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The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two-Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers.
Shibata, M, Toyoshima, J, Kaneko, Y, Oda, K, Kiyota, T, Kambayashi, A, Nishimura, T
Clinical pharmacology in drug development. 2021;(3):283-290
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Abstract
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 Cmax and AUCt of peficitinib were within predefined limits of 0.8 to 1.25). The AUClast and the Cmax 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.
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Investigation of Potential Drug-Drug Interactions between Peficitinib (ASP015K) and Methotrexate in Patients with Rheumatoid Arthritis.
Zhu, T, Moy, S, Valluri, U, Cao, Y, Zhang, W, Sawamoto, T, Chindalore, V, Akinlade, B
Clinical drug investigation. 2020;(9):827-838
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Abstract
BACKGROUND Methotrexate is frequently used to treat rheumatoid arthritis. Peficitinib (ASP015K; Smyraf®), an oral Janus kinase inhibitor indicated for the treatment of rheumatoid arthritis, may be coadministered with methotrexate. OBJECTIVE The objective of this study was to investigate potential drug-drug interactions of peficitinib with methotrexate and the short-term safety of coadministration. PATIENTS AND METHODS This phase I, open-label, single-sequence study included patients with rheumatoid arthritis taking a stable dose of methotrexate. Patients received their prescribed methotrexate dose (Day 1) and then peficitinib (100 mg) twice daily from Day 3 until the morning of Day 9; a second methotrexate dose was coadministered with peficitinib on Day 8. Serial blood samples were collected for methotrexate concentration after dosing on Days 1 (methotrexate alone) and 8 (methotrexate plus peficitinib) and for peficitinib concentration after dosing on Days 7 (peficitinib alone) and 8 (methotrexate plus peficitinib). Pre-dose concentrations of peficitinib were measured (Days 3-8). RESULTS Peficitinib concentrations reached steady state on Day 5. Administration of peficitinib did not result in changes to methotrexate area under the concentration-time curve from time zero to infinity or maximum observed concentration following a methotrexate dose (15-25 mg), and there was no significant effect of methotrexate (15-25 mg) on peficitinib area under the concentration-time curve within a 12-hour dosing interval. There were no new tolerability or safety signals after coadministration of peficitinib and methotrexate. One patient experienced two serious adverse events and withdrew from the study without receiving peficitinib. CONCLUSIONS Pharmacokinetic results showed no significant interactions between peficitinib and methotrexate. CLINICALTRIALS. GOV IDENTIFIER NCT01754805.
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Assessing the feasibility of NaF-PET/CT versus FDG-PET/CT to detect abdominal aortic calcification or inflammation in rheumatoid arthritis patients.
Seraj, SM, Raynor, WY, Revheim, ME, Al-Zaghal, A, Zadeh, MZ, Arani, LS, Rojulpote, C, Werner, TJ, Gerke, O, Høilund-Carlsen, PF, et al
Annals of nuclear medicine. 2020;(6):424-431
Abstract
OBJECTIVE We aimed to determine whether NaF-PET/CT or FDG-PET/CT can detect abdominal aortic molecular calcification and inflammation in patients with rheumatoid arthritis (RA). METHODS In this study, 18 RA patients (4 women, 14 men; mean age 56.0 ± 11.7) and 18 healthy controls (4 women, 14 men; mean age 55.8 ± 11.9) were included. The controls were matched to patients by sex and age (± 4 years). All subjects of this study underwent NaF-PET/CT scanning 90 min following the administration of NaF. FDG-PET/CT imaging was performed 180 min following intravenous FDG injection. Using OsiriX software, the global mean standardized uptake value (global SUVmean) in abdominal aorta was calculated for both FDG and NaF. The NaF SUVmean and FDG SUVmean were divided by the blood pool activity providing target-to-background ratios (TBR) namely, NaF-TBRmean and FDG-TBRmean. The CT calcium volume score was obtained using a growing region algorithm based on Hounsfield units. RESULTS The average NaF-TBRmean score among RA patients was significantly greater than that of healthy controls (median 1.61; IQR 1.49-1.88 and median 1.40; IQR 1.23-1.52, P = 0.002). The average CT calcium volume score among RA patients was also significantly greater than that of healthy controls (median 1.96 cm3; IQR 0.57-5.48 and median 0.004 cm3; IQR 0.04-0.05, P < 0.001). There was no significant difference between the average FDG-TBRmean scores in the RA patients when compared to healthy controls (median 1.29; IQR 1.13-1.52 and median 1.29; IQR 1.13-1.52, respectively, P = 0.98). CONCLUSION Quantitative assessment with NaF-PET/CT identifies increased molecular calcification in the wall of the abdominal aorta among patients with RA as compared with healthy controls, while quantitative assessment with FDG-PET/CT did not identify a difference in aortic vessel wall FDG uptake between the RA and healthy control groups.
