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Investigation of Potential Drug-Drug Interactions between Peficitinib (ASP015K) and Methotrexate in Patients with Rheumatoid Arthritis.

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.

SUBMITTER: Zhu T

PROVIDER: S-EPMC7452880 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Investigation of Potential Drug-Drug Interactions between Peficitinib (ASP015K) and Methotrexate in Patients with Rheumatoid Arthritis.

Zhu Tong T Moy Selina S Valluri Udaya U Cao Ying Y Zhang Wenhui W Sawamoto Taiji T Chindalore Vishala V Akinlade Bola B

Clinical drug investigation 20200901 9

<h4>Background</h4>Methotrexate is frequently used to treat rheumatoid arthritis. Peficitinib (ASP015K; Smyraf<sup>®</sup>), an oral Janus kinase inhibitor indicated for the treatment of rheumatoid arthritis, may be coadministered with methotrexate.<h4>Objective</h4>The objective of this study was to investigate potential drug-drug interactions of peficitinib with methotrexate and the short-term safety of coadministration.<h4>Patients and methods</h4>This phase I, open-label, single-sequence stu ...[more]

PMID: 32591978

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Project description:BackgroundPeficitinib (ASP015K), a novel oral Janus kinase inhibitor, has demonstrated efficacy and safety in the treatment of patients with rheumatoid arthritis (RA). This study evaluated the effect of peficitinib on patient- and physician-reported outcomes in Asian patients with RA and an inadequate response to prior disease-modifying antirheumatic drugs (DMARDs).MethodsPatients from two randomized, placebo-controlled, double-blind, phase 3 trials (RAJ3 and RAJ4) received once-daily peficitinib 100 mg, peficitinib 150 mg, or placebo, alone or in combination with DMARDs (RAJ3), or in combination with methotrexate (RAJ4). Mean changes in Work Productivity and Activity Impairment (WPAI) questionnaire domain scores from baseline, and percentages of patients achieving minimal clinically important differences (MCIDs) for patient- and physician-reported outcomes (WPAI, Health Assessment Questionnaire - Disability Index [HAQ-DI], and Subject's Global Assessment of Pain [SGAP]), and Physician's Global Assessment of disease activity (PGA) were evaluated at weeks 4, 8, 12, and 12/early termination (ET).ResultsData from 1025 patients were analyzed. At week 12/ET in both studies, patients who received peficitinib 100 mg or 150 mg reported significantly improved WPAI domain scores from baseline (except for absenteeism in RAJ4) compared with placebo (both doses, p<0.05). A higher proportion of peficitinib- versus placebo-treated patients achieved MCID in WPAI, HAQ-DI, SGAP, and PGA in studies RAJ3 and RAJ4. Significant differences with peficitinib versus placebo were evident in both studies as early as week 4 in HAQ-DI (peficitinib 150 mg only), SGAP, and PGA, and week 8 in WPAI loss of work productivity and daily activity impairment. At week 12/ET, significantly higher proportions of patients receiving peficitinib versus placebo achieved MCID in HAQ-DI, SGAP, PGA, and WPAI domains of presenteeism (RAJ3 only), loss of work productivity (RAJ3 only), and daily activity impairment (p<0.05 for all comparisons).ConclusionsPeficitinib 100 mg or 150 mg administered daily over 12 weeks resulted in clinically meaningful improvements in outcomes that are important to RA patients, including pain, physical function, and work productivity and activity. These observations were reinforced through similar improvements in physicians' rating of disease activity.Trial registrationRAJ3: ClinicalTrials.gov, NCT02308163 , registered 4 December 2014. RAJ4: ClinicalTrials.gov, NCT02305849 , registered 3 December 2014.

