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Clinical Evaluation of MK-2640: An Insulin Analog With Glucose-Responsive Properties.

Krug, Alexander W; Visser, Sandra A G; Tsai, Kuenhi; Kandala, Bhargava; Fancourt, Craig; Thornton, Bob; Morrow, Linda; Kaarsholm, Niels C; Bernstein, Harold S; Stoch, S Aubrey; Crutchlow, Michael; Kelley, David E; Iwamoto, Marian.
Clin Pharmacol Ther; 105(2): 417-425, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30125349
The goal of this investigation was to examine clinical translation of glucose responsiveness of MK-2640, which is a novel insulin saccharide conjugate that can bind the insulin receptor or mannose receptor C type 1 (MRC1), the latter dependent upon glucose concentration. In a rising dose study in 36 healthy adults under euglycemic clamp conditions, rising exposures revealed saturation of MK-2640 clearance, likely due to saturation of clearance by MRC1. Potency of MK-2640 was ~25-fold reduced relative to regular human insulin. In a randomized, 2-period crossover trial in 16 subjects with type 1 diabetes mellitus to evaluate glucose-responsiveness of i.v. administered MK-2640, we were unable to demonstrate a glucose-dependent change in MK-2640 clearance, although a significant glucose-dependent augmentation of glucose infusion rate was observed. These pharmacokinetic (PK) and pharmacodynamic (PD) data provide crucial insights into next steps for developing an insulin saccharide conjugate as a clinically effective glucose-responsive insulin analog.
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