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Population pharmacokinetics of tofacitinib in patients with psoriatic arthritis?.

ABSTRACT: OBJECTIVE:Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This analysis characterized the pharmacokinetics (PK) of tofacitinib in adult patients with active PsA and evaluated the impact of covariates (baseline characteristics) on the disposition of tofacitinib. MATERIALS AND METHODS:Data were pooled from two phase 3 studies of tofacitinib of up to 12 months' duration in patients with active PsA (OPAL Broaden (NCT01877668); OPAL Beyond (NCT01882439)). This analysis included 650 tofacitinib-treated patients with 3,252 tofacitinib plasma concentration measurements. Tofacitinib PK was described using a one-compartment disposition model parameterized in terms of apparent oral clearance (CL/F) and apparent volume of distribution (V/F) with first-order absorption rate (Ka) and a lag time. Covariates evaluated were baseline age, baseline body weight, sex, race, ethnicity, baseline creatinine clearance (BCCL), and baseline C-reactive protein. RESULTS:The estimates (95% confidence interval) of PK model parameters of a reference patient were CL/F: 20.4 (18.6, 21.8) L/h; V/F: 110 (108, 113) L; and Ka: 13.8 (12.1, 16.6)/h. Among the covariates, only BCCL led to clinically relevant changes in exposure; however, this was consistent with the known contribution of renal excretion to the total clearance of tofacitinib (~ 30%). CONCLUSION:Tofacitinib did not require dose modification or restrictions for age, body weight, sex, race, ethnicity, or baseline disease severity in patients with active PsA based on the magnitude of exposure relative to a reference patient. Dosing adjustments for renal impairment were derived from a separate phase 1 study.

SUBMITTER: Xie R

PROVIDER: S-EPMC6704728 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Population pharmacokinetics of tofacitinib in patients with psoriatic arthritis .

Xie Rujia R Deng Chenhui C Wang Qiang Q Kanik Keith S KS Nicholas Timothy T Menon Sujatha S

International journal of clinical pharmacology and therapeutics 20190901 9

<h4>Objective</h4>Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This analysis characterized the pharmacokinetics (PK) of tofacitinib in adult patients with active PsA and evaluated the impact of covariates (baseline characteristics) on the disposition of tofacitinib.<h4>Materials and methods</h4>Data were pooled from two phase 3 studies of tofacitinib of up to 12 months' duration in patients with active PsA (OPAL Broaden (NCT01877668); OPAL Beyond ...[more]

PMID: 31319908

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Project description:IntroductionRisankizumab is an anti-IL23 monoclonal antibody approved for the treatment of moderate to severe plaque psoriasis and active psoriatic arthritis (PsA). This work characterizes the pharmacokinetics of risankizumab in PsA compared with psoriasis and evaluates the efficacy and safety exposure-response relationships in PsA.MethodsThe population pharmacokinetic analyses included data from 1527 participants that originated from one phase 1 healthy participant study, one phase 2 dose-ranging study in patients with PsA with an open-label extension study, and two pivotal phase 3 studies in patients with PsA, where the clinical regimen of risankizumab 150 mg administered subcutaneously (SC) at weeks 0, 4, and every 12 weeks thereafter was compared with placebo. Pharmacokinetics were analyzed using nonlinear mixed-effects modeling. Simulation analyses using the final model were conducted to evaluate the impact of covariates on exposure. Data from 1407 patients with PsA from the phase 3 studies were included in the exposure-response analyses. Graphical analyses were used to evaluate efficacy and safety exposure-response relationships, and logistic regression was conducted for further assessment of efficacy exposure-response relationships.ResultsRisankizumab pharmacokinetics were well described by a two-compartment model with first-order SC absorption and elimination. None of the evaluated covariates showed clinically relevant impact on exposure. On the basis of the final model, systemic clearance, steady-state volume of distribution, and terminal phase elimination half-life were estimated to be ~ 0.31 L/day, 11.1 L, and 26.3 days, respectively, for a typical 90 kg patient with PsA. Absolute SC bioavailability was estimated to be 83.5%. Exposure-response quartile analyses suggested that exposures associated with the clinical regimen maximized efficacy across the endpoints evaluated. No exposure dependency was observed for key safety endpoints.ConclusionsRisankizumab exhibited linear and time-independent pharmacokinetics in patients with PsA and was comparable to patients with plaque psoriasis. Efficacy and safety exposure-response analyses support that the clinical regimen achieved robust efficacy with a favorable safety profile for patients with active PsA.Clinical trialsNCT02596217, NCT02719171, NCT02986373, NCT03671148, and NCT03675308.Clinical trialsNCT02596217, NCT02719171, NCT02986373, NCT03671148, and NCT03675308.

