Properties of Pramlintide and Insulin upon Mixing
Properties of Pramlintide and Insulin upon Mixing
Purpose: The pharmacokinetics, pharmacodynamics, and safety of pramlintide and various insulin formulations in patients with type 1 diabetes mellitus (DM) when given as separate injections or mixed in the same syringe before injection were studied.
Methods: In two randomized, open-label, placebo-controlled, five-period-crossover studies, patients with type 1 DM received preprandial injections of pramlintide, short-acting insulin, and long-acting insulin administered either by separate injections or after mixing in various combinations. Serum free insulin and plasma glucose concentrations were measured for 10 hours and plasma pramlintide concentrations for 5 hours after injection.
Results: Blood samples were collected from a total of 51 patients. All treatments involving mixtures were comparable to separate injections with respect to the area under the concentration-versus-time curve (AUC) and the maximum concentration ( Cmax) of serum free insulin. There were some minor differences in the AUC and Cmax of pramlintide. No injection-site reactions or other unexpected adverse events were observed.
Conclusion: Mixing pramlintide with short- or long-acting insulin in the same syringe before subcutaneous injection did not affect the pharmacodynamics of glucose or the pharmacokinetics of insulin or pramlintide in a clinically significant manner.
Type 1 diabetes mellitus (DM) is most often caused by an autoimmune-mediated destruction of pancreatic β-cells that generally renders patients absolutely deficient in two glucoregulatory peptide hormones, insulin and amylin. For more than 80 years, insulin replacement therapy has been the primary pharmacologic treatment for this disease, and many short- and long-acting insulin formulations are available for mealtime and basal insulin replacement, including premixed formulations containing stable mixtures of short- and long-acting insulin products. Although alternative routes of insulin administration have been explored for decades, subcutaneous injection remains the standard route. Except for long-acting insulin analogue glargine, formulated at pH 4, all currently available insulin products are formulated at pH 7-8.
Amylin, a β-cell hormone that is normally cosecreted with insulin in response to meals, is also completely deficient in patients with type 1 DM. Amylin exhibits several glucoregulatory effects that complement those of insulin in postprandial glucose regulation, suggesting that mealtime amylin administration, as an adjunct to mealtime insulin replacement, may facilitate improvement of postprandial and overall glycemic control in patients with type 1 DM.
Naturally occurring human amylin is unsuitable for clinical use because of several physicochemical properties, including poor solubility, self-aggregation, and formation of β-pleated sheets, amyloid fibrils, and amyloid plaques. Selectively substituting proline for Ala-25, Ser-28, and Ser-29 addresses the suboptimal physicochemical properties of human amylin while preserving the important metabolic actions. Pramlintide acetate injection, which contains this amylin analogue, is a sterile, clear, colorless, aqueous solution also containing mannitol (for isotonicity) and m -cresol (a preservative).
Short-term and long-term clinical trials have found that adding preprandial pramlintide injections to insulin therapy reduced postprandial glucose excursions and improved overall glycemic control (hemoglobin A1c levels) in patients with type 1 DM. In these clinical studies, pramlintide was administered via separate subcutaneous injections in addition to insulin. In general, this practice was accepted and adhered to by the study participants; however, it is possible that, if pramlintide becomes available for clinical use, some patients might either inadvertently or deliberately mix pramlintide and insulin in the same syringe before injection.
We studied the pharmacokinetics, pharmacodynamics, and safety of pramlintide and various insulin formulations in patients with type 1 DM when given as separate injections or mixed in the same syringe before injection.
Purpose: The pharmacokinetics, pharmacodynamics, and safety of pramlintide and various insulin formulations in patients with type 1 diabetes mellitus (DM) when given as separate injections or mixed in the same syringe before injection were studied.
Methods: In two randomized, open-label, placebo-controlled, five-period-crossover studies, patients with type 1 DM received preprandial injections of pramlintide, short-acting insulin, and long-acting insulin administered either by separate injections or after mixing in various combinations. Serum free insulin and plasma glucose concentrations were measured for 10 hours and plasma pramlintide concentrations for 5 hours after injection.
Results: Blood samples were collected from a total of 51 patients. All treatments involving mixtures were comparable to separate injections with respect to the area under the concentration-versus-time curve (AUC) and the maximum concentration ( Cmax) of serum free insulin. There were some minor differences in the AUC and Cmax of pramlintide. No injection-site reactions or other unexpected adverse events were observed.
Conclusion: Mixing pramlintide with short- or long-acting insulin in the same syringe before subcutaneous injection did not affect the pharmacodynamics of glucose or the pharmacokinetics of insulin or pramlintide in a clinically significant manner.
Type 1 diabetes mellitus (DM) is most often caused by an autoimmune-mediated destruction of pancreatic β-cells that generally renders patients absolutely deficient in two glucoregulatory peptide hormones, insulin and amylin. For more than 80 years, insulin replacement therapy has been the primary pharmacologic treatment for this disease, and many short- and long-acting insulin formulations are available for mealtime and basal insulin replacement, including premixed formulations containing stable mixtures of short- and long-acting insulin products. Although alternative routes of insulin administration have been explored for decades, subcutaneous injection remains the standard route. Except for long-acting insulin analogue glargine, formulated at pH 4, all currently available insulin products are formulated at pH 7-8.
Amylin, a β-cell hormone that is normally cosecreted with insulin in response to meals, is also completely deficient in patients with type 1 DM. Amylin exhibits several glucoregulatory effects that complement those of insulin in postprandial glucose regulation, suggesting that mealtime amylin administration, as an adjunct to mealtime insulin replacement, may facilitate improvement of postprandial and overall glycemic control in patients with type 1 DM.
Naturally occurring human amylin is unsuitable for clinical use because of several physicochemical properties, including poor solubility, self-aggregation, and formation of β-pleated sheets, amyloid fibrils, and amyloid plaques. Selectively substituting proline for Ala-25, Ser-28, and Ser-29 addresses the suboptimal physicochemical properties of human amylin while preserving the important metabolic actions. Pramlintide acetate injection, which contains this amylin analogue, is a sterile, clear, colorless, aqueous solution also containing mannitol (for isotonicity) and m -cresol (a preservative).
Short-term and long-term clinical trials have found that adding preprandial pramlintide injections to insulin therapy reduced postprandial glucose excursions and improved overall glycemic control (hemoglobin A1c levels) in patients with type 1 DM. In these clinical studies, pramlintide was administered via separate subcutaneous injections in addition to insulin. In general, this practice was accepted and adhered to by the study participants; however, it is possible that, if pramlintide becomes available for clinical use, some patients might either inadvertently or deliberately mix pramlintide and insulin in the same syringe before injection.
We studied the pharmacokinetics, pharmacodynamics, and safety of pramlintide and various insulin formulations in patients with type 1 DM when given as separate injections or mixed in the same syringe before injection.
Source...