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Decreased ALKBH5, FTO, and YTHDF2 in Peripheral Blood Are as Risk Factors for Rheumatoid Arthritis.
Luo, Q, Gao, Y, Zhang, L, Rao, J, Guo, Y, Huang, Z, Li, J
BioMed research international. 2020;:5735279
Abstract
ALKBH5 (alkylation repair homolog protein 5), FTO (fat mass and obesity-associated protein), and RNA N6-methyladenosine (m6A) demethylase, are essential for the m6A mRNA modification. YTHDF2 (YT521-B homology domains 2) called m6A "readers" can recognize m6A modification. As the key enzymes of m6A methylation modification, ALKBH5, FTO, and YTHDF2 have been implicated in many diseases. However, little is known about the role of ALKBH5, FTO, and YTHDF2 in rheumatoid arthritis (RA). We measured the mRNA expression of ALKBH5, FTO, and YTHDF2 in RA patients and controls by quantitative real-time polymerase chain reaction, and the global m6A content was detected by an ELISA-like format. The mRNA expression of ALKBH5, FTO, and YTHDF2 in RA patients was further analyzed to investigate its correlations with disease activity. And, multivariate analysis (logistic regression) was used to analyze the risk factors. The mRNA expression of ALKBH5, FTO, and YTHDF2 in RA patients was significantly decreased compared to controls. The mRNA expression of ALKBH5 was significantly increased in RA patients that received regular treatment. The mRNA expression of FTO was associated with disease activity score 28 (DAS28), complement 3 (C3), immunoglobulin G (IgG), and lymphocyte-to-monocyte ratio (LMR), some common markers for RA disease activity. The mRNA expression of YTHDF2 was associated with RBC, L%, N%, NLR, and LMR. Furthermore, logistic regression analysis revealed that decreased expression of ALKBH5, FTO, and YTHDF2 in peripheral blood was a risk factor for RA. Moreover, the peripheral blood global m6A content was significantly increased in patients with RA compared to CON, and increased m6A contents negatively correlated with decreased mRNA expression of FTO. In conclusion, this study firstly demonstrates the critical role of ALKBH5, FTO, and YTHDF2 in RA, which provides novel insights into recognizing the pathogenesis of RA and a promising biomarker for RA.
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Levels of the Novel Endogenous Antagonist of Ghrelin Receptor, Liver-Enriched Antimicrobial Peptide-2, in Patients with Rheumatoid Arthritis.
Francisco, V, Tovar, S, Conde, J, Pino, J, Mera, A, Lago, F, González-Gay, MA, Dieguez, C, Gualillo, O
Nutrients. 2020;(4)
Abstract
Rheumatoid arthritis (RA) is a debilitating, chronic, inflammatory, autoimmune disease associated with cachexia. The substitutive therapy of gut hormone ghrelin has been pointed at as a potential countermeasure for the management of metabolic and inflammatory complications in RA. The recent discovery of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous inverse agonist/antagonist of the ghrelin receptor makes feasible the development of a more rational pharmacological approach. This work aimed to assess the serum LEAP2 levels, in a cohort of RA patients, in comparison with healthy individuals and determine its correlation with inflammatory parameters. LEAP2 levels were determined by a commercial ELISA kit, plasma C-reactive protein (CRP) levels were evaluated using immunoturbidimetry, and serum levels of inflammatory mediators, namely IL-6, IL-8, IL-1β, MIP1α, MCP1, and LCN2, were measured by XMap multiplex assay. LEAP2 serum levels were significantly increased in RA patients (n = 101) compared with control subjects (n = 26). Furthermore, the LEAP2 levels significantly correlated with CRP and inflammatory cytokines, but not with BMI. These data reveal LEAP2 as a new potential RA biomarker and indicated the pharmacological control of LEAP2 levels as a novel approach for the treatment of diseases with alterations on the ghrelin levels, such as rheumatoid cachexia.
