Christian Hove Rasmussen
Novo Nordisk A/S
Objectives: Mixtures of soluble and crystalline insulin aspart are currently used in formulated concentrations of 100 U/mL. The purpose of this study is to predict the effect of increasing the concentration of the insulin up to 5 times on the observed pharmacokinetics. An increase in insulin concentration is relevant for obese or insulin resistant subjects since it minimizes the injection volume or the number of injections required for administering a given dose.
Methods: A variety of data from the literature was used to identify the mechanisms governing the absorption process, including images from micro CT scanning, histological cross sections, and measurements of subcutaneous blood flow. The involved mechanisms included dissolution of insulin crystals, self-association of soluble insulin, degradation of both crystalline and soluble insulin in subcutis, and a flow-dependent absorption rate. Most of these processes were characterized using parameters determined from separate experiments and the processes were combined in a biosimulation-type model [1]. To test the performance of the model and identify remaining parameters, individual pharmacokinetic profiles from 19 type 1 diabetic subjects having received soluble human insulin, insulin aspart and biphasic insulin aspart (crossover design) [2] were used to perform a population-based pharmacokinetic analysis in MONOLIX.
Results: The model was able to describe the individual profiles of the subjects using reasonable physiological parameter values. Using these parameters, insulin concentrations of up to 500 U/mL were simulated. The overall absorption process was found to be significantly slower for higher concentrations compared to 100 U/mL. Thus, cmax was lower for both soluble and crystalline insulin and, additionally, a reduction in bioavailability was observed for crystalline mixtures. Both effects were predicted to be most pronounced for human crystalline insulin.
Conclusions: Concentrated insulin mixtures were predicted to be more protracted than 100 U/mL formulations with observed reductions cmax and in some cases reduced bioavailability. Thus, concentrated formulations of insulin are not predicted to be bioequivalent with U100, and subjects using crystalline insulins switching from 100 U/mL to e.g. 500 U/mL would possibly need to adjust their dose. The findings for soluble human insulin correspond with results from two clinical studies for 500 U/mL human insulin [3, 4].
References:
[1] Rasmussen CH, Søeborg T, Mosekilde E, Colding-Jørgensen M (2012) Absorption Kinetics of Insulin Mixtures after Subcutaneous Administration. Chapter 15 in: Mosekilde E, Sosnovtseva O, Rostami-Hodjegan (2012) Biosimulation in Biomedical Research, Health Care and Drug Development. Springer
[2] Ma Z, Parkner T, Frystyk J, Laursen T, Lauritzen T, Christiansen JS (2012) A comparison of pharmacokinetics and pharmacodynamics of insulin aspart, biphasic insulin aspart 70, biphasic insulin aspart 50 and human insulin; a randomized, quadruple crossover study. Diabetes Technol Ther (in press)
[3] Segal AR, Brunner JE, Burch FT, Jackson JA (2010) Use of concentrated insulin human regular (U-500) for patients with diabetes. Am J Health Syst Pharm 67(18):1526-1535
[4] de la Peña A, Riddle M, Morrow LA, Jiang HH, Linnebjerg H, Scott A, Win KM, Hompesch M, Mace KF, Jacobson JG, Jackson JA (2011) Pharmacokinetics and pharmacodynamics of high-dose human regular U-500 insulin versus human regular U-100 insulin in healthy obese subjects. Diabetes Care 34(12):2496-2501
Reference: PAGE 21 () Abstr 2551 [www.page-meeting.org/?abstract=2551]
Poster: Endocrine