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      Comparison of the Pharmacokinetics, Safety, and Tolerability of the Autoinjector (AI) and Pre-Filled Syringe (PFS) of SB4 in Healthy Subjects

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          Abstract

          Purpose

          SB4 is an etanercept biosimilar, approved by the European Commission (EC) and the US Food and Drug Administration (FDA) following a demonstration of equivalent efficacy and safety and comparable quality data to the reference product. This study aimed to demonstrate equivalent pharmacokinetic (PK) profiles, safety, and tolerability between SB4 autoinjector (AI) and SB4 pre-filled syringe (PFS).

          Patients and methods

          This was an open-label, two-period, two-sequence, single-dose, cross-over study to evaluate bioequivalence of PK profiles, safety, and tolerability between SB4 AI and PFS in healthy adults. Treatment periods were separated by 14 days resulting in a 35-day washout between investigational product (IP) administration in Periods 1 and 2.

          Results

          A total of 50 subjects were randomized: 24 subjects in Sequence I and 26 in Sequence II, and 6 subjects discontinued from the study. The primary PK endpoints including area under the concentration–time curve from time zero to infinity (AUC inf) and to the last quantifiable concentration (AUC last), and maximum serum concentration (C max) were all within the equivalence margin of 80.00–125.00%. Safety and tolerability were comparable between the two treatments.

          Conclusion

          PK profiles showed that SB4 AI and PFS were bioequivalent in healthy subjects. Safety assessment was also comparable between the two treatments.

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          Most cited references 18

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          Medication adherence in patients with rheumatoid arthritis: a critical appraisal of the existing literature.

          Adherence to medication in patients with rheumatoid arthritis is low, varying from 30 to 80%. Improving adherence to therapy could therefore dramatically improve the efficacy of drug therapy. Although indicators for suboptimal adherence can be useful to identify nonadherent patients, and could function as targets for adherence-improving interventions, no indicators are yet found to be consistently and strongly related to nonadherence. Despite this, nonadherence behavior could conceptually be categorized into two subtypes: unintentional (due to forgetfulness, regimen complexity or physical problems) and intentional (based on the patient's decision to take no/less medication). In case of intentional nonadherence, patients seem to make a benefit-risk analysis weighing the perceived risks of the treatment against the perceived benefits. This weighing process may be influenced by the patient's beliefs about medication, the patient's self-efficacy and the patient's knowledge of the disease. This implicates that besides tackling practical barriers, clinicians should be sensitive to patient's personal beliefs that may impact medication adherence.
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            Long-term efficacy and safety in patients with rheumatoid arthritis continuing on SB4 or switching from reference etanercept to SB4

            Objectives SB4 (Benepali, Brenzys) is a biosimilar of reference etanercept (ETN). In a randomised, double-blind, 52-week study, SB4 demonstrated comparable efficacy and safety to ETN in patients with rheumatoid arthritis (RA). The open-label extension period evaluated long-term efficacy, safety and immunogenicity when continuing SB4 versus switching from ETN to SB4. Methods In the randomised, double-blind phase, patients received weekly subcutaneous administration of 50 mg SB4 or ETN with background methotrexate for up to 52 weeks. Patients in the Czech Republic and Poland who completed the 52-week visit were enrolled in the open-label extension period and received SB4 for 48 additional weeks. Efficacy, safety and immunogenicity were assessed up to week 100. Results Of 245 patients entering the extension period, 126 continued to receive SB4 (SB4/SB4) and 119 switched to SB4 (ETN/SB4). American College of Rheumatology (ACR) response rates were sustained and comparable between SB4/SB4 and ETN/SB4 with ACR20 response rates at week 100 of 77.9% and 79.1%, respectively. Other efficacy results, including radiographic progression, were also comparable between the groups. After week 52, rates of treatment-emergent adverse events were 47.6% (SB4/SB4) and 48.7% (ETN/SB4); one patient/group developed non-neutralising antidrug antibodies. No cases of active tuberculosis or injection-site reactions were reported during the extension period. One patient (SB4/SB4) died of hepatic cancer. Conclusions SB4 was effective and well tolerated over 2 years in patients with RA. Efficacy, safety and immunogenicity were comparable between the SB4/SB4 and ETN/SB4 groups, showing no risk associated with switching patients from ETN to SB4. Trial registration number NCT01895309; 2012-005026-30
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              A randomized phase l pharmacokinetic study comparing SB4 and etanercept reference product (Enbrel®) in healthy subjects

              Aims SB4 has been developed as a biosimilar of etanercept. The primary objective of the present study was to demonstrate the pharmacokinetic (PK) equivalence between SB4 and European Union ‐sourced etanercept (EU‐ETN), SB4 and United States‐sourced etanercept (US‐ETN), and EU‐ETN and US‐ETN. The safety and immunogenicity were also compared between the treatments. Methods This was a single‐blind, three‐part, crossover study in 138 healthy male subjects. In each part, 46 subjects were randomized at a 1:1 ratio to receive a single 50 mg subcutaneous dose of the treatments (part A: SB4 or EU‐ETN; part B: SB4 or US‐ETN; and part C: EU‐ETN or US‐ETN) in period 1, followed by the crossover treatment in period 2 according to their assigned sequences. PK equivalence between the treatments was determined using the standard equivalence margin of 80–125%. Results The geometric least squares means ratios of AUCinf, AUClast and Cmax were 99.04%, 98.62% and 103.71% (part A: SB4 vs. EU‐ETN); 101.09%, 100.96% and 104.36% (part B: SB4 vs. US‐ETN); and 100.51%, 101.27% and 103.29% (part C: EU‐ETN vs. US‐ETN), respectively, and the corresponding 90% confidence intervals were completely contained within the limits of 80–125 %. The incidence of treatment‐emergent adverse events was comparable, and the incidence of the antidrug antibodies was lower in SB4 compared with the reference products. Conclusions The present study demonstrated PK equivalence between SB4 and EU‐ETN, SB4 and US‐ETN, and EU‐ETN and US‐ETN in healthy male subjects. SB4 was well tolerated, with a lower immunogenicity profile and similar safety profile compared with those of the reference products.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                08 January 2020
                2020
                : 14
                : 43-50
                Affiliations
                [1 ]Samsung Bioepis Co., Ltd ., Incheon, Republic of Korea
                [2 ]PRA International , Groningen, the Netherlands
                Author notes
                Correspondence: Donghoon Shin Samsung Bioepis Co., Ltd , 107, Cheomdan-daero, Yeonsu-gu, Incheon21987, Republic of KoreaTel +82-31-8061-4534Fax +82-31-8061-4393 Email dh01.shin@samsung.com
                Article
                224103
                10.2147/DDDT.S224103
                6955637
                © 2020 Shin et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 2, Tables: 5, References: 25, Pages: 8
                Funding
                This study was sponsored by Samsung Bioepis Co., Ltd.
                Categories
                Clinical Trial Report

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