Project description:IntroductionRisk of herpes zoster (HZ) is increased with Janus kinase inhibitor use. We evaluated clinical study data relating to HZ management in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) receiving tofacitinib.MethodsThis post hoc analysis included data from 21 RA and 3 PsA clinical studies; data were pooled for tofacitinib doses. Outcomes of HZ events (serious and non-serious) and tofacitinib treatment changes were evaluated in response to first and second HZ events. Median time to resolution was stratified by dermatomal involvement, history of HZ prior to tofacitinib, changes to tofacitinib treatment, anti-viral and corticosteroid use, and tofacitinib dose.ResultsSeven hundred eighty-three (11.1%, N = 7061) patients with RA experienced ≥ 1 HZ event, 63 (8.0%) of whom had ≥ 2 HZ events. In patients with PsA, 36 (4.6%, N = 783) experienced ≥ 1 HZ event, 1 (2.8%) of whom had ≥ 2 HZ events. For most HZ events, tofacitinib treatment was unchanged or temporarily discontinued. The majority of patients received anti-viral treatment, most within 3 days of onset. Post-herpetic neuralgia developed in 6.9% and 3.2% of patients with RA with first and second events, respectively, and in 2.8% of patients with PsA with a first event. Most first and second events resolved (RA: 97.6% and 96.8%, respectively; PsA: 94.4% and 100%, respectively). Median time to resolution was 22.0 days for first and 15.0 days for second events for RA and 20.5 days for first and 11.0 days for second events (n = 1) for PsA. Time to resolution of first events for RA and PsA was generally numerically shorter for patients with single dermatomal HZ, history of HZ, or anti-viral use versus those without.ConclusionAmong patients receiving tofacitinib, recurrent events were more common in patients with RA versus PsA; HZ duration was shorter for repeat events.Trial registrationNCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02187055, NCT00413699, NCT00661661, NCT01877668, NCT01882439, NCT01976364.

Project description:IntroductionThe safety of tofacitinib in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) has been demonstrated in clinical studies of ≤ 4 and 9.5 years, respectively. Post-marketing surveillance (PMS) data for tofacitinib from spontaneous and voluntary adverse event (AE) reports have been published for RA, but not PsA. To inform the real-world safety profile of tofacitinib in PsA, we evaluated AE reports submitted to the Pfizer safety database (including RA data for context).MethodsEndpoints included AEs, serious AEs (SAEs), AEs of special interest (AESIs; serious infections, herpes zoster, cardiovascular events, malignancies, venous thromboembolism), and fatal cases. Exposure was estimated using IQVIA global commercial sales data. Number, frequency, and reporting rates (RRs; number of events/100 patient-years' [PY] exposure) were summarized by indication and formulation (immediate release [IR] 5 or 10 mg twice daily], modified release [MR] 11 mg once daily, or all tofacitinib). The data-collection period differed by indication (PsA: 14 December 2017 [US approval, IR/MR] to 6 November 2021; RA: 6 November 2012 [US approval, IR] to 6 November 2021; MR approval, 24 February 2016).ResultsA total of 73,525 case reports were reviewed (PsA = 5394/RA = 68,131), with 20,706/439,370 PY (PsA/RA) of exposure. More AEs were reported for IR versus MR (IR/MR: PsA = 8349/7602; RA = 137,476/82,153). RRs for AEs (IR/MR: PsA = 59.6/113.4; RA = 44.0/64.8) and SAEs (PsA = 8.1/13.6; RA = 8.0/9.5) were higher with MR versus IR. AE RRs (RA) in the first 4 years after IR approval were 95.9 (IR; 49,439 PY) and 147.0 (MR; 2000 PY). Frequency of SAEs, AESIs, and fatal cases was mostly similar across formulations and indications. The most frequently-reported AE Preferred Terms (PsA/RA) included drug ineffective (20.0%/17.8%), pain (9.7%/10.6%), condition aggravated (9.9%/10.5%), headache (8.8%/7.9%) and, for PsA, off-label use (10.5%/3.4%).ConclusionsTofacitinib PMS safety data from submitted AE reports were consistent between PsA and RA, and aligned with its known safety profile. Exposure data (lower MR versus IR; estimation from commercial sales data), reporting bias, reporter identity, and regional differences in formulation use limit interpretation.

Project description:IntroductionThis post hoc analysis evaluated influenza adverse events (AEs) across rheumatoid arthritis (RA), ulcerative colitis (UC), and psoriatic arthritis (PsA) tofacitinib clinical programs.MethodsAvailable data from phase 1, randomized phase 2/3/3b/4 clinical trials (completed by 2018), and long-term extension (LTE) studies (up to May 2019) in patients with RA, UC, and PsA were included [randomized or Overall (phase 1-3b/4 and LTE studies) tofacitinib cohorts]. Incidence rates (IRs; events per 100 patient-years) of combined influenza AEs (seasons 2004/2005 to 2018/2019) were analyzed, including by tofacitinib dose [5 or 10 mg twice daily (BID)] and age (< 65 versus ≥ 65 years). Logistic regression models evaluated risk factors for influenza AEs in the RA Overall tofacitinib cohort.ResultsIn randomized cohorts, combined influenza AE IRs were generally similar across tofacitinib, adalimumab, methotrexate, and placebo groups, across indications. Among Overall tofacitinib cohorts, combined influenza AE IRs with tofacitinib 5/10 mg BID, respectively, were higher in the UC (3.66/5.09) versus RA (2.38/2.19) and PsA (1.74/1.29) cohorts. IRs were generally similar across tofacitinib dose and age groups. Most influenza AEs were nonserious and did not require changes to tofacitinib treatment. Significant risk factors for influenza AEs in patients with RA were geographic region, baseline oral corticosteroid and methotrexate use, and tofacitinib dose.ConclusionsIn the RA, UC, and PsA clinical programs, combined influenza AE IRs were highest in UC, while in each indication they were generally similar across tofacitinib, placebo, and comparator groups. Influenza AEs were predominantly nonserious and not associated with changes to tofacitinib treatment.Trial registration numbersNCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612, NCT01877668, NCT01882439, NCT01976364.

