Dataset Information

Population Pharmacokinetic Modeling of Secukinumab in Patients With Moderate to Severe Psoriasis.

ABSTRACT: Secukinumab is a human monoclonal antibody with demonstrated efficacy for moderate to severe psoriasis; it binds to and neutralizes interleukin (IL)-17A. The pharmacokinetic (PK) parameters of secukinumab were best described by a 2-compartment model. Only weight was included in the final model, as other covariates did not affect clinical relevance. The estimated serum clearance of secukinumab was 0.19 L/day, with interindividual variability (IIV) of 32% coefficient of variation (CV), and low total volume of distribution (central compartment volume, 3.61 L with IIV of 30% CV; peripheral compartment volume, 2.87 L with IIV of 18% CV). The bioavailability of secukinumab after subcutaneous dosing was approximately 73%, with an absorption rate of 0.18/day with IIV of 35% CV. The PK profile of secukinumab was linear, with no evidence of a dose dependence of clearance. Clearance and volume of secukinumab varied with body weight in an allometric relationship. The time to maximum serum concentration at steady state occurred approximately 6 days after dosing for both secukinumab 300 mg and secukinumab 150 mg. Overall, the PK properties of secukinumab were typical of a 150-kDa human IgG1 antibody interacting with a soluble target.

SUBMITTER: Bruin G

PROVIDER: S-EPMC5485066 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Population Pharmacokinetic Modeling of Secukinumab in Patients With Moderate to Severe Psoriasis.

Bruin Gerard G Loesche Christian C Nyirady Judit J Sander Oliver O

Journal of clinical pharmacology 20170308 7

Secukinumab is a human monoclonal antibody with demonstrated efficacy for moderate to severe psoriasis; it binds to and neutralizes interleukin (IL)-17A. The pharmacokinetic (PK) parameters of secukinumab were best described by a 2-compartment model. Only weight was included in the final model, as other covariates did not affect clinical relevance. The estimated serum clearance of secukinumab was 0.19 L/day, with interindividual variability (IIV) of 32% coefficient of variation (CV), and low tot ...[more]

PMID: 28273356

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Project description:IntroductionPatients with moderate-to-severe plaque psoriasis who experience poor clinical outcomes, including patients with obesity or prior treatment, need improved treatment options. Risankizumab specifically inhibits interleukin 23 and has demonstrated superior efficacy in active-comparator studies in patients with moderate-to-severe plaque psoriasis. We compared the efficacy of risankizumab with that of secukinumab across patient subgroups.MethodsSubgroup analyses using data from the phase 3 IMMerge study (NCT03478787) were performed. Efficacy in adults with moderate-to-severe psoriasis treated with risankizumab 150 mg and secukinumab 300 mg was assessed as the proportion of patients who achieved ≥ 90% improvement in Psoriasis Area Severity Index (PASI 90) at week 52 across demographics and disease characteristics. Post hoc analyses evaluated the proportion of patients who achieved PASI 90 and the least-squares mean percent PASI improvement from baseline at week 52 by body weight and body mass index (BMI), PASI 90 by prior treatment, and clinical response [PASI 90, PASI 100, and/or static Physician's Global Assessment (sPGA) score of clear (0) or almost clear (1)] at week 16 and maintained particular response at week 52. Logistic regression analyses examined the effect of covariates (age, sex, BMI, baseline PASI, treatment) and potential interactions on PASI 90 at week 52.ResultsMore patients who received risankizumab (n = 164) compared with secukinumab (n = 163) achieved PASI 90 at week 52, regardless of demographics and disease characteristics (BMI, prior treatment, disease duration, and maintenance of clinical response at week 52). Improvements in PASI were greater in patients taking risankizumab than those taking secukinumab, regardless of weight or BMI. Results from logistic regression analysis showed treatment type had a significant impact on PASI 90 (risankizumab versus secukinumab, p < 0.0001).ConclusionRisankizumab showed consistently greater efficacy compared with secukinumab across different patient subgroups, and this was maintained through 52 weeks.Trial registrationClinicalTrials.gov identifier; NCT03478787.

Project description:OBJECTIVE:To conduct a cost-effectiveness analysis from the perspective of the Spanish National Health System (NHS) comparing ixekizumab versus secukinumab. DESIGN:A Markov model with a lifetime horizon and monthly cycles was developed based on the York model. Four health states were included: a biological disease-modifying antirheumatic drug (bDMARD) induction period of 12 or 16?weeks, maintenance therapy, best supportive care (BSC) and death. Treatment response was assessed based on both Psoriatic Arthritis Response Criteria (PsARC) and ?90% improvement in the Psoriasis Area Severity Index score (PASI90). At the end of the induction period, responders transitioned to maintenance therapy. Non-responders and patients who discontinued maintenance therapy transitioned to BSC. Clinical efficacy data were derived from a network meta-analysis. Health utilities were generated by applying a regression analysis to Psoriasis Area Severity Index and Health Assessment Questionnaire?Disability Index scores collected in the ixekizumab SPIRIT studies. Results were subject to extensive sensitivity and scenario analysis. SETTING:Spanish NHS. PARTICIPANTS:A hypothetical cohort of bDMARD-naïve patients with psoriatic arthritis and concomitant moderate-to-severe psoriasis was modelled. INTERVENTIONS:Ixekizumab and secukinumab. RESULTS:Ixekizumab performed favourably over secukinumab in the base-case analysis, although cost savings and quality-adjusted life-year (QALY) gains were modest. Total costs were €153?901 compared with €156?559 for secukinumab (difference -€2658). Total QALYs were 9.175 vs 9.082 (difference 0.093). Base-case results were most sensitive to the annual bDMARD discontinuation rate and the modification of PsARC and PASI90 response to ixekizumab or secukinumab. CONCLUSION:Ixekizumab provided more QALYs at a lower cost than secukinumab, with differences being on a relatively small scale. Sensitivity analysis showed that base-case results were generally robust to changes in most input parameters. TRIAL REGISTRATION NUMBER:SPIRIT-P1: NCT01695239; Post-results, SPIRIT-P2: NCT02349295; Post-results.