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Switch from reference etanercept to SDZ ETN, an etanercept biosimilar, does not impact efficacy, safety, and immunogenicity of etanercept in patients with moderate-to-severe rheumatoid arthritis: 48-week results from the phase III, randomized, double-blind EQUIRA study.
Jaworski, J, Matucci-Cerinic, M, Schulze-Koops, H, Buch, MH, Kucharz, EJ, Allanore, Y, Kavanaugh, A, Young, P, Babic, G
Arthritis research & therapy. 2019;(1):130
Abstract
BACKGROUND Sandoz etanercept (SDZ ETN; GP2015) is an etanercept biosimilar with equivalent efficacy and comparable safety and immunogenicity to reference etanercept (ETN) in patients with moderate-to-severe chronic plaque-type psoriasis. METHODS EQUIRA was a phase III, double-blind study conducted in patients with moderate-to-severe rheumatoid arthritis and inadequate response to disease-modifying anti-rheumatic drugs. Eligible patients were randomized 1:1 to receive subcutaneous 50 mg SDZ ETN or ETN, once-weekly, for 24 weeks. At week 24, patients with at least moderate EULAR response in the SDZ ETN group continued SDZ ETN treatment, and those in the ETN group were switched to receive 50 mg SDZ ETN, for up to 48 weeks. Patients received concomitant methotrexate at a stable dose (10-25 mg/week) and folic acid (≥ 5 mg/week). Equivalence between SDZ ETN and ETN for change from baseline in disease activity score including 28 joint count C-reactive protein (DAS28-CRP) at week 24 (primary endpoint) and comparable safety and immunogenicity profile of SDZ ETN and ETN have previously been demonstrated at week 24. Herein, we present the 48-week results of the study after a single switch from ETN to its biosimilar at week 24. RESULTS The least squares mean (standard error) change in DAS28-CRP from baseline up to week 48 was comparable between "continued SDZ ETN" (- 2.90 [0.12], n = 148) and "switched to SDZ ETN" (- 2.78 [0.13], n = 131) groups. The proportion of patients achieving EULAR good/moderate responses based on DAS28-erythrocyte sedimentation rate and ACR20/50/70 response rates were comparable between the two groups. The proportion of patients with at least one treatment-emergent adverse event was 42.9% in the "continued SDZ ETN" and 38.0% in the "switched to SDZ ETN" groups. Serious adverse events occurred in 4 patients in each of the two groups. After week 24, none of the patients in the switched group developed anti-drug antibodies (ADAs), while 4 patients in the continued SDZ ETN group had single-event, very low titer, non-neutralizing ADAs detected. CONCLUSIONS The 48-week results from the EQUIRA study demonstrate that switch from ETN to SDZ ETN in patients with moderate-to-severe rheumatoid arthritis does not impact the efficacy, safety, or immunogenicity of etanercept. TRIAL REGISTRATION EudraCT number 2012-002009-23 , Registered 19 April 2012-prospectively registered.
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Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III randomised, double-blind, placebo-controlled trial (RAJ4) in Japan.
