Similar pharmacokinetics and pharmacodynamics of rapid-acting insulin lispro products SAR342434 and US- and EU-approved Humalog in subjects with type 1 diabetes.

AIM: To compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 3 rapid-acting insulin lispro products: SAR342434 solution, United States (US)-approved Humalog and European Union (EU)-approved Humalog. METHODS: In a single-centre, randomized, double-blind, 3-treatment, 3-period, 6-sequence, crossover, euglycaemic clamp study (NCT02273258), adult male subjects with type 1 diabetes were randomized to receive 0.3 U/kg of SAR342434 solution, US-approved and EU-approved Humalog under fasted conditions. PK and PD (glucose infusion rate [GIR]) were assessed up to 12 hours. RESULTS: Of the 30 subjects randomized, 28 completed all 3 treatment periods. Mean concentration and GIR vs time profiles were similar for all 3 products. Exposure (INS-Cmax , INS-AUClast and INS-AUC) and activity (GIRmax and GIR-AUC0-12h ) of SAR342434, US-approved and EU-approved Humalog were similar in all comparisons (point estimates of treatment ratios, 0.95-1.03 for PK parameters and 1.00-1.07 for PD parameters), with 90% confidence intervals for the ratios of geometric least squares means within the pre-specified bioequivalence limit (0.80-1.25) and no significant differences in time-related parameters. Within-subject variability of exposure and activity was low across the 3 clamps, indicating high day-to-day reproducibility in clamp performance, irrespective of the individual product. Adverse events were similar for all 3 products. No safety concerns were noted in vital signs or in laboratory and electrocardiogram data. CONCLUSIONS: The results of this study demonstrate similarity in insulin lispro exposure profiles and PD activity of SAR342434 solution to both US- and EU-approved Humalog, and between both US- and EU-approved Humalog, supporting the use of SAR342434 solution for injection as a follow-on product.

Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects.

BACKGROUND: Lixisenatide is a once-daily, prandial, short-acting glucagon-like peptide-1 receptor agonist. Its main antidiabetic effect is to delay gastric emptying to control postprandial plasma glucose excursions. The dose-response relationship of the integrated insulinotropic and gastrostatic response to lixisenatide in healthy volunteers after a standardized liquid meal was investigated. METHODS: Twenty healthy subjects received acetaminophen 1000 mg with a standardized liquid meal 60 min after a single subcutaneous injection of placebo or lixisenatide 2.5, 5, 10 or 20 µg in randomized order separated by a 2- to 7-day washout. Acetaminophen pharmacokinetics served as a surrogate to assess rate of gastric emptying. Postprandial plasma glucose, insulin, C-peptide and glucagon were assessed for 5 h after the meal test, and lixisenatide pharmacokinetics were determined for 6 h. RESULTS: After lixisenatide administration and prior to the standardized meal, insulin and C-peptide transiently increased, while fasting plasma glucose decreased in a dose-dependent manner. After the meal, postprandial plasma glucose, insulin and C-peptide were dose proportionally reduced with lixisenatide versus placebo for up to 6 h. Compared with placebo, glucagon levels were transiently lower after any lixisenatide dose, with more sustained reductions after the meal and no apparent dose-related trends. Acetaminophen absorption was significantly reduced and delayed compared with placebo for lixisenatide doses ≥5 µg and demonstrated dose-dependent slowing of gastric emptying. Lixisenatide displayed near dose-proportional exposure, with gastrointestinal events increasing with dose. CONCLUSIONS: Lixisenatide reduced fasting plasma glucose via stimulation of glucose-dependent insulin release and controlled postprandial plasma glucose by delaying gastric emptying, demonstrating it to be a valuable option for overall glycaemic control.

Insulin glargine metabolite 21(A) -Gly-human insulin (M1) is the principal component circulating in the plasma of young children with type 1 diabetes: results from the PRESCHOOL study.

BACKGROUND AND AIMS: Insulin glargine metabolite 21(A) -Gly-human insulin (M1) is the principal component circulating in plasma of adults with type 1 diabetes. The objective of this study was to confirm this finding in young children and to rule out accumulation of parent insulin glargine. DESIGN AND METHODS: Children with type 1 diabetes from the PRESCHOOL study, aged 2-6 yr, were treated with insulin glargine for 24 wk (n = 62). Blood samples were drawn at weeks 1, 2, and 4 approximately 24 h after the last dose and analyzed for glargine, M1, and Thr(30B) -des-M1 (M2) using immunoaffinity purification and liquid chromatography with mass spectrometry. The lower limit of quantification was 33 pmol/L for all analytes. RESULTS: M1 was the principal active component circulating in plasma. Mean (SD) plasma Ctrough values were 101 (138), 80 (122), and 79 (102) pmol/L following glargine doses of 0.33 (0.02), 0.34 (0.02), and 0.38 (0.03) U/kg at weeks 1, 2, and 4, respectively. Parent insulin glargine and M2 concentrations were below the level of quantification. These results are in line with those observed in adults and indicate no accumulation of the parent compound in this patient population. CONCLUSION: In young children with type 1 diabetes, the principal component circulating in plasma after subcutaneous injection of insulin glargine is M1, the pharmacologically active component. No accumulation of the parent insulin glargine was observed. These data provide additional evidence on the safety profile of insulin glargine in young children (Clinical trial identifier: NCT00993473).

