Publications (2)0 Total impact
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Conference Proceeding: A New Class of GLP-1 Analog, SKL-18287; Pharmacological Profiles
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ABSTRACT: First generation GLP-1 analogs, exenatide and liraglutide have been launched as treatment for T2DM. But they require daily injection for patients. Therefore the development of 2nd-generation GLP-1 analogs, LAR, which have better pharmacological and pharmacokinetic profiles is underway, to give more effective benefits to patients. SKL-18287 (hereafter “SKL”) is designed to have DPP-IV resistance and plasma protein binding ability. SKL is a novel GLP-1 analog that modifies native GLP-1 with several natural amino acids without any chemical modifications and is currently developed as a sustained release product. The pharmacological profiles of SKL using various models were investigated. 1) SKL exhibited strong stability when co-incubated with rat plasma in vitro, and more than 80% of SKL persisted after 48 hr incubation. 2) In mouse insulinoma cell line, MIN6, SKL increased glucose stimulated insulin secretion in a concentration dependent manner. The maximum increment of SKL (92%) was comparable to that of native GLP-1 (100%). 3) The blood glucose lowering effect in the glucose tolerance test (ipGTT) of C57BL/6J mice was investigated. The single subcutaneously injected SKL (1, 3 nmol/kg) reduced 48-57% of area under the blood glucose - time curve (AUC0-60min) (exendin 4, or “Ex4” [0.06 nmol/kg]: 55%, all p<0.01 vs. vehicle as 100%). Moreover SKL exhibited a similar blood glucose lowering effect in the second challenge of ipGTT at 3 hr after the first ipGTT, whereas Ex4 did not (AUC0-60min: SKL: 46 -54%; p<0.01 vs. vehicle, Ex4: 10%; ns). In other word, the effect of SKL was sustained longer than that of Ex4. 4) The blood glucose lowering effect of SKL on the random fed state of db/db mice was investigated. In this model, SKL also exhibited an excellent blood glucose lowering effect with dose dependent manner up to 5 hr after a single subcutaneous injection. In conclusion, these results indicated that SKL is expected to be more effective than existing GLP-1 analogs. Additionally, considering its structural, pharmacokinetic, and ease manufacturing characteristics, we believe that SKL has a potential impact as a new class of GLP-1 analog.American Diabetes Association 70th Scientific Sessions Poster presentation P-586, Orlando, Florida; 01/2010 -
Conference Proceeding: Novel Long-Acting GLP-1 Analog (SKL-18287); Pharmacokinetics and Pharmacodynamics
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ABSTRACT: GLP-1 is rapidly degraded by the DPP-IV enzyme. Therefore, the blood level of GLP-1 must be maintained for a long time for the treatment of T2DM. With the appearance of excenatide and liraglutide, it became possible to treat patients by drug injection once or twice a day, but a lower administration frequency is more desirable for patient compliance. Novel, long-acting GLP-1 analog (SKL-18287) is designed to have DPP-IV resistance and plasma protein binding ability, and is composed only of natural amino acids without any chemical modifications. SKL-18287 is stable for more than 24 hours at 37 °C in rat plasma and human plasma, and shows better stability than excendin-4. The pharmacokinetic and pharmacodynamic profiles of SKL-18287 were studied and compared with those of excenatide and liraglutide. When SKL-18287 was administered intravenously to rats, cynomolgus monkeys, beagle dogs and mini pigs, the apparent volume of distribution approximated that of the plasma volume, which suggests that a large fraction of analog is localized to systemic circulation. After subcutaneous administration, the plasma concentration reached maximum at 5-10 hours and was eliminated monoexponentially. The bioavailability in animals was 50% or more. The half life was extended depending on the body weight of the animal. As a result of the animal scale-up, the t1/2 of SKL-18287 in humans was estimated at 21 hours and is predicted to be longer in comparison with excenatide and liraglutide. On the other hand, the glucose lowering effect was investigated in Zucker diabetic fatty (ZDF) rats. After subcutaneous administration, plasma glucose levels decreased up to 14 hours in non-fasting conditions. PK/PD analysis suggested that the glucose lowering effect was directly predicted by the plasma concentration profiles of SKL-18287. SKL-18287 is expected to improve hyperglycemia of T2DM with administration once a day. In addition, a longer continuing effect will be achieved by use of a controlled release formula.American Diabetes Association 70th Scientific Session poster presentation P-599, Orlando, Florida; 01/2010
