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Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity within the human genome's set of protein kinases. Currently approved formulations for tofacitinib citrate are immediate-release (IR) tablets, modified-release (MR) tablets, and IR solution. A once daily MR microsphere formulation was developed for use in pediatric patients. Demonstration of bioequivalence (BE) between the 10 mg once daily (q.d.) MR microsphere formulation and 5 mg twice daily (b.i.d.) IR solution is needed to enable the exposure-response analyses-based bridging to support regulatory approval. To assess BE between MR microsphere and IR solution, an innovative approach was utilized with physiologically-based pharmacokinetic (PBPK) virtual BE trials (VBE) in lieu of a clinical BE trial. A PBPK model was developed to characterize the absorption of different formulations of tofacitinib using Simcyp ADAM module. VBE trials were conducted by simulating PK profiles using the verified PBPK model and integrating the clinically observed intrasubject coefficient of variation (ICV) where BE was assessed with a predetermined sample size and prespecified criteria. The VBE trials demonstrated BE between IR solution 5 mg b.i.d. and MR microsphere 10 mg q.d. after a single dose on day 1 and after multiple doses on day 5. This research presents an innovative approach that incorporates clinically observed ICV in PBPK model-based VBE trials, which could reduce unnecessary drug exposure to healthy volunteers and streamline new formulation development strategies., (© 2024 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: In the realm of autoimmune rheumatic diseases, understanding JAK inhibitors (JAKi) nuances is vital. Baricitinib, tofacitinib, upaacitinib, filgotinib, and peficitinib exhibit subtle yet impactful pharmacokinetic (PK) and pharmacodynamic (PD) variations., Areas Covered: This narrative review critically assesses PK and PD distinctions among globally approved JAKi for rheumatoid arthritis, which primarily guide clinical decisions in autoimmune diseases, particularly rheumatoid arthritis. It explores the intricate JAK-STAT signaling pathway, offering insights into JAKs' roles in inflammation, hematopoiesis, and immune homeostasis. Emphasis on PK parameters, including absorption, distribution, metabolism, and excretion, along with CYP3A4 drug interactions, is highlighted. The review underscores integrating PK and PD properties, considering patient-specific factors like hepatic and renal clearance, for judicious JAKi selection in RA and related autoimmune conditions. The literature has been collected from all available databases based on the review question., Expert Opinion: Integrating PK and PD properties with patient-specific factors is pivotal for judicious JAKi selection. Recognizing disparities in PK and PD across diseases, ethnicities, and environmental factors is crucial for personalized JAKi choices. This expert opinion underscores the significance of a second compartment analysis, elucidating the interplay between PK and PD and its impact on JAKi efficacy.

Upadacitinib, a selective Janus kinase inhibitor, is the first orally administered therapy approved for the treatment of Crohn's disease (CD). This work characterized the pharmacokinetics of upadacitinib in CD patients and evaluated the relationships between upadacitinib steady-state plasma exposures and efficacy as well as safety parameters during the 12-week induction and the 52-week maintenance periods, to provide dosing recommendations for the treatment of CD. Upadacitinib pharmacokinetics in CD patients administered the extended-release formulation were consistent with patient populations in other approved indications. None of the evaluated CD-specific patient characteristics (e.g., disease location and prior gastrointestinal surgeries) had a meaningful impact on upadacitinib pharmacokinetics. Exposure-response analyses during 12-week induction treatment showed that response across all evaluated efficacy end points were approaching a plateau at median plasma exposures associated with 45 mg QD. Analyses for the maintenance period demonstrated that 30 mg QD is predicted to provide an additional 8% to 10% benefit for endoscopic response and endoscopic remission compared with 15 mg QD in patients who failed biologics. The analyses for safety showed a statistically significant relationship between increasing upadacitinib plasma exposures and the percentage of patients experiencing >2 g/dL decrease in hemoglobin from Baseline during induction and showed shallow relationships for serious infections and herpes zoster during the maintenance period. These results demonstrated adequate absorption of the extended-release formulation of upadacitinib in CD patients. The exposure-response analyses confirmed that 45 mg QD dose maximized efficacy as induction treatment and supported the selection of 15 mg QD or 30 mg QD as the maintenance doses., (© 2024 AbbVie Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Janus kinases (JAK) are enzymes involved in signaling pathways that activate the immune system. Upadacitinib, an oral small molecule, is the first JAK inhibitor approved by FDA and EMA for the treatment of moderately to severely active Crohn's disease (CD), following successful phase II and III trials. Compared to other JAK inhibitors, upadacitinib has a high selectivity toward JAK1. This characteristic could improve its efficacy and safety., Areas Covered: This review provides an overview of the available knowledge on the pharmacokinetics of upadacitinib as induction and maintenance therapy for CD., Expert Opinion: The approval of newer targeted small molecules drug, including JAK inhibitors, marked a significant advancement in terms of effectiveness. In fact, the oral administration, the rapid absorption, the excellent bioavailability and the short serum time of maximum concentration are some of the advantages compared to biologics. The selective inhibition of JAK1 by upadacitinib allows for high efficacy while maintaining a reliable safety profile.

Background: Janus kinase inhibitors are antirheumatic immunosuppressive drugs that target intracellular Janus kinases (JAKs). Baricitinib is a selective and reversible orally administered JAK1/JAK2 inhibitor approved for treating rheumatoid arthritis, atopic dermatitis, and alopecia areata in adult patients. Expanded access to baricitinib has been approved for treating pediatric patients affected by rare Mendelian autoinflammatory diseases with type I interferon-mediated damage. Knowledge of the pharmacokinetic properties and target plasma levels of baricitinib in pediatric patients is limited. In this study, a novel LC-MS/MS method for measuring baricitinib in plasma, validated according to the ICH M10 guidelines, is presented., Methods: Sample preparation was performed by adding 10 µL of IS working solution (150 ng/mL) and 200 µL of MeOH to each plasma sample. Chromatographic separation was conducted using a Thermo Scientific Accucore Polar Premium column (50 mm × 2.1 mm, i.d. 2.6 m). This method was applied to 7 real anonymous plasma samples obtained from pediatric patients treated with baricitinib at IRCCS Istituto Giannina Gaslini (Genoa, Italy). Patients of both sexes had a median age of 14 years (range, 10-17 years)., Results: The LC-MS/MS method resulted linear over wide concentration ranges (1.024-100 ng/mL) and was accurate and reproducible in the absence of matrix effects, allowing for robust, specific, and rapid quantification of baricitinib from a low amount of plasma (50 µL). The plasma concentration of baricitinib in the samples of the patients, expressed as mean ± SD, was 11.25 ± 10.86 ng/mL., Conclusions: This novel LC-MS/MS method is suitable for the therapeutic drug monitoring of baricitinib and can help guide therapy optimization in pediatric patients., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Background: Golidocitinib is an orally available, potent and highly selective JAK (Janus kinase)-1 inhibitor of JAK/STAT3 signaling under clinical development for the treatment of cancer and autoimmune diseases. The objectives of the two reported studies were to investigate the pharmacokinetics (PK), safety, and tolerability of golidocitinib in healthy Chinese participants as compared to those healthy Western participants, as well as the food effect exploration., Methods: Two phase I studies (JACKPOT2 and JACKPOT3) were conducted in USA and China, respectively. In JACKPOT2 study, participants were randomized into placebo or golidocitinib arm in single-ascending dose cohorts (5 - 150 mg) and multiple-ascending dose cohorts (25 - 100 mg, once daily) for 14 days. In the food effect cohort, golidocitinib (50 mg) was administrated shortly after a high-fat meal (fed conditions) as compared to under fasting conditions. In JACKPOT3 study conducted in China, participants were randomized to placebo or golidocitinib arm in single-ascending dose cohorts (25 - 150 mg)., Results: Exposure of golidocitinib generally increased in a dose-proportional manner across a dose range of 5 mg to 150 mg (single dose) and 25 mg to 100 mg (once daily). High-fat food did not alter the PK of golidocitinib with statistical significance. Low plasma clearance and extensive volume of distribution characterizes PK of golidoctinib, and long half-life across the dose levels supported once daily dosing. The inter-ethnic difference in primary PK parameters was evaluated. The result suggested slightly higher peak plasma concentrations (C max ) but comparable area under the plasma concentration-time curve (AUC) was observed in Asian (Chinese) subjects as compared to Caucasian and/or Black subjects, while it was not considered clinically relevant. Golidocitinib was well tolerated without Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher drug-related treatment emergent adverse events (TEAE) reported., Conclusion: No noticeable inter-ethnic difference was observed among Asian, Black, and Caucasian healthy subjects in anticipation of the favorable PK properties of golidocitinib. The effect of food on the bioavailability of golidocitinib was minor following a single oral administration of 50 mg. These data guided to use the same dose and regimen for multinational clinical development., Clinical Trial Registrations: https://clinicaltrials.gov/ct2/show/NCT03728023?term=NCT03728023&draw=2&rank=1, identifier (NCT03728023); http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier (CTR20191011)., Competing Interests: KC, ZY, YZ, ZL, XD and DL were employed by Dizal Pharmaceuticals. The authors declare that the studies (JACKPOT2 and JACKPOT3) received funding from Dizal Pharmaceuticals. The funder had the following involvement in the studies: the study design, interpretation of data, manuscript draft and review for both JACKPOT2 and JACKPOT3 studies., (Copyright © 2023 Chen, Guan, Yang, Zhou, Liu, Deng, Liu, Hu and Chen.)

