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Upadacitinib pharmacokinetics and exposure-response analyses of efficacy and safety in psoriatic arthritis patients - Analyses of phase III clinical trials.

ABSTRACT: 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.

SUBMITTER: Muensterman E

PROVIDER: S-EPMC8742648 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThis integrated analysis describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, at 15 and 30 mg once daily for up to 3 years of exposure in patients with active psoriatic arthritis (PsA) who had a prior inadequate response or intolerance to ≥ 1 non-biologic or biologic disease-modifying antirheumatic drug.MethodsSafety data were pooled and analyzed from two randomized, placebo-controlled phase 3 trials. Both trials evaluated upadacitinib 15 mg and 30 mg once daily, and one trial also evaluated adalimumab 40 mg every other week. Treatment-emergent adverse events (TEAEs) and laboratory data were summarized for four groups: pooled placebo, pooled upadacitinib 15 mg, pooled upadacitinib 30 mg, and adalimumab. TEAEs were reported as exposure-adjusted event rates (events per 100 patient-years [E/100 PY]) up to a data cut-off of June 29, 2020.ResultsA total of 2257 patients received ≥ 1 dose of upadacitinib 15 mg (N = 907) or 30 mg (N = 921) for 2504.6 PY of exposure or adalimumab (N = 429) for 549.7 PY of exposure. Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase (CPK) were the most common TEAEs with upadacitinib. Rates of malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs), and deaths were similar across treatment groups. Rates of herpes zoster (HZ) and opportunistic infections (OI; excluding tuberculosis, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab. Serious infection, anemia, and CPK elevations were most frequent with upadacitinib 30 mg. Potentially clinically significant laboratory abnormalities were uncommon.ConclusionsUpadacitinib 15 mg and adalimumab had similar safety profiles with the exception of HZ and OIs, consistent with what was observed in rheumatoid arthritis. Rates of malignancies, MACEs, VTEs, and deaths were comparable among patients receiving upadacitinib and adalimumab. No new safety risks emerged with longer-term exposure to upadacitinib.Trial registration numbersSELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.

Project description:ObjectiveAnalyze tofacitinib efficacy and safety by background methotrexate (MTX) dose in patients with psoriatic arthritis (PsA).MethodsThis post hoc analysis pooled data from two phase III, double-blind trials (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) including patients receiving tofacitinib 5 or 10 mg twice daily (BID), or placebo, with stable MTX. Efficacy outcomes at month 3 stratified by MTX dose (≤ 15 month 3 stratified by MTX dose vs > 15 mg/week) were American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI); Psoriasis Area and Severity Index (PASI)50/75; change from baseline in HAQ-DI; physician's global assessment of PsA (PGA-PsA-visual analog scale [VAS]); patient's global joint and skin assessment (PGJS-VAS), Leeds Enthesitis Index (LEI); and Dactylitis Severity Score (DSS). Safety assessments included adverse events and laboratory parameters.ResultsFive hundred fifty-six patients received tofacitinib 5 mg BID (n = 186), 10 mg BID (n = 178), or placebo (n = 192), plus MTX (≤ 15 mg/week, n = 371; > 15 mg/week, n = 185). At month 3, tofacitinib efficacy was generally greater than placebo. Patients receiving tofacitinib 5 mg BID demonstrated greater numerical improvements in efficacy outcomes at month 3 with MTX > 15 mg/week vs MTX ≤ 15 mg/week; patients receiving tofacitinib 10 mg BID displayed the opposite. The safety profile was generally consistent between groups; headache was associated with MTX > 15 mg/week; decreased hemoglobin levels were observed in patients receiving tofacitinib 10 mg BID and MTX ≤ 15 mg/week.ConclusionEfficacy of tofacitinib was generally numerically greater than placebo, regardless of MTX dose. Tofacitinib 5 mg BID was generally more efficacious with MTX > 15 mg/week vs ≤ 15 mg/week; the opposite was observed for tofacitinib 10 mg BID. Headache was more frequent with MTX > 15 mg/week.Trial registrationClinicalTrials.gov . Identifier: NCT01877668 (registration: June 14, 2013) and NCT01882439 (registration: June 20, 2013). Key Points • Methotrexate is widely used in the treatment of psoriatic arthritis; however, there are limited data on the impact of varying background methotrexate doses on the efficacy and safety of Janus kinase inhibitors in patients with psoriatic arthritis. • This post hoc analysis assessed the impact of background methotrexate dose (≤ 15 or > 15 mg/week) on tofacitinib efficacy and safety in patients with psoriatic arthritis. • Results indicated that tofacitinib efficacy was generally numerically greater than placebo, regardless of methotrexate dose. Tofacitinib 5 mg twice daily, in combination with a higher dose of background methotrexate, was more efficacious compared with a lower dose of background methotrexate; the opposite was observed for tofacitinib 10 mg twice daily. • Headache was more frequent with the higher methotrexate dose. Data should be interpreted with caution due to the small sample sizes.

