SummaryWhat is known and objective: SB5 is a biosimilar to the reference adalimumab (ADL) currently in development. The primary study objective was to demonstrate pharmacokinetic (PK) equivalence of SB5 to European Union-sourced adalimumab (EU-ADL), and United States-sourced adalimumab (US-ADL) in healthy subjects. Safety, tolerability and immunogenicity were also assessed as secondary objectives. Methods:In this phase I, single-blind trial, 189 healthy volunteers were randomized to a single 40 mg dose of SB5, EU-ADL or US-ADL and PK was evaluated for 71 days afterwards. Serum adalimumab concentrations were measured using an enzymelinked immunosorbent assay (ELISA) test. PK parameters were calculated based on actual sampling times relative to dosing and non-compartmental analysis methods, and equivalence was determined using predefined margins of 0.8-1.25.Results and discussion: Baseline characteristics and demographics were comparable between the three groups. Mean values of area under the concentration-time curve from time zero to infinity (AUC inf ), maximum serum concentration (C max ) and AUC from time zero to the last quantifiable concentration (AUC last ) were similar between groups, and 90% confidence interval for these parameters were within the predefined equivalence margins for all pairwise comparisons. No discontinuations due to treatment-emergent adverse events (TEAEs) or deaths were reported.Number and kind of TEAEs were comparable between the three groups and considered mild to moderate. The incidence of subjects with antidrug antibodies (ADA) and the overall incidence of neutralizing antibody (NAb) were comparable across the three groups.What is new and conclusion: The PK of SB5 was equivalent to that of EU-ADL and US-ADL. SB5 was well tolerated with similar safety and immunogenicity profile to EU-ADL and US-ADL. K E Y W O R D S bioequivalence, biosimilar, clinical pharmacokineticsThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
ObjectiveSB2, a biosimilar to infliximab reference product (INF), has an identical amino acid sequence and similar physicochemical functional properties to its reference product. The primary objective of this study is to demonstrate pharmacokinetic (PK) bioequivalence between SB2 and EU-sourced INF (EU-INF), between SB2 and US-sourced INF (US-INF), and between EU-INF and US-INF.MethodsThis study was a randomized, single-blind, three-arm, parallel group study in 159 healthy subjects. All subjects received a single 5 mg/kg intravenous infusion of study drug and then were observed for 10 weeks to study PK, safety and immunogenicity. The primary PK parameters were area under the concentration-time curve (AUC) from time zero to infinity (AUCinf), AUC from time zero to the last quantifiable concentration (AUClast) and maximum concentration (Cmax). Bioequivalence for the primary PK parameters was to be concluded using an analysis of variance (ANOVA) if the 90 % confidence intervals (CIs) for the ratio of geometric least squares means (LSMeans) of the treatments compared were completely contained within the pre-defined equivalence margin, 0.8–1.25.ResultsAll of the 90 % CIs for the geometric LSMean ratios of primary PK parameters for each comparison were within the pre-defined equivalence margin. The proportion of subjects who experienced treatment-emergent adverse events was comparable between treatments. The incidences of anti-drug antibodies between the three treatments were comparable.ConclusionThis study demonstrated biosimilarity of SB2 to its marketed reference products of infliximab in terms of PK equivalence in healthy subjects. SB2 was generally well tolerated and showed comparable safety and immunogenicity profiles to the reference products (ClinicalTrials.gov Identifier: NCT01922336).
This study evaluated the potential impact of concomitant digoxin on the pharmacokinetics and pharmacodynamics of dabigatran etexilate, a novel oral direct thrombin inhibitor. Healthy volunteers (n = 23) received 150 mg dabigatran etexilate twice daily on days 1 to 3 and once on day 4 in 1 period. Digoxin was given in another period as a loading dose of 0.5 mg early on day 1 and 0.25 mg in the evening of day 1 and on the mornings of days 2 to 4. In a third treatment period, dabigatran etexilate together with digoxin was given on days 1 to 4. Exposure to dabigatran was not significantly altered with concomitant digoxin-the maximum concentration (Cmax,ss ) and area under the concentration-time curve at steady state over 1 dosing interval (AUCτ,ss ) of dabigatran with and without digoxin were essentially unchanged. The pharmacokinetic profile of digoxin also remained unchanged in the presence of dabigatran etexilate. Dabigatran's anticoagulant effect, assessed by blood coagulation time assays, was not influenced by digoxin. Dabigatran etexilate and digoxin can be coadministered without the need for dose adjustment of either drug.