Project description:BACKGROUND:Peficitinib (ASP015K), a novel oral Janus kinase inhibitor, has demonstrated efficacy and safety for the treatment of rheumatoid arthritis (RA) in randomized, controlled trials of up to 52?weeks' duration. However, safety and effectiveness after long-term treatment have not been assessed. METHODS:This was an interim analysis of an ongoing open-label, multicenter extension study in RA patients who completed phase 2b (RAJ1; 12?weeks) and phase 3 (RAJ3 and RAJ4; 52?weeks) peficitinib studies in Asia (mainly Japan). Eligible patients (n?=?843) received oral peficitinib once daily (100?mg, or 50?mg for patients transferring from RAJ1). The peficitinib dose could be increased (up to 150?mg) or reduced (to 50?mg) at the discretion of the investigator. Efficacy variables assessed included American College of Rheumatology (ACR) response rates, ACR components, and disease activity score in 28 joints based on C-reactive protein (DAS28-CRP). RESULTS:Results up to May 2018 are summarized. Mean peficitinib duration of exposure was 22.7?months and the maximum dose was 100?mg in most (66.5%) patients. ACR responses were maintained during the extension study, with ACR20/50/70 response rates of 71.6%, 52.1%, and 34.7% at week 0 and 78.9%, 61.4%, and 42.7% at end of treatment, respectively. ACR components and DAS28-CRP showed improvements from baselines of the preceding studies and continued to show improvements during the extension study. Treatment-emergent adverse events (TEAEs) were reported in 757/843 (89.8%) patients, the most common being nasopharyngitis (39.7%) and herpes zoster (11.7%). The majority of TEAEs were severity grade 1/2. Drug-related TEAEs leading to permanent study drug discontinuation occurred in 55/843 (6.5%) patients. Regarding AEs of special interest, the incidence per 100 patient-years of serious infections was 2.3 (95% CI 1.6?-?3.1), herpes zoster-related disease 6.8 (95% CI, 5.6?-?8.3), and malignancies 1.1 (95% CI, 0.7?-?1.8). One death from diffuse large B cell lymphoma during the study and one death from uterine sarcoma after the study were considered probably and possibly related to study drug, respectively. CONCLUSIONS:The effectiveness of peficitinib was maintained or improved during long-term administration and treatment up to 6?years was well tolerated in Asian patients with RA. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01638013, registered retrospectively 11 July 2012.

Project description:IntroductionThis final analysis of a long-term extension (LTE) study assessed the safety, tolerability, and effectiveness of peficitinib (ASP015K), a pan-Janus kinase inhibitor, in Asian patients with rheumatoid arthritis (RA).MethodsPatients had previously completed the 12-week phase 2b (RAJ1), or 52-week phase 3 (RAJ3 and RAJ4) peficitinib studies in Japan, Korea, and Taiwan, and received oral peficitinib 50 or 100 mg/day. Dose increase to 150 mg/day or reduction to 50 mg/day was permitted. Efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP), and ACR components. Safety endpoints included treatment-emergent adverse events (TEAEs), and incidence rates (IRs) of adverse events of special interest per 100 patient-years (PY).ResultsOverall, 843 patients received peficitinib for a mean 32.0 months (maximum 85.2 months), and most (64.4%) received peficitinib 100 mg/day as a maximum dose. Respective ACR20/50/70 response rates were maintained from baseline (week 0 of LTE; 71.6, 52.1, and 34.7%) to end of treatment (78.7, 63.3, and 44.1%); continuous improvements in ACR components and DAS28-CRP were observed from the baselines of preceding studies and throughout the LTE. Overall, 796/843 (94.4%) patients experienced TEAEs; most were severity grade 1/2. Most common TEAEs were nasopharyngitis (47.0%) and herpes zoster (17.3%). Drug-related TEAEs leading to permanent discontinuation occurred in 140 (16.6%) patients, and IRs (95% confidence interval) per 100 PY of serious infections, herpes zoster-related disease, and malignancies were 2.7 (2.1, 3.4), 7.3 (6.2, 8.6), and 1.2 (0.9, 1.8), respectively. Two deaths occurred during the study; one each from diffuse large B cell lymphoma and pneumonia, which were, respectively considered probably and possibly related to study drug.ConclusionsImprovements in effectiveness variables were maintained during this long-term study of peficitinib in Asian patients with RA; peficitinib was generally well tolerated over a mean 32 months' duration.Trial registrationClinicalTrials.gov. NCT01638013, retrospectively registered on 11 July 2012 https://clinicaltrials.gov/ct2/show/NCT01638013 .

Dataset Information

Investigation of Potential Drug-Drug Interactions between Peficitinib (ASP015K) and Methotrexate in Patients with Rheumatoid Arthritis.

Publications

Investigation of Potential Drug-Drug Interactions between Peficitinib (ASP015K) and Methotrexate in Patients with Rheumatoid Arthritis.

Similar Datasets

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