Project description:IntroductionThis article aims to describe malignancies in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), or non-radiographic axial spondyloarthritis (nr-axSpA) treated with upadacitinib (UPA) or active comparators.MethodsThis integrated safety analysis includes data from 11 phase 3 UPA trials across RA (6 trials), PsA (2 trials), AS (2 trials; one phase 2b/3), and nr-axSpA (1 trial). Treatment-emergent adverse events (TEAEs) were summarized for RA (pooled UPA 15 mg [UPA15], pooled UPA 30 mg [UPA30], adalimumab 40 mg [ADA], methotrexate monotherapy [MTX]), PsA (pooled UPA15, pooled UPA30, ADA), AS (pooled UPA15), and nr-axSpA (UPA15). TEAEs were reported as exposure-adjusted event rates (events/100 patient-years).ResultsMedian treatment duration ranged from 1.0 to 4.0 years (with a maximum of 6.6 years in RA). Across treatments and indications, rates of malignancy excluding nonmelanoma skin cancer (NMSC) ranged from 0.2 to 1.1, while NMSC ranged from 0.0 to 1.4. In RA, rates of malignancy excluding NMSC were generally similar between UPA15, UPA30, ADA, and MTX (breast and lung cancer were the most common). In RA and PsA, Kaplan-Meier analyses revealed no differences in event onset of malignancy excluding NMSC with UPA15 versus UPA30 over time. In RA, NMSC rates were higher with UPA30 than UPA15; both UPA15 and UPA30 were higher than ADA and MTX. In PsA, rates of malignancy excluding NMSC and NMSC were generally similar between UPA15, UPA30, and ADA. In AS and nr-axSpA, malignancies were reported infrequently. Few events of lymphoma were reported across the clinical programs.ConclusionRates of malignancy excluding NMSC were generally similar between UPA15, UPA30, ADA, and MTX and were consistent across RA, PsA, AS, and nr-axSpA. A dose-dependent increased rate of NMSC was observed with UPA in RA.Trial registrationClinicaTrials.gov identifier: NCT02706873, NCT02675426, NCT02629159, NCT02706951, NCT02706847, NCT03086343, NCT03104400, NCT03104374, NCT03178487, and NCT04169373.

Project description:BACKGROUND AND OBJECTIVES:Upadacitinib is a janus kinase (JAK) 1 inhibitor being developed for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. This work characterized upadacitinib population pharmacokinetics in healthy subjects and RA patients and the effects of covariates on upadacitinib exposure. METHODS:Upadacitinib plasma concentrations (n = 6399) from 107 healthy subjects and 466 RA patients from three phase I and two 12-week RA phase IIb trials (1-48 mg immediate-release doses across studies) were analyzed using non-linear mixed-effects modeling. The models were qualified using bootstrap and stochastic simulations. RESULTS:A two-compartment model with first-order absorption and elimination described upadacitinib pharmacokinetics. Estimates (95% bootstrap confidence interval) for upadacitinib oral clearance, steady-state volume of distribution, absorption lag time, and mean absorption time were 39.7 (37.8-41.5) L/h, 210 (196-231) L, 0.48 (0.47-0.49) h, and 0.08 (0.04-0.12) h, respectively, for a typical healthy male. Matching on other covariates, a 16 and 32% higher upadacitinib area under the concentration-time curve (AUC) was estimated for females relative to males, and for subjects with RA relative to healthy volunteers, respectively. Subjects with RA with mild or moderate renal impairment were estimated to have 16 and 32% higher upadacitinib AUC, respectively, compared with subjects with RA with normal renal function. Upadacitinib clearance was not correlated with body weight. CONCLUSIONS:Upadacitinib pharmacokinetics follow dose-proportional, bi-exponential disposition. A slightly lower upadacitinib clearance is estimated in subjects with RA than in healthy volunteers, consistent with observations for other JAK inhibitors. Other covariates (weight, sex, mild or moderate renal impairment) are not associated with clinically relevant effects on upadacitinib exposure. TRIAL REGISTRATION:ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifiers: NCT01741493, NCT02066389, and NCT01960855.

Project description:Background and objectivesUpadacitinib 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.MethodsPharmacokinetic 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.ResultsA 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.ConclusionsA 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.

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Upadacitinib pharmacokinetics and exposure-response analyses of efficacy and safety in psoriatic arthritis patients - Analyses of phase III clinical trials.

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