Janus kinase 1 (JAK1) is a potential target for the treatment of rheumatoid arthritis (RA). In this study, the introduction of a spiro ring with a difluoro-substituted cyclopropionamide resulted in the identification of TUL01101 (compound 36 ) based on a triazolo[1,5- a ]pyridine core of filgotinib. It showed excellent potency on JAK1 with an IC 50 value of 3 nM and exhibited more than 12-fold selectivity for JAK2 and TYK2. Whole blood assay also demonstrated the high activity and selectivity (37-fold for JAK2). At the same time, TUL01101 also demonstrated excellent metabolic stability and pharmacokinetics (PK) profiles were assayed in three species (mouse, rat, and dog). Moreover, it has been validated for effective activity in the treatment of RA both in collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models, with low dose and low toxicity. Now, TUL01101 has progressed into phase I clinical trials.

Abrocitinib is an oral once-daily Janus kinase 1 selective inhibitor being developed for the treatment of moderate-to-severe atopic dermatitis. This study examined the disposition of abrocitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite (M) profiles. The results indicated abrocitinib had a systemic clearance of 64.2 L/h, a steady-state volume of distribution of 100 L, extent of absorption >90%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 60%. The half-life of both abrocitinib and total radioactivity was similar, with no indication of metabolite accumulation. Abrocitinib was the main circulating drug species in plasma (∼26%), with 3 major monohydroxylated metabolites (M1, M2, and M4) at >10%. Oxidative metabolism was the primary route of elimination for abrocitinib, with the greatest disposition of radioactivity shown in the urine (∼85%). In vitro phenotyping indicated abrocitinib cytochrome P450 fraction of metabolism assignments of 0.53 for CYP2C19, 0.30 for CYP2C9, 0.11 for CYP3A4, and ∼0.06 for CYP2B6. The principal systemic metabolites M1, M2, and M4 were primarily cleared renally. Abrocitinib, M1, and M2 showed pharmacology with similar Janus kinase 1 selectivity, whereas M4 was inactive. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of abrocitinib, a Janus kinase inhibitor for atopic dermatitis, in humans, as well as characterization of clearance pathways and pharmacokinetics of abrocitinib and its metabolites., (Copyright © 2022 by The Author(s).)

Abrocitinib, an oral once-daily Janus kinase 1 selective inhibitor, is under development for the treatment of atopic dermatitis. This phase 1, nonrandomized, open-label, single-dose study (NCT03660241) investigated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of abrocitinib and its metabolites following a 200-mg oral dose. Twenty-three subjects with varying degrees of renal function (normal, moderate, and severe impairment) were enrolled. Active moiety exposures were calculated as the sum of unbound exposures for abrocitinib and its active metabolites. For abrocitinib, the adjusted geometric mean ratios (GMRs; %) for area under the concentration-time curve from time 0 extrapolated to infinite time and maximum plasma concentration were 182.91 (90% confidence interval [CI], 117.09-285.71) and 138.49 (90% CI, 93.74-204.61), respectively, for subjects with moderate renal impairment vs normal renal function; corresponding GMRs were 121.32 (90% CI, 68.32-215.41) and 99.11 (90% CI, 57.30-171.43) for subjects with severe impairment vs normal renal function. Metabolite exposures generally increased in subjects with renal impairment. The GMRs of unbound area under the concentration-time curve from time 0 extrapolated to infinite time and maximum plasma concentration of active moiety were 210.20 (90% CI, 154.60-285.80) and 133.87 (90% CI, 102.45-174.92), respectively, for subjects with moderate renal impairment vs normal renal function. Corresponding values were 290.68 (90% CI, 217.39-388.69) and 129.49 (90% CI, 92.86-180.57) for subjects with severe renal impairment vs normal renal function. Abrocitinib was generally safe and well tolerated. Both moderate and severe renal impairment led to higher exposure to abrocitinib active moiety, suggesting that abrocitinib dose should be reduced by half for patients with moderate or severe renal impairment. ClinicalTrials.gov identifier: NCT03660241., (© 2021 Pfizer Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO. We found that specific substituents at the quinazoline 2-position prevented AO metabolism and this was rationalized through computational docking studies in the AO binding site, but they compromised kinome selectivity. Results presented here highlight that AO metabolism is a potential issue in the lung.

Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT-PsA program in two global phase III studies, which evaluated upadacitinib 15 and 30 mg q.d. The analyses described here characterized upadacitinib pharmacokinetics and exposure-response relationships for efficacy and safety endpoints using data from the SELECT-PsA studies. Upadacitinib pharmacokinetics in patients with PsA were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in patients with RA. Exposure-response relationships for key efficacy and safety endpoints were characterized using data from 1916 patients with PsA. The percentage of patients achieving efficacy endpoints at week 12 (American College of Rheumatology [ACR]50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, whereas no clear exposure-response trend was observed for ACR20 at week 12 or ACR20/50/70 at week 24 within the range of plasma exposures evaluated in the phase III PsA studies. No clear trends for exposure-response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin less than 8 g/dl, lymphopenia (grade ≥ 3), or neutropenia (grade ≥ 3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease greater than 2 g/dl from baseline at week 24. Based on exposure-response analyses, the upadacitinib 15 mg q.d. regimen is predicted to achieve robust efficacy in patients with PsA and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections., (© 2021 AbbVie Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Abrocitinib (Cibinqo ® ) is an oral small-molecule inhibitor of Janus kinase 1 (JAK1) being developed by Pfizer for the treatment of moderate-to-severe atopic dermatitis (AD). In September 2021, abrocitinib was approved in the UK and Japan for the treatment of moderate-to-severe AD in adults and adolescents 12 years and older who are candidates for systemic therapy. Abrocitinib has also received a positive CHMP opinion in the EU for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy. Regulatory applications for the drug have also been submitted for review to several other countries, including the USA and Australia. This article summarizes the milestones in the development of abrocitinib leading to this first approval for the treatment of moderate-to-severe AD., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Upadacitinib, a novel selective Janus kinase 1 (JAK1) inhibitor, has been recently approved by the US FDA for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantitative analysis of upadacitinib in beagle dog plasma was developed and validated., Methods: Upadacitinib and fedratinib (internal standard, IS) were extracted with ethyl acetate under alkaline condition and then separated and detected. The chromatographic column was Waters Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm), the mobile phase was acetonitrile and 0.1% formic acid in water with gradient elution procedure, and the flow rate was 0.40 mL/min. Under the positive ion mode, upadacitinib and IS were monitored by multiple reaction monitoring (MRM) as the following mass transition pairs: m/z 447.00 → 361.94 for upadacitinib and m/z 529.82 → 141.01 for IS., Results: In the concentration range of 1-500 ng/mL, upadacitinib had good linearity, and the lower limit of quantification (LLOQ) was 1 ng/mL. The RSD of the intra- and inter-day precision was less than 10.03%, and the RE of accuracy was -3.79% to 2.58%. The extraction recovery of upadacitinib was more than 80%, the matrix effect was around 100%, and upadacitinib was found to be stable., Conclusion: The novel optimized UPLC-MS/MS assay was an effective tool for the determination of upadacitinib and had been successfully applied to the pharmacokinetic study of upadacitinib in beagle dogs, and this method would also be used to study DDIs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Wang et al.)

Abrocitinib, an oral once-daily Janus kinase 1 selective inhibitor, is under development for treatment of atopic dermatitis. This phase 1, nonrandomized, open-label, single-dose study (NCT03626415) investigated the effect of hepatic impairment on pharmacokinetics (PK), safety, and tolerability of abrocitinib and its metabolites after a 200-mg oral dose. Twenty-four subjects with varying degrees of hepatic function (normal, mild, and moderate impairment) were enrolled (N = 8/group). Active moiety PK parameters were calculated as the sum of unbound PK parameters for abrocitinib and its active metabolites. For abrocitinib, the ratios (percentages) of adjusted geometric means for area under the concentration-time curve from time 0 extrapolated to infinite time (AUC inf ) and maximum plasma concentration (C max ) were 133.33 (90% confidence interval [CI], 86.17-206.28) and 94.40 (90%CI, 62.96-141.55), respectively, for subjects with mild hepatic impairment vs normal hepatic function. The corresponding comparisons of ratios (percentages) for AUC inf and C max were 153.99 (90%CI, 99.52-238.25) and 105.53 (90%CI, 70.38-158.24), respectively, for subjects with moderate hepatic impairment. Exposures of the metabolites were generally lower in subjects with hepatic impairment. For abrocitinib active moiety, the ratios (percentages) of adjusted geometric means of unbound AUC inf were 95.74 (90%CI, 72.71-126.08) and 114.82 (90%CI, 87.19-151.20) in subjects with mild and moderate impairment vs normal hepatic function, respectively. Abrocitinib was generally safe and well tolerated. Hepatic impairment had no clinically relevant effect on the PK and safety of abrocitinib and the exposure of abrocitinib active moiety. These results support the use of abrocitinib without dose adjustment in subjects with mild or moderate hepatic impairment., (© 2021 Pfizer Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma., Objective: We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (Feno), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma., Methods: We conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and Feno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in Feno from baseline to day 14. Baseline was defined as the average Feno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed., Results: Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean Feno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in Feno was -23% (95% CI, -37.3 to -9) for 15 mg QD and -42% (95% CI, -57 to -27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater Feno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition., Conclusions: GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in Feno in mild asthma and was well tolerated without evidence of systemic toxicity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Traditionally, cutaneous drug delivery is studied by skin accumulation or skin permeation, while alternative techniques may enable the interactions between the drug and the skin to be studied in more detail. Time-resolved skin profiling for pharmacokinetic monitoring of two Janus Kinase (JAK) inhibitors, tofacitinib and LEO 37319A, was performed using dermal open-flow microperfusion (dOFM) for sampling of perfusate in an ex vivo and in vivo setup in pig skin. Additionally, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) was performed to investigate depth-resolved skin distributions at defined time points ex vivo in human skin. By dOFM, higher skin concentrations were observed for tofacitinib compared to LEO 37319A, which was supported by the lower molecular weight, higher solubility, lipophilicity, and degree of protein binding. Using MALDI-MSI, the two compounds were observed to show different skin distributions, which was interpreted to be caused by the difference in the ability of the two molecules to interact with the skin compartments. In conclusion, the techniques assessed time- and depth-resolved skin concentrations and were able to show differences in the pharmacokinetic profiles of two JAK inhibitors. Thus, evidence shows that the two techniques can be used as complementary methods to support decision making in drug development.

Itacitinib is a potent, selective JAK-1 inhibitor currently in development for the treatment of chronic graft-vs-host-disease in combination with corticosteroids. Itacitinib is primarily eliminated via cytochrome P450 3A metabolism with minimal renal elimination. The purpose of this open-label study was to investigate the effect of hepatic impairment, as determined by Child-Pugh grade, on itacitinib pharmacokinetics. All participants received a single 300-mg dose of itacitinib orally in the fasted state. Blood samples were collected serially through 96 hours after dosing; 4 hours after dosing, an additional sample was collected for protein binding determination. Participants with moderate hepatic impairment (N = 8) had an approximate 2.5-fold increase in total exposure (area under the plasma concentration-time curve from time 0 to infinity [AUC 0-∞ ]) and an approximate 2-fold increase in maximal exposure (C max ) compared to those with normal hepatic function (N = 8) (geometric mean ratio, 2.51 [90% confidence interval (CI), 1.54-4.08] for AUC 0-∞ and 1.95 [90%CI, 1.14-3.35] for C max ). Participants with severe hepatic impairment (N = 6) had an approximate 4-fold increase in total exposure (AUC 0-∞ ) and an approximate 3.5-fold increase in maximal exposure compared to participants with normal hepatic function (geometric mean ratio, 4.08 [90%CI, 2.41-6.89] for AUC 0-∞ and 3.48 [90%CI, 1.94-6.23] for C max ). Protein binding was similar between participants with moderate or severe hepatic impairment and participants with normal hepatic function, with average unbound fractions (percent free) of 25.7%, 31.5%, and 25.6%, respectively. There were no serious or fatal treatment-related adverse events. The results of this study combined with exposure, efficacy, and safety data from the pivotal study in the relevant patient population will inform final dosing recommendations., (© 2021, The American College of Clinical Pharmacology.)

