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      Comparison of Pharmacokinetic, Pharmacodynamic and Tolerability Profiles of CKD-11101, Darbepoetin Alfa (NESP ®) Biosimilar, to Those of NESP ® After a Single Subcutaneous or Intravenous Administration to Healthy Subjects


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          Darbepoetin alfa (NESP ® and ARANESP ®) has a sustained erythropoietic activity with a longer half-life than conventional recombinant human erythropoietin. CKD-11101 is under clinical development as a biosimilar of darbepoetin alfa. The purpose of this study was to compare the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of CKD-11101 with those of reference drug in healthy subjects.


          This study was performed in two parts for healthy subjects. In each period, CKD-11101 and reference, both at 60 μg, were administered via intravenous (IV) or subcutaneous (SC) route of administration.


          After both IV or SC dose, the geometric mean ratio (GMR) of CKD-11101 to reference drug and its 90% confidence intervals (CIs) for C max, AUC 0–last and AUC 0–∞ were all within 0.8–1.25. No statistically significant differences were noted in the maximum baseline adjusted reticulocyte count or the area under the baseline adjusted reticulocyte count-time between the CKD-11101 and reference drug after IV or SC dose (all p-value>0.05). Both CKD-11101 and reference drug were generally well tolerated.


          After a single IV or SC dose, the CKD-11101 was well tolerated and showed comparable PK and PD characteristics with reference drug.

          Most cited references28

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          2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults

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            Physiology and pharmacology of erythropoietin.

            Human erythropoietin (Epo) is a 30.4 kDa glycoprotein hormone composed of a single 165 amino acid residues chain to which four glycans are attached. The kidneys are the primary sources of Epo, its synthesis is controlled by hypoxia-inducible transcription factors (HIFs). Epo is an essential factor for the viability and proliferation of erythrocytic progenitors. Whether Epo exerts cytoprotection outside the bone marrow still needs to be clarified. Epo deficiency is the primary cause of the anemia in chronic kidney disease (CKD). Treatment with recombinant human Epo (rhEpo, epoetin) can be beneficial not only in CKD but also for other indications, primarily anemia in cancer patients receiving chemotherapy. Considering unwanted events, the administration of rhEpo or its analogs may increase the incidence of thromboembolism. The expiry of the patents for the original epoetins has initiated the production of similar biological medicinal products ('biosimilars'). Furthermore, analogs (darbepoetin alfa, methoxy PEG-epoetin beta) with prolonged survival in circulation have been developed ('biobetter'). New erythropoiesis-stimulating agents are in clinical trials. These include compounds that augment erythropoiesis directly (e.g. Epo mimetic peptides or activin A binding protein) and chemicals that act indirectly by stimulating endogenous Epo synthesis (HIF stabilizers).
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              Evolution of the EU Biosimilar Framework: Past and Future

              The approval of biosimilars in the EU follows a comprehensive scientific assessment based on stringent regulatory standards. While the initial approach to biosimilars was understandably cautious and conservative in that uncharted territory to protect patients’ safety, the analytical and scientific progress and accumulated experience with biosimilars continues to reshape regulatory requirements, generally leading to a reduced burden of clinical trials. This trend is expected to continue, for example, by increasingly employing pharmacodynamic endpoints and biomarkers, but much work remains to make this happen, especially for complex molecules with several or unknown mechanisms of action. We reviewed the available guidance and European Public Assessment Reports (EPARs) of biosimilars approved in the EU via the centralised procedure. This review focuses on the nature and extent of clinical confirmation of biosimilarity considered necessary in addition to analytical and functional data. Cases with conflicting results from different parts of the comparability exercise are discussed, with the aim of identifying whether certain elements of the comparability exercise are more important than others in determining biosimilarity. Taken together, analytical and functional comparison is the foundation of any biosimilar development. In addition, pharmacokinetic similarity is an indispensable prerequisite for any biosimilar approval, so careful planning on behalf of the applicant is mandated to avoid potential failure of such studies, for example, because of large interindividual variability, underpowered trial designs or other methodological causes. Comparative pharmacokinetic studies are a basic requirement for biosimilar development and are usually more sensitive than clinical efficacy trials when detecting potential product-related differences. This may explain why a demonstration of equivalent efficacy could not overrule a finding of dissimilar pharmacokinetic profiles in two cases of biosimilar pegfilgrastim. However, the outcome of efficacy trials depends not only on drug exposure but also on proper pharmacological action of the biological substance in vivo. Therefore, the objectives of both types of studies differ. Efficacy trials should usually be designed as equivalence trials to ensure that the efficacy of the biosimilar is neither decreased nor increased compared with the reference product. However, some remaining uncertainty regarding potentially increased efficacy of the biosimilar may be acceptable in exceptional cases, provided that the data from other parts of the comparability exercise clearly support a conclusion of biosimilarity and safety is assured. In contrast, uncertainties regarding potentially inferior efficacy of the biosimilar may not be acceptable at all. We conclude that the EU biosimilar regulatory framework is robust and able to adapt to advancing knowledge and experience and to strike a balance between regulatory standards, patient safety and feasibility of biosimilar development.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                28 April 2021
                : 15
                : 1735-1747
                [1 ]Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital , Seoul, Republic of Korea
                [2 ]Department of Clinical Research, Chong Kun Dang , Seoul, Republic of Korea
                Author notes
                Correspondence: SeungHwan Lee Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital , 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of KoreaTel +82 2 2072 2343Fax +82 2 742 9252 Email leejh413@snu.ac.kr

                These authors contributed equally to this work

                Author information
                © 2021 Jeon 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).

                : 25 January 2021
                : 06 April 2021
                Page count
                Figures: 5, Tables: 10, References: 29, Pages: 13
                Original Research

                Pharmacology & Pharmaceutical medicine
                pharmacokinetics,pharmacodynamics,biosimilar,darbepoetin alfa


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