Abstract
Background and Objective
Exenatide promotes insulin secretion and inhibits postprandial glucagon secretion. Polyethylene glycolated exenatide injection (PB-119), a derivative obtained by modification of exenatide, is more stable in metabolic behavior than exenatide in vivo. Our study aimed to evaluate the safety, tolerability and pharmacokinetic characteristics of polyethylene glycolated exenatide as a single subcutaneous injection in healthy volunteers.
Methods
Seventy subjects were randomly assigned to 8 incremental dosage groups (2, 5, 10, 25, 50, 100, 200 and 400 µg). The 2- to 50-µg groups had 8 subjects in each group (the ratio of test preparation to placebo was 3:1), and the 100- to 400-µg groups had 10 subjects in each group (the ratio of test preparation to placebo was 4:1). All the subjects received a single subcutaneous injection of polyethylene glycolated exenatide and placebo according to the dosage groups. The tolerability test was conducted in the 2- to 10-µg groups. The pharmacokinetic test was carried out in the 25- to 400-µg groups, and plasma samples were collected to determine the pharmacokinetics of polyethylene glycolated exenatide. After medication, the vital signs of the subjects were monitored, and laboratory tests and electrocardiogram tests were carried out regularly in all the subjects.
Results
All 70 subjects completed the experiment. Except for the 5-µg and 10-µg groups, the safety and tolerability tests showed no adverse reactions in the 2-µg to 50-µg groups. Several subjects in the 100-µg and 200-µg groups had tolerable gastrointestinal tract reactions, and all subjects in the 400-µg group experienced adverse reactions, mainly gastrointestinal tract reactions and liver dysfunction. The pharmacokinetics of polyethylene glycolated exenatide was studied in 36 subjects, which showed slow absorption, a mean peak time of 20–40 h, and a mean elimination half-life of 51–64 h.
Conclusion
The administration of polyethylene glycolated exenatide injection at a single dose of 2–200 µg is safe and tolerable for healthy volunteers. Once-weekly polyethylene glycolated exenatide injection can be recommended.
Clinical Trials Registration
The study was registered at clinicaltrials.gov (No. NCT02084251).
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Change history
06 April 2020
The original version of this article unfortunately contained a mistake.
References
Runge S, Schimmer S, Oschmann J, et al. Differential structural properties of GLP-1 and exendin-4 determine their relative affinity for the GLP-1 receptor N-terminal extracellular domain. Biochemistry. 2007;46:5830–40.
Yan WR, Sun LD. Research progress of glucagon like peptide-1 and its receptor agonists for type 2 diabetes mellitus. Sci Technol Vis. 2017;17:9–12.
Qi LY, Yang LX. Clinical efficacy and safety of glucagon-like peptide-1 receptor agonist in the treatment of type 2 diabetes mellitus. Chin J Clin Ration Drug Use. 2018;11(2C):168–70.
Nielsen LL, Young AA, Parkes DG. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept. 2004;117:77–88.
Parkes DG, Pittner R, Jodka C, et al. Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro. Metabolism. 2001;50:583–9.
Sun CZ, Trevaskis JL, Jodka CM, et al. Bifunctional PEGylated exenatide-amylinomimetic hybrids to treat metabolic disorders: an example of long-acting dual hormonal therapeutics. J Med Chem. 2013;56:9328–41.
Gong N, Ma AN, Zhang LJ, et al. Site-specific PEGylation of exenatide analogues markedly improved their glucoregulatory activity. Br J Pharmacol. 2011;163:399–412.
Li HZ, Xia Y, Shan JN, et al. The immunogenicity and pharmacokinetics comparison of Extended release microspheres in Cynomolgus monkeys. Sichuan J Physiol Sci. 2019;03:1–11.
DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092–100.
Linnebjerg H, Park S, Kothare PA, et al. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul Pept. 2008;151:123–9.
Deng HR, Lin S, Yang XB, et al. Effect of baseline body mass index on glycemic control and weight change with exenatide monotherapy in Chinese drug-naïve type 2 diabetic patients. J Diabetes. 2019;11:509–18.
Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab. 2002;87:1282–90.
Song J, Song XY, Fu Y. Clinical observation of exenatide in the treatment of type 2 diabetes mellitus complicated with obesity. Chin J Diabetes. 2013;21:619–21.
John BB, Robert RH, Jenny H, et al. Effects of exenatide (Exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628–35.
Ai G, Cheng YG. The progress of protein/peptide microspheres for diabetes mellitus. Chin J Pharm. 2008;6(4):206–13.
Junga SJ, Nguyena NTT, Lee SA, et al. In-vivo half-life and hypoglycemic bioactivity of a fusion protein of exenatide and elastin-based polypeptide from recombinant Saccharomyces cerevisiae. J Biotechnol. 2019;303:16–24.
Li ZF, Liu YN, Zeng FD, et al. Safety evaluation of exenatide for injection in Chinese healthy volunteers. Her Med. 2019;38(7):894–8.
Wysham CH, Rosenstock J, Vetter ML, et al. Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes. Diabetes Obes Metab. 2018;20:165–72.
Liu DH, Wang Y, Ji LN, et al. Comparison of clinical efficacy and safety of exenatide and liraglutide in the treatment of type 2 diabetes mellitus. World Latest Med Inf. 2018;18(99):162.
Wysham CH, MacConell LA, Maggs DG, et al. Five-year efficacy and safety data of exenatide once weekly: long-term results from the duration-1 randomized clinical trial. Mayo Clin Proc. 2015;90:356–65.
Henry RR, Klein EJ, Han J, et al. Efficacy and tolerability of exenatide once weekly over 6 years in patients with type 2 diabetes: an uncontrolled open-label extension of the DURATION-1 study. Diabetes Technol Ther. 2016;18:677–86.
Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care. 2014;37:2159–67.
Horowitz M, Aroda VR, Han J, et al. Upper and/or lower gastrointestinal adverse events with glucagon-like peptide-1 receptor agonists: incidences and consequences. Diabetes Obes Metab. 2017;19:672–81.
Fineman MS, Mace KF, Diamant M, et al. Clinical relevance of antiexenatide antibodies: safety, efficacy and cross-reactivity with long term treatment. Diabetes Obes Metab. 2012;14:546–54.
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No funding was received to conduct this study.
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All authors declare no conflicts of interest.
Ethics Approval
The study was approved by the Ethics Committee for Clinical Drug Trials of the First Hospital of Peking Univer-sity (Approval No. 2013L01889).
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All subjects provided written informed consent.
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Cui, H., Zhao, CY., Lv, Y. et al. Safety, Tolerability and Pharmacokinetics of Single Dose Polyethylene Glycolated Exenatide Injection (PB-119) in Healthy Volunteers. Eur J Drug Metab Pharmacokinet 45, 361–369 (2020). https://doi.org/10.1007/s13318-020-00605-9
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DOI: https://doi.org/10.1007/s13318-020-00605-9