Obviously, the Exendin-4-IgG4 fusion protein in the half-life is much longer than Dulaglutide, which is due to the size of whole immunoglobulin G more than the fragment of Fc. a high dose of the fusion protein led normal BALB/c mice to the lower blood glucose level but did not cause severe hypoglycemia. Especially, the half-life time of the fusion protein in cynomolgus monkeys was about 180 hours, almost the longest half-life time among the developed GPL-1 analogues, which suggested a longer half-life time in human being. Conclusions: The intact antibody-like fusion protein has more advantages than the Fc fusion protein including the intention of prolonging the half-life. These results also suggested the fusion protein was a safe and long-acting potential anti-diabetic agent. 0.05, compared with Time 3 (blood glucose level at 3 h after administration). Pharmacokinetics in cynomolgus monkeys After a SC dose of 0.72 mg/kg Exendin-4-IgG4 fusion protein, the plasma concentrations of Exendin-4-IgG4 fusion protein reached the maximum value between 6 h and 24 h and disappeared slow (Number 4; Table 5). The pharmacokinetic profile of Exendin-4-IgG4 fusion protein in cynomolgus monkeys was summarized in Table 6. The average ideals of t1/2, Tmax, Cmax and AUClast were 174.47 8.46 h, 18.00 10.39 h, 5.12 1.49 g/ml and 0.78 0.07 h mg/ml respectively. The half-life of Exendin-4-IgG4 fusion protein after a single dose of 0.72 mg/kg was more than 174 hours in three monkeys (Table 6). Throughout the experiment, the monkeys showed no abnormalities in mental state and behavioral activities, no monkey died during the experiments, and Exendin-4-IgG4 fusion Metformin HCl protein was well tolerated. Open in a separate window Number 4 Pharmacokinetics of Exendin-4-IgG4 fusion protein in cynomolgus monkeys. The plasma concentrations of Exendin-4-IgG4 fusion protein in cynomolgus monkeys after a single SC administration in the dose of 0.72 mg/kg. Table 5 The plasma concentrations of Exendin-4-IgG4 fusion protein in cynomolgus monkeys after a single SC administration (imply SD)
Cfp (ng/ml)261.20 73.85709.44 26.253425.37 493.114958.23 1693.813302.04 1587.192077.52 360.931400.86 195.941219.82 85.821250.01 114.351076.54 131.10270.82 15.89274.87 1.63262.68 10.10255.48 14.38 Open in a separate window Cfp indicates plasma concentration of Exendin-4-IgG4 fusion protein. Table 6 Pharmacokinetic guidelines of Exendin-4-IgG4 fusion protein in cynomolgus monkeys (imply SD)
AUClast (h mg/ml)
AUCinf (h mg/ml)
1184.24246.770.780.85225.110.85168.292169.39244.690.720.78225.070.92186.883169.7863.890.640.71249.011.02190.75Mean174.4718.005.120.720.78233.070.93181.97SD8.4610.391.490.070.0713.810.0912.01CV4.8557.7429.109.499.105.939.176.60 Open in a separate window Pharmacokinetic guidelines were determined from your mean plasma concentration data Metformin HCl from three animals per time point. Cmax shows maximal observed plasma concentration; Tmax shows time of maximal observed plasma concentration; AUClast shows area under the plasma concentration curve from zero to last observed time ; AUCinf shows area under the plasma concentration curve from zero to infinity; t1/2 shows removal half-life; Cl shows clearance like a function of bioavailability; Vd shows apparent volume of distribution at stable state like a function of bioavailability; MRT shows mean residence time. Conversation The anti-diabetes drug Exendin-4 (Exenatide, trade name Byetta) is definitely a new class of injectable type 2 diabetes drug, which was jointly developed by Eli IGF1 Lilly and Organization and Amylin Pharmaceuticals. It was authorized by the US Food and Drug Administration (FDA) in 2005. On January 27, 2012, the FDA authorized a sustained-release dose form of Exenatide, which was the first once-a-week restorative drug in the treatment of type 2 diabetes . Dulaglutide (LY2189265) a GPL-1 analogue covalently linked to a constant fragment (Fc) of a human being immunoglobulin class 4 (IgG4) offers almost completed the clinical tests . Others GPL-1 analogue were Metformin HCl developing including Lixisenatide, Albiglutide as well as CJC-1134-Personal computer. CJC-1134-Personal computer was a recombinant human being serum albumin-exendin-4 conjugated protein . In this study, we describe the Metformin HCl executive of Exendin-4-IgG4 fusion protein, a recombinant fusion protein linking the Exendin-4-encoding gene and the genes encoding the human being antibody heavy-chain constant region (4).