Background: Pathogenesis of atopic dermatitis (AD) involves the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. A cream formulation of ruxolitinib, a potent selective JAK1/JAK2 inhibitor, was developed for topical delivery., Method: Pharmacokinetic data were obtained from three double-blind, vehicle-controlled studies in patients with AD: a phase II study with ruxolitinib cream 0.15%, 0.5%, or 1.5% once daily or 1.5% twice daily (BID), and two phase III studies with 0.75% or 1.5% BID. Effects of baseline characteristics on pharmacokinetics were examined. Correlations were attempted between plasma concentrations and change in hematological parameters over time., Results: Ruxolitinib plasma concentrations at steady-state (C ss ) increased with cream strength in a less-than-dose-proportional manner. In the phase III studies, overall mean (standard deviation [SD]) C ss after ruxolitinib cream 0.75% and 1.5% BID (23.8 [35.0] and 35.7 [55.0] nM) were a fraction of the half-maximal inhibitory concentration for thrombopoietin-stimulated phosphorylated STAT3 inhibition (281 nM), a JAK/STAT signaling marker. Three covariates were identified for C ss : dose, percent body surface area (%BSA) treated, and baseline Investigator's Global Assessment score. Mean (SD) bioavailability of ruxolitinib cream 1.5% BID was 6.22% (7.66%). There were no correlations between C ss and any hematological changes except for a transient increase in platelets at week 2., Conclusions: Plasma ruxolitinib concentrations after treatment with topical ruxolitinib cream in patients with up to 20% BSA affected by AD are not expected to lead to systemic plasma concentrations that may be associated with adverse effects commonly associated with oral JAK inhibitors. CLINICALTRIALS.GOV: NCT03011892; NCT03745638; NCT03745651.

The purpose of this study was to evaluate the bioequivalence of a generic immediate-release tofacitinib tablet versus a brand-named immediate-release tofacitinib tablet under fasting and fed conditions, and the food effect on pharmacokinetic profiles of the both formulations. This randomized, open-label, 2-period, crossover, bioequivalence study included 52 healthy Chinese subjects (fasting cohort: n = 26; fed cohort: n = 26). The subjects were assigned to receive a single 5-mg dose of generic or brand-named tofacitinib. Blood samples were collected at predosing and up to 14 hours after dosing. Tofacitinib concentrations in plasma were analyzed by high-performance liquid chromatography-tandem mass spectrometry. Safety was monitored. There were no significant differences in maximum plasma concentration, area under the plasma concentration-time curve from time zero to time t (AUC 0-t ), AUC from time zero to infinity (AUC 0-∞ ) , and terminal elimination half-life between the test and reference formulations (all P > .05); high-fat food had no significant effect on AUC 0-t , AUC 0-∞, or terminal elimination half-life of immediate-release tofacitinib tablets (all P > .05). The 90% confidence intervals of the test/reference ratios of log-transformed maximum plasma concentration, AUC 0-t , and AUC 0-∞ were within the range of 80% to 125% under both fasting and fed conditions. No serious adverse events were reported. The 2 formulations of immediate-release tofacitinib tablets are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese volunteers. Food had no clinically relevant effects on drug exposure of tofacitinib., (© 2020, The American College of Clinical Pharmacology.)

This phase 1 study characterized the effect of multiple doses of upadacitinib, an oral Janus kinase 1 selective inhibitor, on the pharmacokinetics of the cytochrome P450 (CYP) 2B6 substrate bupropion. Healthy subjects (n = 22) received a single oral dose of bupropion 150 mg alone (study period 1) and on day 12 of a 16-day regimen of upadacitinib 30 mg once daily (study period 2). Serial blood samples for measurement of bupropion and hydroxybupropion plasma concentrations were collected in each study period. The central values (90% confidence intervals) for the ratios of change were 0.87 (0.79-0.96) for bupropion maximum plasma concentration (C max ), 0.92 (0.87-0.98) for bupropion area under the plasma-concentration time curve from time 0 to infinity (AUC inf ), 0.78 (0.72-0.85) for hydroxybupropion C max , and 0.72 (0.67-0.78) for hydroxybupropion AUC inf when administered with, relative to when administered without, upadacitinib. After multiple-dose administration of upadacitinib 30 mg once daily, upadacitinib mean ± SD AUC 0-24 was 641 ± 177 ng·h/mL, and C max was 83.3 ± 30.7 ng/mL. These results confirm that upadacitinib has no relevant effect on pharmacokinetics of substrates metabolized by CYP2B6., (© 2020 AbbVie Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We characterized tofacitinib pharmacokinetics in patients with moderate to severe UC, and the effects of covariates on variability in pharmacokinetic parameter estimates. Data were pooled from 1 8-week phase 2 and 2 8-week phase 3 induction studies, and a 52-week phase 3 maintenance study (N = 1096). Population pharmacokinetic analysis was conducted using nonlinear mixed-effects modeling. Potential predictors of apparent oral clearance (CL/F) and volume of distribution (V/F) were evaluated. The PK was described by a 1-compartment model parameterized in terms of CL/F (26.3 L/hour [h]) and V/F (115.8 L), with first-order absorption (K a ; 9.85 h -1 ) and lag time (0.236 h). The derived elimination half-life was approximately 3.05 h. In the final model, baseline creatinine clearance, sex, and race (Asian vs non-Asian) were significant covariates for CL/F; significant covariates for V/F were age, sex, and body weight; baseline albumin and baseline Mayo score were not significant covariates. CL/F between-patient variability was estimated at 22%. Tofacitinib exposure did not change significantly over the duration of induction/maintenance treatment in patients with UC. Although statistically significant covariate effects on CL/F and V/F were observed, the magnitude of the effects are not clinically significant. Therefore, dose adjustment/restrictions for age, body weight, sex, race, or baseline disease severity are not required during tofacitinib treatment. ClinicalTrials.gov numbers: NCT00787202, NCT01465763, NCT01458951, NCT01458574., (© 2021 Pfizer Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open-label, randomized, 2-way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150-mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect). Bioequivalence was compared with the developmental 150-mg tablet. Samples for pharmacokinetic analysis were collected before dose and ≤72 hours after dose. Safety assessments included adverse events, vital signs, and laboratory variables. In total, 40 and 18 subjects were randomized to the bioequivalence and food effect studies, respectively. The 2 peficitinib formulations were bioequivalent (90% confidence intervals of the geometric mean ratios for C max and AUC t of peficitinib were within predefined limits of 0.8 to 1.25). The AUC last and the C max of the marketed tablet were 36.8% and 56.4% higher, respectively, under fed versus fasted conditions. Peficitinib was well tolerated. The marketed 150-mg tablet formulation of peficitinib was bioequivalent to the developmental 150-mg formulation, with no discernible safety differences. Bioavailability increased under fed conditions with the marketed tablet formulation., (© 2020 Astellas Pharma Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

The use of Janus kinase (JAK) inhibitors is a new approach in the therapy of inflammatory diseases with immune base. Tofacitinib is one of these inhibitors targeting JAK1 and JAK3, and its efficacy has been demonstrated in the treatment of moderate to severe ulcerative colitis (UC). It is a small synthetic molecule administered orally, with a fast bioavailability and elimination rate, predictable pharmacokinetics and lack of immunogenicity, which are convenient characteristics for both efficacy and safety. This article reviews the pharmacological characteristics of tofacitinib and its safety profile., (Copyright © 2020 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, contribute to the destruction of insulin-secreting β cells by CD8 + T cells in type 1 diabetes (T1D). We previously showed that JAK1/JAK2 inhibitors reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own does not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain cytokines, including IL-2, IL-7 IL-15, and IL-21, may also affect the progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We used a JAK1-selective inhibitor, ABT 317, to better understand the specific role of JAK1 signaling in autoimmune diabetes. ABT 317 reduced IL-21, IL-2, IL-15 and IL-7 signaling in T cells and IFN-γ signaling in β cells, but ABT 317 did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, ABT 317 reduced CD8 + T cell proliferation as well as the number of KLRG + effector and CD44 hi CD62L lo effector memory CD8 + T cells in spleen. ABT 317 also prevented MHC class I upregulation on β cells. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with ABT 317 while still on treatment at 40 days and 44% remained normoglycemic after a further 60 days from discontinuing the drug. Our results indicate that ABT 317 blocks common γ chain cytokines in lymphocytes and interferons in lymphocytes and β cells and are thus more effective against diabetes pathogenesis than IFN-γ receptor deficiency alone. Our studies suggest use of this class of drug for the treatment of type 1 diabetes., Competing Interests: At the time of the study, AL and LO were both employees of Abbvie. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Ge, Jhala, Fynch, Akazawa, Litwak, Pappas, Catterall, Vakil, Long, Olson, Krishnamurthy, Kay and Thomas.)