Takeuchi, T, Tanaka, Y, Tanaka, S, Kawakami, A, Iwasaki, M, Katayama, K, Rokuda, M, Izutsu, H, Ushijima, S, Kaneko, Y, et al
Annals of the rheumatic diseases. 2019;(10):1305-1319
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OBJECTIVE To evaluate the efficacy and safety of the oral Janus kinase (JAK) inhibitor peficitinib versus placebo in Japanese patients with rheumatoid arthritis (RA). METHODS In this multicentre, double-blind, parallel-group, placebo-controlled phase III study, patients with RA and inadequate response to methotrexate (MTX) were randomised 1:1:1 to placebo, peficitinib 100 mg once daily or peficitinib 150 mg once daily with MTX for 52 weeks. Based on baseline randomisation, at week 12, non-responders receiving placebo were switched to peficitinib until the end of treatment; the remaining patients were switched to peficitinib at week 28. Primary efficacy variables were American College of Rheumatology (ACR)20 response rate at week 12/early termination (ET) and change from baseline in van der Heijde-modified total Sharp score (mTSS) at week 28/ET. RESULTS 519 patients were randomised and treated. Significantly more (p<0.001) peficitinib (58.6%, 100 mg; 64.4%, 150 mg) than placebo (21.8%) recipients achieved ACR20 response at week 12/ET. Significantly lower (p<0.001) mean changes from baseline in mTSS at week 28/ET occurred in peficitinib (1.62, 100 mg; 1.03, 150 mg) than placebo (3.37) recipients. Peficitinib was associated with haematological and biochemical parameter changes, and increased incidence of serious infections and herpes zoster-related disease. One death from suicide occurred in a patient in the placebo group after switching to peficitinib 100 mg. CONCLUSIONS In Japanese patients with RA and inadequate response to MTX, peficitinib demonstrated significant superiority versus placebo in reducing RA symptoms and suppressing joint destruction. Peficitinib had an acceptable safety and tolerability profile, with no new safety signals compared with other JAK inhibitors. TRIAL REGISTRATION NUMBER NCT02305849.
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Efficacy and Safety of 22-Oxa-Calcitriol in Patients with Rheumatoid Arthritis: A Phase II Trial.
Li, C, Yin, S, Yin, H, Cao, L, Zhang, T, Wang, Y
Medical science monitor : international medical journal of experimental and clinical research. 2018;:9127-9135
Abstract
BACKGROUND Calcitriol (1 alpha, 25-dihydroxy vitamin D3) is a good vitamin D supplement but can cause hypercalcemia. Whereas, 22-oxa-1 alpha, 25-dihydroxy vitamin D3 (22-oxa-calcitriol) has less hypercalcemic activity than calcitriol and is reported to be effective for cell-proliferative diseases. The objective of the study was to compare renal function and blood tests of arthritis patients receiving calcitriol supplements with those receiving 22-oxa-calcitriol supplements. MATERIAL AND METHODS A total of 369 patients with clinically confirmed rheumatoid arthritis were included in this phase II trial. Patients received lactose powder (the placebo group, n=123), 50 000 IU/week of 22-oxa-calcitriol (the treatment group, n=123), or 50 000 IU/week of calcitriol (the control group, n=123) for 6 weeks. At the time of enrollment and after 6 weeks of supplementation, renal function tests, blood tests, and secondary outcome measures were evaluated. One-way ANOVA and the chi-squared test for independence were performed for continuous data and constant data at a 95% of confidence level. RESULTS Both 22-oxa-calcitriol and calcitriol successfully decreased swollen joints in patients with rheumatoid arthritis, and both improved Health Assessment Questionnaire Disease Activity Index scores and serum vitamin D levels. The intensity of improvement of serum vitamin D levels in both groups was the same (P<0.0001, q=0.24); however, calcitriol caused hypercalcemia (P<0.0001, q=12.59). CONCLUSIONS This study found that 22-oxa-calcitriol was a good option for vitamin D supplementation in rheumatoid arthritis patients.
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Peficitinib, a JAK Inhibitor, in the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate.
