Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites.

Abstract

Abbreviations: ANCOVA, analysis of covariance; ANOVA, analysis of variance; IRI, immunoreactive insulin; NEFA, nonesterified fatty acid; T 75% , time in hours for 25% of the administered radioactivity to disappear after bolus subcutaneous injection.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Pharmacokinetics of 125 I-Labeled Insulin Glargine (HOE 901) in Healthy MenComparison with NPH insulin and the influence of different subcutaneous injection sitesOBJECTIVE -To determine the subcutaneous absorption rates and the appearance in plasma of 3 formulations of the long-acting human insulin analog insulin glargine (HOE 901) differing only in zinc content (15, 30, and 80 µg/ml). RESULTS -In study 1, the time in hours for 25% of the administered radioactivity to disappear after bolus subcutaneous injection (T 75% ) for NPH insulin indicated a significantly faster absorption rate compared with the 2 insulin glargine formulations (3.2 vs. 8.8 and 11.0 h, respectively, P Ͻ 0.0001). Mean residual radioactivity with NPH insulin was also significantly lower at 24 h (21.9 vs. 43.8 and 52.2%, P Ͻ 0.0001). The calculated plasma exogenous insulin concentrations after NPH insulin were substantially higher than those with insulin glargine, reaching a peak within the first 6 h after administration before declining. Insulin glargine, however, did not exhibit a distinct peak. Weighted average plasma glucose concentration between 0 and 6 h was significantly lower after NPH compared with insulin glargine (P Ͻ 0.001). In study 2, there were no significant differences in the absorption characteristics of insulin glargine between the 3 injection sites (T 75% = 11.9, 15.3, and 13.2 h for arm, leg, and abdomen, respectively) or in residual radioactivity at 24 h. RESEARCH DESIGN AND METHODSCONCLUSIONS -Subcutaneous absorption of insulin glargine is delayed compared with NPH insulin. There is little or no difference in the absorption rate of insulin glargine between the main subcutaneous injection sites. r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s Diabetes Care

Comparison of insulin detemir and insulin glargine in a basal—bolus regimen, with insulin aspart as the mealtime insulin, in patients with type 1 diabetes: A 52-week, multinational, randomized, open-label, parallel-group, Treat-to-Target noninferiority trial

“…[1][2][3][4] This may make it difficult to achieve stable glycemic control over 24 hours, as both the variability and pronounced peak can result in unexpected hyperglycemia or hypoglycemia.…”

Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence

“…41 Compared with NPH insulin, insulin glargine is characterized by a smoother, relatively flat, GIR curve ( figure 2). There appears to be little or no difference in the absorption rate of insulin glargine between various subcutaneous injection sites (e.g., arm, leg, abdomen), 37 nor was absorption adversely affected by 30 minutes of intense exercise. 42 Euglycemic clamp data gathered with insulin detemir in subjects with type 1 diabetes revealed a duration of action of 19.9 hours for a typical dose of 0.4 units/kg.…”

“…9 Pharmacokinetic/pharmacodynamic studies have confirmed that, compared to NPH insulin, both long-acting analogs have a more prolonged and consistent duration of action, without the marked post-injection peak characteristic of NPH insulin. [34][35][36][37][38] Duration of action is most reliably measured through euglycemic clamp studies in patients with type 1 diabetes, rather than in healthy subjects or those with type 2 diabetes, because of the confounding influence of endogenous insulin secretion. 39 Studies of this nature with insulin glargine have reported a duration of action of 20 to 24 hours after single dose administration 35,36,40 and 24 to 25.6 hours at steady-state.…”

Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir

“…23 NPH insulin, for example, is characterised by a peak in the pharmacokinetic profile 4-6 h after injection followed by a steady decline, rather than a low and constant absorption. 25 The combination of a peak in effect and the unpredictability of the time and extent of this peak inevitably incurs a risk of hypoglycaemia, and as basal insulins are often dosed in the evening there is a real risk of nocturnal hypoglycaemia. This limits the tolerable dose and has led to the search for basal insulin analogues with improved pharmacokinetic and pharmacodynamic properties.…”

“…27,28 Nevertheless, this principle was successfully used in later years to produce insulin glargine (Gly A21 Arg B31 Arg B32 human insulin), in which two arginine residues added to the C-terminus of the B-chain shift the isoelectric point from pH 5.4 to 6.7. 25,29 A second strategy aimed at producing an improved basal insulin was to engineer a stable hexamer by substituting the zinc ions situated in the core of the hexameric structure with cobalt ions. 30,31 This complex, named Co(III)insulin, was found to be absorbed slowly as a hexamer and then undergo enzymatic cleavage into monomers in the circulation.…”