Background and Aims: Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473-an oral gut-selective pan-JAK inhibitor-from in vitro characterization through a Phase 1b study in patients with UC., Methods: TD-1473 JAK inhibition potency was evaluated in vitro; plasma pharmacokinetics, safety and efficacy were assessed in mice. In a first-time-in-human study, plasma pharmacokinetics and safety were assessed after single and multiple [14 days] ascending doses administered orally to healthy subjects. The Phase 1b study randomized patients with moderately to severely active UC to receive once-daily oral TD-1473 20, 80 or 270 mg, or placebo for 28 days. Plasma and colonic tissue concentrations were measured; safety was assessed; and efficacy was evaluated by UC clinical parameters, disease-surrogate biomarkers, endoscopy, histology and colonic tissue JAK signalling., Results: TD-1473 exhibited potent pan-JAK inhibitory activity in vitro. Oral TD-1473 administration to mice achieved high, biologically active colonic tissue concentrations with low plasma exposure and decreased oxazolone-induced colitis activity without reducing blood cell counts vs placebo. TD-1473 administration in healthy human subjects and patients with UC yielded low plasma exposure and was generally well tolerated; treatment in patients with UC resulted in biologically active colonic tissue concentrations and descriptive trends toward reduced clinical, endoscopic and histological disease activity vs placebo., Conclusion: Gut-selective pan-JAK inhibition with TD-1473 administration resulted in high intestinal vs plasma drug exposure, local target engagement, and trends toward reduced UC disease activity. [Clinicaltrials.gov NCT02657122, NCT02818686]., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Introduction: Inflammatory bowel diseases (IBDs) are immune-mediated chronic inflammatory disorders of the gastrointestinal tract whose pathogenesis is not yet fully understood. Despite the advent of biological agents, there are still unmet needs for IBD patients, due to suboptimal rate of sustained remission achieved. Small molecule drugs (SMDs), the next generation of selective drugs in IBD, show promising results in ongoing trials., Areas Covered: We describe the pharmacodynamics and pharmacokinetic features of novel SMDs and their main differences with biologic agents., Expert Opinion: Small molecule drugs are a promising class of drugs for the treatment of ulcerative colitis and Crohn's disease with good results in inducing and maintaining remission. Hence, over the next few years physicians will have numerous options of small molecule drugs for the treatment of patients with IBD. This group of drugs are potentially easier to use over biological agents due to pharmacokinetic features such as oral administration, short half-life, high volume of distribution, and lack of immunogenicity. On the other hand, drug-drug interactions can happen with small-molecule drugs, principally due to competitive metabolic and clearance mechanisms.

Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non-RA subjects (n = 24) in an open-label, parallel-group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma-concentration-time curve from time 0 to infinity (AUC inf ) and maximum observed concentration (C max ) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUC inf and C max , were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment-emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment., (© 2019 Astellas Pharma Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a membrane-to-nucleus signaling cascade that effects activation of gene transcription. JAK inhibitors have demonstrated effectiveness in autoimmune diseases such as rheumatoid arthritis. An increased risk of infection, mainly varicella-zoster reactivation, with these new agents is of concern. Comorbid conditions, along with pharmacokinetic variations in drug metabolism in the older population, further increase the risk of adverse outcomes. Newly raised concerns for potential adverse effects such as deep vein thrombosis and pulmonary embolism are essential considerations for clinicians. Older patients are at increased risk because of multiple comorbid conditions and pharmacokinetic changes related to drug metabolism and excretion. Both the US FDA and the European Medicines Agency have issued warnings regarding this risk. These warnings highlight individuals aged > 50 years with concomitant cardiovascular risk factors. Furthermore, the FDA released a black box warning for increased thromboembolic risk associated with JAK inhibitors. As the use of these drugs increases, a solid understanding of adverse effects and risks is critical to those treating older adults.

Background & Aims: We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD)., Methods: We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo; or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily; or 24 mg upadacitinib once daily and were evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using the multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%., Results: Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo. Endoscopic remission was achieved by 10% (P < .1 vs placebo), 8%, 8% (P < .1 vs placebo), 22% (P < .01 vs placebo), and 14% (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections vs placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol levels compared with patients in the placebo group., Conclusions: In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients compared with placebo. Upadacitinib's benefit/risk profile supports further development for treatment of CD. (Clinicaltrials.gov, Number: NCT02365649)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: We evaluated the efficacy and safety of upadacitinib, an oral selective inhibitor of Janus kinase 1, as induction therapy for ulcerative colitis (UC)., Methods: We performed a multicenter, double-blind, phase 2b study of 250 adults with moderately to severely active UC and an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressive agents, and/or biologic therapies. Patients were randomly assigned to groups that received placebo or induction therapy with upadacitinib (7.5 mg, 15 mg, 30 mg, or 45 mg, extended release), once daily for 8 weeks. The primary endpoint was the proportion of participants who achieve clinical remission according to the adapted Mayo score at week 8. No multiplicity adjustments were applied., Results: At week 8, 8.5%, 14.3%, 13.5%, and 19.6% of patients receiving 7.5 mg, 15 mg, 30 mg, or 45 mg upadacitinib, respectively, achieved clinical remission compared with none of the patients receiving placebo (P = .052, P = .013, P = .011, and P = .002 compared with placebo, respectively). Endoscopic improvement at week 8, defined as endoscopic subscore of ≤ 1, was achieved in 14.9%, 30.6%, 26.9%, and 35.7% of patients receiving upadacitinib 7.5 mg, 15 mg, 30 mg, or 45 mg, respectively, compared with 2.2% receiving placebo (P = .033, P < .001, P < .001, and P < .001 compared with placebo, respectively). One event of herpes zoster and 1 participant with pulmonary embolism and deep venous thrombosis (diagnosed 26 days after treatment discontinuation) were reported in the group that received upadacitinib 45 mg once daily. Increases in serum lipid levels and creatine phosphokinase with upadacitinib were observed., Conclusion: In a phase 2b trial, 8 weeks of treatment with upadacitinib was more effective than placebo for inducing remission in patients with moderately to severely active UC. (ClinicalTrials.gov, Number: NCT02819635)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Upadacitinib is a Janus kinase 1 inhibitor developed for treatment of moderate to severe rheumatoid arthritis (RA) and was recently approved by the US Food and Drug Administration for this indication in adults who have had an inadequate response or intolerance to methotrexate. Upadacitinib is currently under regulatory review by other agencies around the world. Ongoing trials are investigating the use of upadacitinib in other inflammatory autoimmune diseases. In this article, we review the clinical pharmacokinetic data available to date for upadacitinib that supported the clinical development program in RA and ultimately regulatory applications for upadacitinib in treatment of patients with moderate to severe RA.