Results of this randomized, open-label, three-way crossover design study in healthy male and female volunteers showed that atorvastatin had no influence on the pharmacokinetic/pharmacodynamic profile of dabigatran, and vice versa, dabigatran etexilate had no impact on the pharmacokinetic/pharmacodynamic profile of atorvastatin. Both drugs were well tolerated when given alone or in combination.
BackgroundSB5, a biosimilar to adalimumab reference product (ADL), has an identical amino acid sequence, similar physicochemical and in vitro functional properties to its reference drug.ObjectivesThe primary objective of this study was to demonstrate pharmacokinetic (PK) equivalence between SB5 and EU sourced ADL (EU-ADL), SB5 and US sourced ADL (US-ADL), and between EU-ADL and US-ADL. Safety, tolerability, and immunogenicity were investigated as secondary objectives.MethodsThis study was a randomised, single-blind, 3-arm, parallel group study in 189 healthy subjects. In each arm, all subjects received a single 40 mg dose of SB5, EU-ADL, or US-ADL by subcutaneous injection on Day 1 and then were observed for 71 days during which the PK, safety, tolerability, and immunogenicity measurements were made. The serum concentration of adalimumab was measured using an enzyme-linked immunosorbent assay (ELISA). The primary PK parameters were area under the concentration-time curve from time zero to infinity (AUCinf), area under the concentration-time curve from time zero to the last quantifiable concentration (AUClast), and maximum concentration (Cmax). Equivalence for the primary PK parameters was to be concluded if the 90% confidence intervals (CIs) for the ratio of geometric least squares means (LSMeans) of the groups compared were completely contained within the pre-defined equivalence margin of 0.8 to 1.25 using an analysis of variance (ANOVA).ResultsAll of the 90% CIs for the geometric LSMeans ratios of primary PK parameters for SB5 and EU-ADL comparison, SB5 and US-ADL comparison, and EU-ADL and US-ADL comparison were within the pre-defined equivalence margin of 0.8 to 1.25 (Table). The proportion of subjects who experienced treatment-emergent adverse events (TEAEs) was comparable between the SB5, EU-ADL, and US-ADL groups. The most frequent TEAEs were nasopharyngitis and headache. The majority of TEAEs were mild to moderate in severity. Two serious adverse events (SAEs) were reported. Both SAEs were assessed not to be related to the study drugs. There were no statistically significant differences in the incidence of post-dose anti-drug antibodies between the three groups.Table 1.Comparison of primary PK parameters between the treatmentsComparisonPK parametersRatio90% CISB5 vs EU-ADLAUCinf (μg·h/mL)0.9900.885; 1.108AUClast (μg·h/mL)1.0270.915; 1.153Cmax (μg/mL)0.9570.870; 1.054SB5 vs US-ADLAUCinf (μg·h/mL)1.0010.890; 1.126AUClast (μg·h/mL)1.0250.911; 1.153Cmax (μg/mL)0.9720.881; 1.073EU-ADL vs US-ADLAUCinf (μg·h/mL)1.0110.904; 1.131AUClast (μg·h/mL)0.9980.887; 1.122Cmax (μg/mL)1.0160.920; 1.121ConclusionsThis study demonstrated PK equivalence between SB5 and EU-ADL, SB5 and US-ADL, and between EU-ADL and US-ADL in healthy subjects. All three adalimumab products were generally well tolerated with similar safety profiles.Disclosure of InterestD. Shin Employee of: Samsung Bioepis, Y. Kim Employee of: Samsung Bioepis, H. S. Kim Employee of: Samsung Bioepis, R. Fuhr Grant/research support from: Samsung Bioepis, T. Körnick...
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