ctrough, Cmin, and t1/2 were similar in Cohorts 2 and 3, but higher in Cohort 1. Median time to Cmax (Tmax) was similar between cohorts. Apparent clearance and volume of distribution decreased with decreasing age. Tofacitinib was well tolerated, with no serious adverse events or discontinuations due to adverse events reported. Taste acceptability was confirmed. CONCLUSIONS: PK findings from this study in children with polyarticular course JIA established dosing regimens and acceptable taste for use in subsequent studies within the tofacitinib pediatric development program. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01513902 .

Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. METHODS: ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than -13·0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. FINDINGS: 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI -6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (-6 [-14 to 3]) or tofacitinib and methotrexate (-8 [-16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. INTERPRETATION: Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. FUNDING: Pfizer Inc.

Brief Report: Remission Rates With Tofacitinib Treatment in Rheumatoid Arthritis: A Comparison of Various Remission Criteria.

OBJECTIVE: Tofacitinib is an oral JAK inhibitor that is used for the treatment of rheumatoid arthritis (RA). In previous clinical trials of tofacitinib, a Disease Activity Score in 28 joints (DAS28)-based analysis was used to assess outcomes. In this study, remission rates according to various remission criteria were evaluated across 5 phase III randomized controlled studies. METHODS: In all 5 studies, tofacitinib was administered at a dosage of 5 mg twice daily or 10 mg twice daily, either as monotherapy or with background methotrexate or other conventional synthetic disease-modifying antirheumatic drugs. One of the studies included adalimumab 40 mg once every 2 weeks. In addition to the 4-variable DAS28 using the erythrocyte sedimentation rate (DAS28-4[ESR]), a primary efficacy variable used in the phase III studies, disease activity was assessed post hoc by the 4-variable DAS28 using the C-reactive protein level (DAS28-4[CRP]), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), and Boolean-based assessment. RESULTS: A total of 3,306 patients were analyzed (1,213 of these patients received tofacitinib 5 mg twice daily, 1,212 received tofacitinib 10 mg twice daily, 679 received placebo, and 202 received adalimumab 40 mg every 2 weeks). Remission rates varied according to the criteria used, with higher rates in the active-treatment groups for the DAS28-4(CRP) than for other scores. At month 3, remission rates with tofacitinib 5 mg twice daily were 18-22% using the DAS28-4(CRP), 5-10% using the DAS28-4(ESR), 4-7% using the SDAI, 5-6% using the CDAI, and 2-7% using the Boolean-based method. In contrast, the remission rates with placebo varied from 0% to 7%, with small differences between the DAS28-4(ESR) and the DAS28-4(CRP). CONCLUSION: Although tofacitinib at dosages of 5 mg twice daily and 10 mg twice daily was effective compared with placebo in achieving disease remission, regardless of the disease activity measure, remission rates were substantially higher when the DAS28-4(CRP) was used. The presence or absence and type of acute-phase reactants in remission criteria were significant contributors to remission rates across treatment groups. This finding has important consequences for trial design and clinical practice.

Use of a risk characterisation approach to contextualise the safety profile of new rheumatoid arthritis treatments: a case study using tofacitinib.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To characterise the relative safety profile of tofacitinib to biologic disease-modifying antirheumatic drugs (bDMARDs), the accrued patient-years (pt-yrs) of exposure needed in an RA clinical trial programme to detect a potential increase in risk of specific adverse events (AEs) was determined. This case study/framework was constructed on the pt-yrs' accrual within pooled phase (P)1, P2 and P3, as well as long-term extension, studies of tofacitinib in RA (March 2015 data-cut) and published AE incidence rates for bDMARDs. Sample size calculations were based on a Poisson distribution to estimate pt-yrs' exposure required for 90 % probability that the lower bound of the 95 % confidence interval for tofacitinib/bDMARD would be >1, assuming that tofacitinib rates were 1.2×/1.5×/2.0× greater than comparator rates. AE rates for bDMARDs were derived from sources intended to optimise similarity with the tofacitinib database in terms of baseline characteristics, study duration and follow-up. Based on the tofacitinib exposure accrued (19,406 pt-yrs), data were sufficient (90 % probability) to detect potential differences over external bDMARD comparator rates in serious infections (≥1.2×), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE) and lymphoma (each ≥1.5×), as well as opportunistic infections and gastrointestinal perforations (≥2×), should they exist. This risk characterisation approach can support the comparative safety of new RA medications. To date, tofacitinib safety appears similar to approved published data from bDMARDs with respect to serious infections, malignancies (excluding NMSC), NMSC, MACE, lymphoma, opportunistic infections and gastrointestinal perforations.