Purpose: To determine if a validated Level A in-vitro in-vivo correlation (IVIVC) could be achieved with the extrudable core system (ECS) osmotic tablet platform. Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis., Methods: Fast-, medium-, and slow-release modified-release formulations of 11 mg tofacitinib ECS tablets, and one formulation of 22 mg tofacitinib ECS tablet, were manufactured. In vitro dissolution of the tofacitinib ECS tablets was performed using USP Apparatus 2 (paddles) and in vivo pharmacokinetic (PK) data were obtained from a Phase 1 study in healthy volunteers. A 5 mg immediate-release formulation tablet was included to support deconvolution of the tofacitinib ECS PK tablet data to obtain the in vivo absorption profiles. A linear, piecewise correlation and a simple linear correlation were used to build and validate two IVIVC models., Results: The prediction errors (PEs) for the linear, piecewise correlation met the Food and Drug Administration's criteria for establishing a Level A IVIVC, with a maximum absolute individual internal PE of 4.6%, a maximum absolute average internal PE of 3.9%, and a maximum absolute external PE of 8.4% obtained., Conclusions: This study demonstrates that the tofacitinib ECS osmotic tablet platform can achieve a Level A IVIVC, similar to other osmotic delivery systems., Competing Interests: Declaration of Competing Interest Christine Alvey, Thomas Stock, and Manisha Lamba were employees of Pfizer Inc at the time the study was conducted. The remaining authors are current employees and shareholders of Pfizer Inc., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Previous studies showed the potential effectiveness of delgocitinib ointment, a novel topical Janus kinase inhibitor, in atopic dermatitis (AD)., Objective: This study aimed to evaluate the efficacy and safety of delgocitinib 0.5% ointment., Methods: In part 1, a 4-week double-blind period, Japanese patients aged 16 years or older with moderate or severe AD were randomly assigned in a 2:1 ratio to delgocitinib 0.5% ointment or vehicle ointment. Eligible patients entered part 2, a 24-week extension period, to receive delgocitinib 0.5% ointment., Results: At the end of treatment in part 1, the least-squares mean percent changes from baseline in the modified Eczema Area and Severity Index score, the primary efficacy endpoint, were significantly greater in the delgocitinib group than in the vehicle group (-44.3% vs 1.7%, P < .001). The improvement in modified Eczema Area and Severity Index score was maintained in part 2. Most adverse events were mild and unrelated to delgocitinib across the study periods., Limitations: Only Japanese patients were included. The vehicle-controlled period lasted only 4 weeks. In part 2, topical corticosteroids were allowed for the treatment of worsening of AD., Conclusion: Delgocitinib ointment was effective and well tolerated in Japanese adult patients with moderate to severe AD for up to 28 weeks., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Upadacitinib (ABT-494) is a selective Janus kinase (JAK)1 inhibitor being developed for treatment of several inflammatory disorders. A population pharmacokinetic model was developed for upadacitinib using 11,658 plasma concentrations from 1145 subjects from 4 phase 1 and 5 phase 2 studies in healthy subjects and subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, or atopic dermatitis. A 2-compartment model with first-order absorption and lag time for the immediate-release formulation and mixed zero- and first-order absorption with lag time for the extended-release formulation, and linear elimination adequately described upadacitinib plasma concentration-time profiles. The oral bioavailability of upadacitinib extended-release formulation was estimated to be approximately 80% relative to the immediate-release formulation. Covariates included in the final model were creatinine clearance, subject population (healthy subjects vs subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease vs subjects with rheumatoid arthritis) and sex on apparent oral clearance and sex and body weight on apparent volume of distribution of the central compartment. Female subjects had 21% higher upadacitinib steady-state area under the plasma concentration-time curve (AUC) compared to male subjects. Compared to healthy subjects, subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease had 21% higher upadacitinib steady-state AUC, while subjects with rheumatoid arthritis had 35% higher steady-state AUC. Subjects with mild or moderate renal impairment were estimated to have 10% or 22% higher AUC, respectively, compared to subjects with normal renal function. Based on final model parameter estimates, effects of the tested covariates are not expected to result in clinically relevant changes in upadacitinib steady-state exposures., (© 2019, The American College of Clinical Pharmacology.)

Baricitinib, is a selective and reversible Janus kinase inhibitor, is commonly used to treat adult patients with moderately to severely active rheumatoid arthritis (RA). A fast, reproducible and sensitive method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the quantification of baricitinib in rat plasma has been developed. Irbersartan was used as the internal standard (IS). Baracitinib and IS were extracted from plasma by liquid-liquid extraction using a mixture of n-hexane and dichloromethane (1:1) as extracting agent. Chromatographic separation was performed using Acquity UPLC HILIC BEH 1.7 µm 2.1 × 50 mm column with the mobile phase consisting of 0.1% formic acid in acetonitrile and 20 mM ammonium acetate (pH 3) (97:3). The electrospray ionization in the positive-mode was used for sample ionization in the multiple reaction monitoring mode. Baricitinib and the IS were quantified using precursor-to-production transitions of m / z 372.15 > 251.24 and 429.69 > 207.35 for baricitinib and IS, respectively. The method was validated according to the recent FDA and EMA guidelines for bioanalytical method validation. The lower limit of quantification was 0.2 ng/mL, whereas the intra-day and inter-day accuracies of quality control (QCs) samples were ranged between 85.31% to 89.97% and 87.50% to 88.33%, respectively. Linearity, recovery, precision, and stability parameters were found to be within the acceptable range. The method was applied successfully applied in pilot pharmacokinetic studies.

To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.