Kivitz, AJ, Gutierrez-Ureña, SR, Poiley, J, Genovese, MC, Kristy, R, Shay, K, Wang, X, Garg, JP, Zubrzycka-Sienkiewicz, A
Arthritis & rheumatology (Hoboken, N.J.). 2017;(4):709-719
Abstract
OBJECTIVE To evaluate the efficacy and safety of orally administered once-daily peficitinib in combination with methotrexate (MTX) in patients with moderate-to-severe rheumatoid arthritis (RA) who had an inadequate response to MTX. METHODS In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging trial, patients with RA (n = 378) were treated with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg plus MTX, or matching placebo plus MTX once daily for 12 weeks. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 12. RESULTS ACR20 response rates at week 12 were 43.9%, 61.5% (P < 0.05 versus placebo), 46.4%, 57.7%, and 44.4% in the peficitinib 25 mg, 50 mg, 100 mg, 150 mg, and placebo groups, respectively. Significant decreases from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level were seen in the peficitinib 50 mg (P < 0.05) and 150 mg (P < 0.01) groups compared with placebo at week 12. Overall, the incidence of adverse events (AEs) was similar between peficitinib and placebo. The most common AEs were urinary tract infection (n = 22 [6%]), upper respiratory tract infection (n = 16 [4%]), and diarrhea (n = 16 [4%]). There were 3 cases of herpes zoster infection (2 in the peficitinib 100 mg group and 1 in the 150 mg group) and 2 cases of serious infection (viral infection in the peficitinib 100 mg group and erysipelas in the 150 mg group). CONCLUSION The ACR20 response rate in the group receiving peficitinib 50 mg plus MTX was significantly different compared with the rate in patients receiving placebo, but there were no apparent dose-dependent responses, and the placebo response rate was high. Peficitinib plus MTX in patients with moderate-to-severe RA was well tolerated, with limited safety signals emerging.
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A phase III, randomized, two-armed, double-blind, parallel, active controlled, and non-inferiority clinical trial to compare efficacy and safety of biosimilar adalimumab (CinnoRA®) to the reference product (Humira®) in patients with active rheumatoid arthritis.
Jamshidi, A, Gharibdoost, F, Vojdanian, M, Soroosh, SG, Soroush, M, Ahmadzadeh, A, Nazarinia, MA, Mousavi, M, Karimzadeh, H, Shakibi, MR, et al
Arthritis research & therapy. 2017;(1):168
Abstract
BACKGROUND This study aimed to compare efficacy and safety of test-adalimumab (CinnoRA®, CinnaGen, Iran) to the innovator product (Humira®, AbbVie, USA) in adult patients with active rheumatoid arthritis (RA). METHODS In this randomized, double-blind, active-controlled, non-inferiority trial, a total of 136 patients with active RA were randomized to receive 40 mg subcutaneous injections of either CinnoRA® or Humira® every other week, while receiving methotrexate (15 mg/week), folic acid (1 mg/day), and prednisolone (7.5 mg/day) over a period of 24 weeks. Physical examinations, vital sign evaluations, and laboratory tests were conducted in patients at baseline and at 12-week and 24-week visits. The primary endpoint in this study was the proportion of patients achieving moderate and good disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR)-based European League Against Rheumatism (EULAR) response. The secondary endpoints were the proportion of patients achieving American College of Rheumatology (ACR) criteria for 20% (ACR20), 50% (ACR50), and 70% (ACR70) responses along with the disability index of health assessment questionnaire (HAQ), and safety. RESULTS Patients who were randomized to CinnoRA® or Humira® arms had comparable demographic information, laboratory results, and disease characteristics at baseline. The proportion of patients achieving good and moderate EULAR responses in the CinnoRA® group was non-inferior to the Humira® group at 12 and 24 weeks based on both intention-to-treat (ITT) and per-protocol (PP) populations (all p values >0.05). No significant difference was noted in the proportion of patients attaining ACR20, ACR50, and ACR70 responses in the CinnoRA® and Humira® groups (all p values >0.05). Further, the difference in HAQ scores and safety outcome measures between treatment arms was not statistically significant. CONCLUSION CinnoRA® was shown to be non-inferior to Humira® in terms of efficacy at week 24 with a comparable safety profile to the reference product. TRIAL REGISTRATION IRCT.ir, IRCT2015030321315N1 . Registered on 5 April 2015.