Project description:IntroductionSecukinumab, a fully human anti-interleukin-17A monoclonal antibody, has demonstrated superior efficacy to ustekinumab in the phase 3b CLEAR study of moderate to severe plaque psoriasis. Here, we report 16-week results from CLARITY, a second head-to-head trial comparing secukinumab with ustekinumab.MethodsIn the phase 3b CLARITY study, patients were randomized 1:1 to receive subcutaneous secukinumab 300 mg or ustekinumab per label. The co-primary objectives were to demonstrate the superiority of secukinumab over ustekinumab at Week 12 in relation to the proportion of patients with (1) 90% or more improvement from baseline Psoriasis Area and Severity Index (PASI 90) and (2) a score of 0/1 (clear/almost clear) on the modified Investigator's Global Assessment (IGA mod 2011 0/1). Key secondary objectives were also assessed, as was Dermatology Life Quality Index (DLQI) 0/1 (no impact of skin disease on patients' quality of life) response. Missing values were handled by multiple imputation except for DLQI 0/1, where last observation carried forward techniques were utilized.ResultsBoth co-primary objectives were met: secukinumab was superior to ustekinumab for the proportion of patients achieving a PASI 90 (66.5% vs. 47.9%) and IGA mod 2011 0/1 response (72.3% vs. 55.4%) at Week 12 (p < 0.0001). PASI 90 responses were greater with secukinumab compared to ustekinumab from as early as Week 4 (16.7% vs. 4.0%) and out to Week 16 (76.6% vs. 54.2%). Similarly, IGA mod 2011 0/1 findings were greater with secukinumab at Week 4 (26.9% vs. 7.8%) and at Week 16 (78.6% vs. 59.1%). DLQI 0/1 response rates were also greater with secukinumab compared to ustekinumab at Week 4 (33.9% vs. 18.0%), Week 12 (64.0% vs. 51.7%), and Week 16 (68.4% vs. 55.9%).ConclusionThe results of this study confirm the superior efficacy of secukinumab over ustekinumab in treating patients with moderate to severe psoriasis.Trial registrationClinicaltrials.gov Identifier, NCT02826603.FundingNovartis Pharma AG, Basel, Switzerland.

Project description:Background The efficacy and safety of secukinumab in patients with psoriasis has been established in randomised clinical trials. However, data on effectiveness and safety of secukinumab in Latin American real-world settings are scarce.ObjectivesTo evaluate the effectiveness and safety of secukinumab in real-world settings in patients with psoriasis in Latin America.MethodsPURE is an ongoing multinational, prospective, observational study in patients with moderate-to-severe chronic plaque psoriasis in Canada and Latin America assessing the real-world safety and effectiveness of secukinumab and other approved therapies. The study enrolled (1:1) patients treated with secukinumab versus other approved therapies (other Tx) per local standard of care from 81 community- and hospital-based speciality sites (21 in Latin America). Here, we report effectiveness and safety outcomes with secukinumab and other Tx for plaque psoriasis for up to 12 months in a Latin American population.ResultsOverall, 187 patients were included in the analysis, 89 of whom initiated secukinumab treatment and 98 of whom received other Tx. At month 12, 84.4%, 71.1% and 53.3% of patients treated with secukinumab achieved Psoriasis Area and Severity Index (PASI) 75/90/100, respectively, compared with 66.7%, 47.9% and 29.2% of patients who received other Tx. Investigator Global Assessment (IGA) 0/1 responders in secukinumab versus other Tx were 78.3% versus 36.7% at month 3 and 81.8% versus 66.7% at month 12, respectively. Overall, the proportion of patients achieving Dermatology Life Quality Index (DLQI) 0/1 improved from 6.9% at baseline to 76.5% at month 12 in patients treated with secukinumab versus 5.6% at baseline to 54.5% at month 12 in patients on other Tx. No unexpected adverse events were reported during the 12-month observation period.ConclusionSecukinumab demonstrated real-world effectiveness and improved dermatology quality-of-life in chronic plaque psoriasis patients from Latin America.Trial registrationPURE: NCT02786186.

Dataset Information

Population Pharmacokinetic Modeling of Secukinumab in Patients With Moderate to Severe Psoriasis.

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Population Pharmacokinetic Modeling of Secukinumab in Patients With Moderate to Severe Psoriasis.

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