Background: Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic skin lesions., Objective: We sought to evaluate the safety and efficacy of multiple doses of the selective Janus kinase 1 inhibitor upadacitinib in patients with moderate to severe atopic dermatitis., Methods: In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion of this 88-week trial in 8 countries (ClinicalTrials.gov, NCT02925117; ongoing, not recruiting), adults with moderate to severe disease and inadequate control by topical treatment were randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary end point was percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all randomized patients who received study medication, based on actual treatment., Results: Patients (N = 167) enrolled from November 21, 2016, to April 20, 2017. All were randomized and analyzed for efficacy (each upadacitinib group, n = 42; placebo, n = 41); 166 were analyzed for safety (each upadacitinib group, n = 42; placebo, n = 40). The mean (SE) primary efficacy end point was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P = .03, <.001, and <.001). Serious adverse events occurred in 4.8% (2 of 42), 2.4% (1 of 42), and 0% (0 of 42) of upadacitinib groups (vs 2.5% [1 of 40] for placebo)., Conclusions: A dose-response relationship was observed for upadacitinib efficacy; the 30-mg once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Upadacitinib plasma concentrations, efficacy, and safety data from 216 subjects with moderate-to-severe active Crohn's disease (CD) from the 16-week induction period of the CELEST study were analyzed to characterize upadacitinib exposure-response relationships in CD. Subjects in CELEST received either placebo or upadacitinib (3, 6, 12, 24 mg b.i.d. or 24 mg q.d.). Exposure-response models were developed and utilized to simulate efficacy of induction doses of the immediate-release (IR) and extended-release (ER) formulations. Upadacitinib exposures associated with 18-24 mg b.i.d. (IR formulation) or 45-60 mg q.d. (ER formulation) are estimated to have greater efficacy during 12-week induction in patients with CD compared with lower doses. No exposure-response relations were observed with decreases in hemoglobin or lymphocytes at week 16 or with herpes zoster infections, pneumonia, or serious infections during 16 weeks of treatment in this study. These analyses informed the selection of upadacitinib induction dose for phase III studies in CD., (© 2019 AbbVie Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background and Objective: This study measured and compared the exposure and safety of peficitinib (ASP015K), a novel oral Janus kinase inhibitor, in subjects with normal and impaired renal function after a single oral, clinically relevant peficitinib dose., Methods: This was an open-label, parallel-group study conducted at two centres in Japan. Subjects with normal and mildly, moderately, or severely impaired renal function received a single oral dose of peficitinib (one 150 mg tablet) under fasting conditions in a hospital setting. Blood samples were collected prior to administration and up to 72 h post-dose for pharmacokinetic assessment. Safety was assessed up to 7 days post-dose., Results: Peficitinib plasma concentration-time profiles were similar between those with normal and impaired renal function. In subjects with impaired renal function, area under the plasma concentration-time curve and maximum concentration were 0.8- to 1.1-fold those in subjects with no impairment. Two subjects (one in the normal group and one in the mildly impaired group) each experienced a treatment-emergent adverse event (TEAE). There were no serious TEAEs, deaths or TEAEs leading to treatment withdrawal., Conclusions: Peficitinib exposure and TEAEs were similar in subjects with and without renal impairment after a single oral 150 mg dose. Based on these findings, it is not expected that peficitinib dose adjustment will be required in clinical practice, according to the degree of renal impairment. CLINICALTRIALS., Gov Identifier: NCT02603497.

Purpose: To assess the capability of in vivo positron emission tomography (PET) using 18 F-fluorodeoxyglucose ( 18 F-FDG) to quantify changes in inflammatory activity in response to tofacitinib, a Janus kinase (JAK) inhibitor, over a timeframe of a few hours to few days in a preclinical model of rheumatoid arthritis (RA)., Methods: Twenty-four mice with collagen-induced arthritis in the following groups were assessed: Group 1, where the changes in PET measures for the extremity joints were evaluated at the peak and trough plasma drug levels after administration of a single dose of tofacitinib (4 hours apart); Group 2, where joint PET measures were assessed before treatment and after 6 days of administration of a daily dose of tofacitinib; and group 3 (controls), where joint PET measures were derived from the same mice, 6 days apart., Results: At about peak plasma levels of the drug after a single tofacitinib administration, there was a reduction in PET measures compared to pretreatment values, suggesting decreased inflammatory activity. These measures were equivalent to those obtained after 6 days of daily dosing by tofacitinib. However, PET measures at trough plasma levels of the drug from tofacitinib administration were significantly higher than those at peak plasma drug levels and equivalent to pretreatment measures. There were insignificant changes in PET measures for the control animals., Conclusion: 18 F-FDG PET can detect changes in inflammatory activity occurring in response to the JAK inhibitor tofacitinib: (a) during peak and trough plasma drug levels, that is within mere hours of treatment; and (b) over a span of days., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

The relationships between upadacitinib, an oral selective Janus kinase 1 inhibitor, plasma exposures, and its efficacy (assessed by the American College of Rheumatology 20%/50%/70% responses over time) in moderate-to-severe active rheumatoid arthritis (RA) were characterized using data from 574 patients, on background methotrexate and inadequate response to methotrexate or anti-TNF therapy, from two phase II trials conducted with twice-daily dosing of an immediate-release formulation. The developed time-continuous Markov models were used to simulate efficacy of once-daily (q.d.). regimens of upadacitinib extended-release incorporating sources of uncertainty. Upadacitinib plasma concentrations associated with 15 and 30 mg extended-release q.d. doses were predicted to achieve that plateau of response across RA subpopulations. Results from these analyses provided the rationale that supported selection and de-risked evaluation of upadacitinib extended-release doses for the first time in >4,000 patients in five large phase III trials., (© 2019 AbbVie Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: A highly potent pan-Janus kinase (JAK) inhibitor with excellent kinome selectivity was developed for topical delivery to treat severe asthma. This poorly soluble drug discovery candidate, iJAK-001, is expected to exhibit long duration of JAK/STAT pathway inhibition at low doses in asthmatics because of depot effect after dry powder inhalation. Human dose projection for inhaled molecules with low aqueous solubility remains to be a daunting challenge because of several limitations: (1) bioanalytical measurement of dissolved fraction after inhalation of solid particles is uncertain; (2) distribution of these particles is not homogenous in the lung; (3) in vitro solubility measurements to estimate fraction dissolved may not be a reflection of local surface lung concentration; (4) lack of a surrogate biomarker of lung target engagement, and (5) invasive procedure needed to sample human lung tissue in the clinic. Methods: We leveraged in silico , in vitro , and in vivo tools preclinically and found significant differences in lung to plasma partition ratio when iJAK-001 was given intravenously (IV) or intratracheally in a solution-based formulation versus that in suspension, as well as pharmacodynamic response in preclinical asthma models when delivered systemically via IV infusion versus inhaled. Results and Conclusion: The combined results from above suggest that caution must be exercised using either lung or plasma exposure for human dose projection. Instead, using the local inhibitor concentration estimate based on delivery efficiency, dose, fraction absorbed, and rate of absorption normalized by lung (cardiac) blood flow may be more appropriate for dose projection.