Project description:OBJECTIVE:Metabolic syndrome (MetS) is a cluster of concurrent risk factors for cardiovascular disease and type 2 diabetes. This post hoc analysis explored key efficacy and safety endpoints in patients with psoriatic arthritis (PsA) and MetS treated with tofacitinib. METHODS:Tofacitinib 5 and 10 mg twice daily and placebo data were pooled from two Phase 3 studies (OPAL Broaden [12 months; ClinicalTrials.gov identifier NCT01877668]; OPAL Beyond [6 months; ClinicalTrials.gov identifier NCT01882439]); patients received one background conventional synthetic disease-modifying antirheumatic drug. Patients were stratified by baseline presence/absence of MetS. Efficacy and safety were reported to month 3 (tofacitinib and placebo) and 6 (tofacitinib only). Efficacy outcomes included: American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI) response, Psoriasis Area Severity Index (PASI)75 response, and enthesitis/dactylitis resolution rates; and changes from baseline (?) in C-reactive protein, HAQ-DI, Patient's/Physician's Global Assessment of Arthritis, and patient-reported outcomes. Safety outcomes included treatment-emergent all-causality adverse events (AEs), ? in lipid/hepatic values, and liver parameter increases. RESULTS:Of 710 patients, 41.4% (n = 294) had baseline MetS. All efficacy outcomes improved with both tofacitinib doses versus placebo, to month 3; tofacitinib efficacy was consistent to month 6, regardless of MetS status. MetS did not appear to affect the incidence of AEs or ? in lipid/hepatic values with tofacitinib up to month 3 or 6. Arterial thromboembolism and myocardial infarction (adjudicated major adverse cardiovascular events) were each reported once in tofacitinib-treated patients with MetS. CONCLUSION:Regardless of baseline MetS status, tofacitinib showed greater efficacy versus placebo in patients with active PsA. The tofacitinib safety profile appeared similar in patients with versus without MetS.

Project description:BackgroundTofacitinib is a Janus Kinase (JAK) inhibitor used for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), dosed as 5 mg twice daily (BID). It is primarily metabolized by the cytochrome P-3A (CYP3A) enzyme, and therefore, the manufacturer recommends to halve the dose when using CYP3A-inhibiting co-medication. Combining half-dose tofacitinib with a registered CYP3A inhibitor (cobicistat) could reduce costs and improve patient experience.ObjectivesPrimary: bioequivalence of tofacitinib 5 mg combined with cobicistat once daily (QD; intervention) to tofacitinib 5 mg BID (control). Secondary: safety, patient preference (7-point Likert scale at study end) and predicted differences in disease activity (DAS28-CRP and probability of ACR20 response) using a validated exposure-response model.DesignOpen-label, cross-over pharmacokinetic study.MethodsWe included patients with RA or PsA, treated with tofacitinib 5 mg BID for ⩾14 days without co-medication affected by CYP3A inhibition. Pharmacokinetic sampling was performed at baseline and after 2-6 weeks of intervention treatment. Bioequivalence was defined as 90% CI of the average tofacitinib concentration (Cavg,ss; intervention to control) falling between 80% and 125%, assessed by non-linear mixed-effects modelling.ResultsBetween 16 September 2019 and 15 January 2021, 30 patients were included, of whom 25 completed both PK measurements. The tofacitinib Cavg,ss was 85% (90% CI: 75-96%). No serious adverse events occurred. Patient preference was 56% for intervention versus 18% for control. No relevant differences in median predicted disease activity were found (DAS28-CRP: 0.03, 95% CI: -0.16 to 0.22; ACR20: -0.01, -0.07 to 0.05).ConclusionDue to slightly lower tofacitinib concentrations during intervention treatment, pharmacokinetic bioequivalence could not formally be established. However, pharmacokinetic boosting may be an attractive strategy for cost reduction of tofacitinib because of its safety, similar predicted pharmacodynamics and patient preference.RegistrationThis study was registered on 29 May 2019 in the Netherlands Trial Register (register number: NL7766).

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Population pharmacokinetics of tofacitinib in patients with psoriatic arthritis?.

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Population pharmacokinetics of tofacitinib in patients with psoriatic arthritis .

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Population pharmacokinetics of tofacitinib in patients with psoriatic arthritis?.

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Population pharmacokinetics of tofacitinib in patients with psoriatic arthritis .

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Population pharmacokinetics of tofacitinib in patients with psoriatic arthritis .