Results of a double-blind, randomized, comparative, cross-sectional study of the pharmacokinetics and pharmacodynamics of genetically engineered human insulin preparations

Justification. On average, about 12 % of all global healthcare spending on diabetes. One of the first domestic human insulin preparations was Rinsulin® R, the biosimilar (bioanalog) of Humulin® Regular. The clinical research program for biosimilars of insulin preparations includes pharmacology studies: pharmacokinetics, pharmacodynamics and clinical safety research. Purpose. Evaluation of the biosimilarity of the Rinsulin® R (biosimilar) and Humulin® Regular (original) preparations in the conditions of hyperinsulinemic euglycemic clamp in healthy volunteers. Materials and methods. The study was conducted on healthy male volunteers aged 18 to 50 years. Study design is a double-blind, randomized, cross-sectional study of comparative pharmacokinetics and pharmacodynamics of drugs. The drugs were injected subcutaneously into the anterior abdominal wall at a dose of 0.3 IU / kg once. The duration of blood sampling to determine the pharmacokinetic parameters was 10 hours: the concentration of insulin in the blood was determined by enzyme-linked immunosorbent assay. Based on the level of glycemia, the glucose infusion rate was adjusted, the data of which were used to calculate the pharmacodynamic parameters. Results and discussion. It was found that the studied drugs are characterized by a high degree of similarity of pharmacokinetics and pharmacodynamics. 90 % confidence intervals for the ratios of the geometric mean values of the primary pharmacokinetics AUC_ins.0-t and C_ins.max fully correspond to the permissible limits of 80-125 % and are, respectively, 88.61-111.52 and 85.411-109,51 %. 95 % confidence intervals for the ratios of the geometric mean values of the primary pharmacodynamics AUC_GIR0-t and GIR_max fully correspond to the permissible limits of 80-125 % and are, respectively, 93.48-112.29 and 95.75-109.17 %. Of particular clinical significance are the synchronous onset of action of drugs, the time of onset of the maximum effect and duration of action. The frequency of adverse events was comparable in the drug groups. Conclusions. Rinsulin® R and Humulin® Regular are equivalent.

инсулин генно-инженерный человеческий, биосимиляр, фармакокинетика, фармакодинамика, гиперинсулинемический эугликемический клэмп, genetic engineering human insulin, biosimilar, pharmacokinetics, pharmacodynamics, hyperinsulinemic euglycemic clamp

1. Diabetes Atlas. IDF, 2017.

2. Федеральный регистр больных сахарным диабетом. [Federal'nyj registr bol'nyh saharnym diabetom. [Internet] (In Russ).] URL: http://diaregistry.ru (дата обращения 03.2019).

3. King P, Peacock I, Donnelly R. The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes. British journal of clinical pharmacology. 1999;48(5):643–648.

4. Демидов Н.А., Мишра О.А. Эффективность и безопасность использования Ринсулина Р и Ринсулина НПХ в условиях амбулаторной практики // РМЖ. – 2016. – № 12. – С. 782–785. [Demidov NA, Mishra OA. Effektivnost' i bezopasnost' ispol'zovaniya Rinsulina R i Rinsulina NPH v usloviyah ambulatornojpraktiki. RMJ. 2016;12:782–785. (In Russ).]

5. Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues (EMEA/CHMP/BMWP/32775/2005_Rev. 1).

6. Guideline on similar biological medicinal products (CHMP/437/04 Rev. 1).

7. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005 Rev. 1).

8. Guideline on the clinical investigation of the pharmacokinetics of therapeutic proteins (EMEA/CHMP/ 89249/2004).

9. Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98).

10. Guideline on Immunogenicity Assessment of Biotechnology-derived Therapeutic Proteins (EMEA/CHMP/BMWP/14327/2006).

11. Решение № 89 от 3 ноября 2016 года "Об утверждении правил проведения исследований биологических лекарственных средств Евразийского экономического союза», глава 15.7 «Доклиническая и клиническая разработка биоаналогичных (биоподобных) лекарственных препаратов, содержащих рекомбинантный инсулин и аналоги инсулина». [Decision № 89 of Nov 3 2016 "Ob utverzhdenii pravil provedeniya issledovaniy biologicheskikh lekarstvennykh sredstv Evraziyskogo ekonomicheskogo soyuza", glava 15.7 "Doklinicheskaya i klinicheskaya razrabotka bioanalogichnyh (biopodobnyh) lekarstvennyh preparatov, soderzhashchih rekombinantnyj insulin i analogi insulina". (In Russ).]

12. Разработка биоаналогичных (биоподобных) лекарственных препаратов, содержащих в качестве фармацевтической субстванции генно-инженерный инсулин человека или аналоги инсулина человека // Руководство по экспертизе лекарственных средств. Том IV. – М.: Полиграф-плюс; 2014. [Razrabotka bioanalogichnykh (biopodobnykh) lekarstvennykh preparatov, soderzhashchikh v kachestve farmatsevticheskoy substvantsii genno-inzhenernyy insulin cheloveka ili analogi insulina cheloveka. In: Rukovodstvo po ekspertize lekarstvennykh sredstv. Vol. IV. Moscow: Poligraf-plyus; 2014. (In Russ).]

13. Heinemann L, Anderson JH. Measurement of insulin absorption and insulin action. Diabetes Technol Ther. 2004 Oct;6(5):698–718. DOI: 10.1089/dia.2004.6.698

14. Heise T, Zijlstra E, Nosek L, et al. Euglycaemic glucose clamp: what it can and cannot do, and how to do it. Diabetes Obes Metab. 2016 Oct;18(10):962–972. DOI: 10.1111/dom.12703

15. Rabiee A, Magruder JT, Grant C, et al. Accuracy and reliability of the Nova StatStrip® glucose meter for real-time blood glucose determinations during glucose clamp studies. J Diabetes Sci Technol. 2010 Sep 1;4(5):1195–1201. DOI: 10.1177/193229681000400519

16. Lindquist KA, Chow K, West A, et al. The StatStrip glucose monitor is suitable for use during hyperinsulinemic euglycemic clamps in a pediatric population. Diabetes technology & therapeutics. 2014;16(5):298–302.

17. Heinemann L, Weyer C, Rauhaus M, et al. Variability of the metabolic effect of soluble insulin and the rapid-acting insulin analog insulin aspart. Diabetes Care. 1998;21(11):1910–1914. DOI: 10.2337/diacare.21.11.1910