Background: ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways., Objectives: The objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. Methods A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28-day period (20 mg, 40 mg and 80 mg once daily)., Results: ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg -1·3 ± 2·1, P = 0·81; 40 mg -3·1 ± 2·7, P = 0·27; 80 mg -4·7 ± 2·1, P = 0·01; placebo -1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE., Conclusions: In patients with moderate-to-severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation., (© 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The past decade has witnessed an explosion in trial data on JAK inhibitors (JAKi). These small molecules target the Janus kinase - signal transducer and activator of transcription (JAK-STAT) pathway, blocking crucial cytokines across a septum of rheumatic diseases. As a class, JAKi are beginning to demonstrate efficacy on par, if not superior to biologics. Two first generation JAKi are licensed for use in inflammatory arthritis; tofacitinib and baricitinib. Next-generation JAKi have been designed with selective affinity for one JAK enzymes, the aim to reduce unwanted adverse effects without declining clinical efficacy. Emerging data with selective JAK1 inhibitors upadacitinib and filgotinib looks very promising. Despite differences in selectivity between JAKi, an overlap exists in their safety profiles. Across the class, a characteristic safety signal is emerging with viral opportunistic infections, particularly herpes zoster. Post marketing drug surveillance will be essential in evaluating the long-term risk with these agents., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Upadacitinib is a selective Janus kinase 1 inhibitor being developed for the treatment of several inflammatory autoimmune diseases, including rheumatoid arthritis. Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A enzymes. This open-label, single-dose, multicenter study assessed the pharmacokinetics of upadacitinib following oral administration of a single 15-mg dose of the upadacitinib extended-release formulation in subjects with mild (n = 6) and moderate (n = 6) hepatic impairment relative to demographically matched healthy subjects (n = 6). Subjects were assigned to 1 of the 3 groups according to the Child-Pugh classification. Relative to subjects with normal hepatic function, the ratios (90% confidence intervals) of upadacitinib area under the plasma concentration-versus-time profile from time 0 to infinity (AUC inf ) for subjects with mild and moderate hepatic impairment were 1.28 (0.91-1.79) and 1.24 (0.87-1.76), respectively. The central ratios of upadacitinib maximum observed concentration (C max ) were 1.04 (0.77-1.39) and 1.43 (1.05-1.95) in subjects with mild and moderate hepatic impairment, respectively, compared with subjects with normal hepatic function. No clinically significant changes in vital signs or hematology measurements were observed, and no new safety events were identified in this study. These results indicate that mild and moderate hepatic impairment has no clinically relevant effect on upadacitinib pharmacokinetics., (© 2019 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Background and Objectives: Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed as an orally administered treatment for patients with moderate to severe rheumatoid arthritis (RA) and other autoimmune disorders. These analyses characterized the population pharmacokinetics of upadacitinib across phase I-III clinical trials using data for immediate-release (IR) and extended-release (ER) formulations., Methods: Pharmacokinetic data from 4170 subjects taking IR doses of 1-48 mg and ER doses of 7.5-30 mg across 12 studies spanning phase I-III clinical trials, with a total of 29,372 upadacitinib plasma concentrations, were analyzed using non-linear mixed-effects modeling. The model was evaluated using bootstrap analyses and visual predictive checks., Results: A two-compartment model with first-order absorption with lag time for the IR formulation, mixed zero- and first-order absorption with lag time for the ER formulation, and linear elimination, adequately described upadacitinib plasma concentration-time profiles. Population estimates of upadacitinib apparent oral clearance and steady-state volume of distribution in healthy volunteers for the ER formulation were 53.7 L/h and 294 L, respectively. The relative bioavailability of the ER formulation compared with the IR formulation was estimated to be 76.2%. Statistically significant covariates were patient population (RA subjects vs. healthy subjects), creatinine clearance, and baseline bodyweight on apparent clearance (CL/F) and bodyweight on volume of distribution of the central compartment (Vc/F). The intersubject variability for upadacitinib CL/F and Vc/F were estimated to be 21% and 24%, respectively, in the phase I studies, and 37% and 53%, respectively, in the phase II/III studies. Upadacitinib area under the concentration-time curve (AUC) was estimated to be only 5% higher or lower for RA patients who were < 60 or > 100 kg, respectively, relative to subjects with a bodyweight of 60-100 kg. RA subjects with mild or moderate renal impairment had 13% and 26% higher AUC, respectively, compared with RA subjects with normal renal function. Sex, race, concomitant use of pH-modifying drugs, moderate cytochrome P450 3A inhibitors, or methotrexate use had no effect on upadacitinib exposure., Conclusions: A robust population pharmacokinetic model was developed for upadacitinib using a large dataset from phase I-III clinical trials in healthy volunteers and subjects with RA. None of the identified covariates had a clinically meaningful effect on upadacitinib exposures. The model is appropriate to use for simulations and to evaluate the exposure-response relationship of upadacitinib.

The Janus kinase (JAK) family of tyrosine kinases has been proven to provide targeted immune modulation. Orally available JAK inhibitors have been used for the treatment of immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). Here, we report the design, synthesis and biological evaluation of 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl) pyrimidin-2-amino derivatives as JAK inhibitors. Systematic structure-activity relationship studies led to the discovery of compound 7j, which strongly inhibited the four isoforms of JAK kinases. Molecular modeling rationalized the importance of cyanoacetyl and phenylmorpholine moieties. The in vivo investigation indicated that compound 7j possessed favorable pharmacokinetic properties and displayed slightly better anti-inflammatory efficacy than tofacitinib at the same dosage. Accordingly, compound 7j was advanced into preclinical development., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Upadacitinib is a novel selective Janus kinase 1 inhibitor developed for treatment of rheumatoid arthritis and other autoimmune diseases. The objective of this study was to assess the pharmacokinetics and safety of a single upadacitinib dose in subjects with normal renal function and in subjects with renal impairment. A total of 24 subjects between the ages of 18 and 75 years were assigned to 1 of 4 renal function groups based on estimated glomerular filtration rate (normal, mild, moderate, severe; N = 6/group). A single 15-mg dose of upadacitinib extended-release formulation was administered under fasting conditions. Serial plasma and urine samples were assayed to evaluate the effect of renal impairment on upadacitinib exposure through regression analysis and analysis of covariance. The primary analysis was the regression analysis of upadacitinib exposures versus estimated glomerular filtration rate. The point estimates for upadacitinib plasma exposure ratios (90% confidence interval [CI]) in subjects with mild, moderate, and severe renal impairment were 1.18 (90%CI, 1.06-1.32), 1.33 (90%CI, 1.11-1.59), and 1.44 (90%CI, 1.14-1.82) for area under the plasma concentration-time curve and 1.06 (90%CI, 0.92-1.23), 1.11 (90%CI, 0.88-1.40), and 1.14 (90%CI, 0.84-1.56) for maximum observed plasma concentration, respectively, relative to subjects with normal renal function based on the regression analysis. The analysis of covariance categorical analysis provided consistent results. Upadacitinib was well tolerated by all subjects, and no safety issues were identified in subjects with renal impairment. Renal impairment has a limited effect on upadacitinib pharmacokinetics. This is in agreement with the known limited role of urinary excretion in upadacitinib elimination. Based on the limited impact on exposure, no dose adjustment is necessary for upadacitinib in subjects with impaired renal function., (© 2019, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Background: Synovial fibroblasts (SF) play a major role in the pathogenesis of rheumatoid arthritis (RA) and develop an aggressive phenotype destroying cartilage and bone, thus termed RASF. JAK inhibitors have shown to be an efficient therapeutic option in RA treatment, but less is known about the effect of JAK inhibitors on activated RASF. The aim of the study was to examine the effects of JAK inhibitors on activated RASF. Methods: Synovium of RA patients was obtained during knee replacement surgeries. Synoviocytes were isolated and pretreated with JAK inhibitors. Pro-inflammatory cytokines and matrix degrading proteinases were measured by ELISA in supernatant after stimulation with oncostatin M or IL-1β. The proliferation of RASF was measured by BrdU incorporation. Cell culture inserts were used to evaluate cell migration. For adhesion assays, RASF were seeded in culture plates. Then, plates were extensively shaken and adherent RASF quantified. Cell viability, cytotoxicity and apoptosis were measured using the ApoTox-Glo™ Triplex and the CellTox™ Green Cytotoxicity Assay. Results: Tofacitinib and baricitinib decreased the IL-6 release of RASF stimulated with oncostatin M. JAK inhibition attenuated the IL-6 release of IL-1β activated and with soluble IL-6 receptor treated RASF. In contrast, only peficitinib and filgotinib decreased the IL-6 release of RASF activated with IL-1β. Peficitinib decreased also the MMP-3, CXCL8, and CXCL1 release at 5 μM. Moreover, peficitinib was the only JAK inhibitor suppressing proliferation of activated RASF at 1 μM. Peficitinib further decreased the migration of RASF without being cytotoxic or pro-apoptotic and without altering cell adhesion. Conclusions: JAK inhibitors effectively suppress the inflammatory response induced by oncostatin M and by transsignaling of IL-6 in RASF. Only peficitinib modulated the IL-1β-induced response of RASF and their proliferation in vitro at concentrations close to reported Cmax values of well tolerated doses in vivo . In contrast to filgotinib, peficitinib also highly suppressed RASF migration showing the potential of peficitinib to target RASF.