Tofacitinib in Combination With Conventional Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis: Patient-Reported Outcomes From a Phase III Randomized Controlled Trial.

OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared patient-reported outcomes (PROs) in patients with RA treated with tofacitinib or placebo in combination with conventional disease-modifying antirheumatic drugs (DMARDs). METHODS: In a 12-month, phase III randomized controlled trial (ORAL Sync), patients (n = 795) with active RA and previous inadequate response to therapy with ≥1 conventional or biologic DMARD were randomized 4:4:1:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, placebo advanced to 5 mg BID, or placebo to 10 mg BID, in combination with stable background DMARD therapy. PROs included patient global assessment of arthritis (PtGA), patient assessment of arthritis pain (Pain), physical function (Health Assessment Questionnaire disability index [HAQ DI]), health-related quality of life (Short Form 36 health survey [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), and sleep (Medical Outcomes Study Sleep [MOS Sleep]). RESULTS: At month 3, statistically significant improvements from baseline versus placebo were reported in PtGA, Pain, HAQ DI, all 8 SF-36 domains, FACIT-F, and MOS Sleep with tofacitinib 10 mg BID, and in PtGA, Pain, HAQ DI, 7 SF-36 domains, FACIT-F, and MOS Sleep with tofacitinib 5 mg BID. Improvements were sustained to month 12. Significantly more tofacitinib-treated patients reported improvements of greater than or equal to the minimum clinically important differences at month 3 versus placebo in all PROs, except the SF-36 role-emotional domain (significant for tofacitinib 10 mg BID). CONCLUSION: Patients with active RA treated with tofacitinib combined with background conventional DMARD therapy reported sustained, significant, and clinically meaningful improvements in PROs versus placebo.

Tofacitinib versus methotrexate in rheumatoid arthritis: patient-reported outcomes from the randomised phase III ORAL Start trial.

OBJECTIVES: To compare patient-reported outcomes (PROs) in methotrexate (MTX)-naive patients (defined as no prior treatment or ≤3 doses) receiving tofacitinib versus MTX. METHODS: In the 24-month, phase III, randomised, controlled, ORAL Start trial (NCT01039688), patients were randomised 2:2:1 to receive tofacitinib 5 mg two times per day (n=373), tofacitinib 10 mg two times per day (n=397) or MTX (n=186). PROs assessed included Patient Global Assessment of disease (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and health-related quality of life (Short Form-36 [SF-36]). RESULTS: PROs improved following tofacitinib and MTX treatment: benefits were sustained over 24 months. Patients receiving tofacitinib reported earlier responses which were significantly different between each tofacitinib dose and MTX at month 3 through month 24. At month 6 (primary end point), significant improvements versus MTX were observed in PtGA, pain, HAQ-DI, SF-36 Physical Component Summary (PCS), 5/8 domain scores and FACIT-F with tofacitinib 5 mg two times per day; all PROs, except SF-36 Mental Component Summary Score and Medical Outcomes Survey-Sleep, with tofacitinib 10 mg two times per day. At month 6, the proportion of patients reporting improvements ≥minimum clinically important difference were significant versus MTX with tofacitinib 5 mg two times per day in PtGA and 3/8 SF-36 domains; and with tofacitinib 10 mg two times per day in PtGA, pain, HAQ-DI, SF-36 PCS, 4/8 domains and FACIT-F. CONCLUSIONS: Patients with rheumatoid arthritis receiving tofacitinib 5 and 10 mg two times per day monotherapy versus MTX reported statistically significant and clinically meaningful improvements in multiple PROs over 24 months; onset of benefit with tofacitinib treatment occurred earlier. TRIAL REGISTRATION NUMBER: NCT01039688.

Efficacy and safety of tofacitinib in patients with active rheumatoid arthritis: review of key Phase 2 studies.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here, the safety and efficacy data from five Phase 2 studies of tofacitinib in patients with RA are summarized. Tofacitinib 1-30 mg twice daily was investigated, as monotherapy and in combination with methotrexate, in patients with RA. Tofacitinib 20 mg once daily was investigated in one study. Tofacitinib 5 and 10 mg twice daily were selected for investigation in Phase 3 studies; therefore, the efficacy and safety of tofacitinib 5 and 10 mg twice daily in Phase 2 studies are the focus of this review. Tofacitinib ≥ 5 mg twice daily was efficacious in a dose-dependent manner, with statistically significant and clinically meaningful reductions in the signs and symptoms of RA and patient-reported outcomes. The safety profile was consistent across studies. The efficacy and safety profile of tofacitinib in Phase 2 studies supported its further investigation and the selection of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for evaluation in Phase 3 studies.

Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose-response analysis.

PF-04171327 is a dissociated agonist of the glucocorticoid receptor (DAGR) being developed to retain anti-inflammatory efficacy while reducing unwanted effects. Our aim was to conduct a longitudinal dose-response analysis to identify the DAGR doses with efficacy similar to or greater than prednisone 10 mg once daily (QD). The data included were from a Phase 2, randomized, double-blind, parallel-group study in 323 subjects with active rheumatoid arthritis on a background of methotrexate. Subjects received DAGR 1, 5, 10 or 15 mg, prednisone 5 or 10 mg, or placebo QD for 8 weeks. The Disease Activity Score 28-4 calculated using C-Reactive Protein (DAS28-4 CRP) was the efficacy endpoint utilized in this dose-response model. For DAGR, the maximum effect (Emax) on DAS28-4 CRP was estimated to be -1.2 points (95 % CI -1.7, -0.84), and the evaluated dose range provided 31-87 % of the Emax; for prednisone 5 and 10 mg, the estimated effects were -0.27 (95 % CI -0.55, 0.006) and -0.94 point (95 % CI -1.3, -0.59), respectively. Stochastic simulations indicated that the DAGR 1, 5, 10 and 15 mg have probabilities of 0.9, 29, 54 and 62 %, respectively, to achieve efficacy greater than prednisone 10 mg at week 8. DAGR 9 mg estimated probability was 50 % suggesting that DAGR ≥9 mg QD has an effect on DAS28-4 CRP comparable to or greater than prednisone 10 mg QD. This work informs dose selection for late-stage confirmatory trials.

Effects of the oral Janus kinase inhibitor tofacitinib on patient-reported outcomes in patients with active rheumatoid arthritis: results of two Phase 2 randomised controlled trials.

OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of tofacitinib on patient-reported outcomes (PRO) in patients with active RA. METHODS: Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36. RESULTS: In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ­DI (monotherapy study) with tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the tofacitinib groups were observed at Weeks 12 and 24. CONCLUSIONS: In patients with active RA, tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.

Evaluation of the Effect of Tofacitinib on the Pharmacokinetics of Oral Contraceptive Steroids in Healthy Female Volunteers.

Tofacitinib is an oral Janus kinase inhibitor. Tofacitinib metabolism is primarily mediated by cytochrome P450 3A4. This phase 1 randomized, open-label, 2-way crossover study (NCT01137708) evaluated the effect of tofacitinib 30 mg twice daily on the single-dose pharmacokinetics of combination oral contraceptives ethinylestradiol (EE) and levonorgestrel (LN). EE and LN were administered as a single Microgynon 30® tablet (30 µg EE and 150 µg LN) to 19 healthy women. In the presence of tofacitinib, the area under the curve from time zero to infinity (AUC∞ ) increased by 6.6% and 0.9% for EE and LN, respectively. Maximal plasma concentrations decreased by 10.4% for EE and increased by 12.2% for LN when coadministered with tofacitinib. The 90% confidence intervals for the adjusted geometric mean ratios for AUC∞ fell within the 80%-125% region for both EE and LN. Mean half-life was similar in the presence and absence of tofacitinib: 13.8 and 13.3 hours, respectively, for EE; 25.9 and 25.4 hours, respectively, for LN. Tofacitinib had no clinically relevant net inhibitory or inductive effect on the pharmacokinetics of EE and LN. Therefore, there is no evidence to suggest dose adjustments of oral contraceptive drugs containing EE or LN when coadministered with tofacitinib.

The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterised by infiltration of immune cells into the affected synovium, release of inflammatory cytokines and degradative mediators, and subsequent joint damage. Both innate and adaptive arms of the immune response play a role, with activation of immune cells leading to dysregulated expression of inflammatory cytokines. Cytokines work within a complex regulatory network in RA, signalling through different intracellular kinase pathways to modulate recruitment, activation and function of immune cells and other leukocytes. As our understanding of RA has advanced, intracellular signalling pathways such as Janus kinase (JAK) pathways have emerged as key hubs in the cytokine network and, therefore, important as therapeutic targets. Tofacitinib is an oral JAK inhibitor for the treatment of RA. Tofacitinib is a targeted small molecule, and an innovative advance in RA therapy, which modulates cytokines critical to the progression of immune and inflammatory responses. Herein we describe the mechanism of action of tofacitinib and the impact of JAK inhibition on the immune and inflammatory responses in RA.