New insulin glargine 300 Units · mL-1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 Units · mL-1.

OBJECTIVE: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a new insulin glargine comprising 300 units · mL(-1) (Gla-300), compared with insulin glargine 100 units · mL(-1) (Gla-100) at steady state in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: A randomized, double-blind, crossover study (N = 30) was conducted, applying the euglycemic clamp technique over a period of 36 h. In this multiple-dose to steady-state study, participants received once-daily subcutaneous administrations of either 0.4 (cohort 1) or 0.6 units · kg(-1) (cohort 2) Gla-300 for 8 days in one treatment period and 0.4 units · kg(-1) Gla-100 for 8 days in the other. Here we focus on the results of a direct comparison between 0.4 units · kg(-1) of each treatment. PK and PD assessments performed on the last treatment day included serum insulin measurements using a radioimmunoassay and the automated euglycemic glucose clamp technique over 36 h. RESULTS: At steady state, insulin concentration (INS) and glucose infusion rate (GIR) profiles of Gla-300 were more constant and more evenly distributed over 24 h compared with those of Gla-100 and lasted longer, as supported by the later time (∼ 3 h) to 50% of the area under the serum INS and GIR time curves from time zero to 36 h post dosing. Tight blood glucose control (≤ 105 mg · dL(-1)) was maintained for approximately 5 h longer (median of 30 h) with Gla-300 compared with Gla-100. CONCLUSIONS: Gla-300 provides more even steady-state PK and PD profiles and a longer duration of action than Gla-100, extending blood glucose control well beyond 24 h.

Effects of lixisenatide once daily on gastric emptying in type 2 diabetes--relationship to postprandial glycemia.

OBJECTIVES: To determine the effects of lixisenatide, a new once-daily (QD) glucagon-like peptide-1 receptor agonist, on postprandial glucose (PPG) and gastric emptying, and the relationship between these effects in patients with type 2 diabetes mellitus (T2DM). METHODS: Data were obtained from a randomized, double-blind, placebo-controlled, parallel-group study with treatment duration of 28 days in patients with T2DM receiving ≤2 oral antidiabetic drugs. Lixisenatide was injected subcutaneously using an ascending dose range (5-20 µg) increased every fifth day in increments of 2.5 µg. Blood glucose was determined before and after three standardized meals (breakfast, lunch, and dinner). Gastric emptying of the standardized breakfast was determined by a (13)C-octanoic acid breath test at baseline (Day-1) and at Day 28. RESULTS: A total of 21 and 22 patients were randomized to lixisenatide 20 µg QD and placebo, respectively. With lixisenatide 20 µg QD, there was a reduction in PPG when compared with placebo after breakfast (p<0.0001), lunch (p<0.001) and dinner (p<0.05). Hence, lixisenatide 20 µg administered in the morning exhibited a pharmacodynamic effect on blood glucose throughout the day. Gastric emptying (50% emptying time) increased substantially from baseline with lixisenatide 20 µg QD, but not with placebo (change from baseline ± SD: -24.1 ± 133.1 min for placebo and 211.5 ± 278.5 min for lixisenatide; p<0.01). There was an inverse relationship between PPG area under the curve after breakfast and gastric emptying with lixisenatide 20 µg QD (n=17, r(2)=0.51, p<0.05), but not with placebo. CONCLUSIONS: In this study, lixisenatide at a dose of 20 µg QD reduced postprandial glycemic excursions in patients with T2DM, possibly as a result of sustained slowing of gastric emptying.

Plasma exposure to insulin glargine and its metabolites M1 and M2 after subcutaneous injection of therapeutic and supratherapeutic doses of glargine in subjects with type 1 diabetes.

OBJECTIVE: In vivo, after subcutaneous injection, insulin glargine (21(A)-Gly-31(B)-Arg-32(B)-Arg-human insulin) is enzymatically processed into 21(A)-Gly-human insulin (metabolite 1 [M1]). 21(A)-Gly-des-30(B)-Thr-human insulin (metabolite 2 [M2]) is also found. In vitro, glargine exhibits slightly higher affinity, whereas M1 and M2 exhibit lower affinity for IGF-1 receptor, as well as mitogenic properties, versus human insulin. The aim of the study was to quantitate plasma concentrations of glargine, M1, and M2 after subcutaneous injection of glargine in male type 1 diabetic subjects. RESEARCH DESIGN AND METHODS: Glargine, M1, and M2 were determined in blood samples obtained from 12, 11, and 11 type 1 diabetic subjects who received single subcutaneous doses of 0.3, 0.6, or 1.2 units · kg(-1) glargine in a euglycemic clamp study. Glargine, M1, and M2 were extracted using immunoaffinity columns and quantified by a specific liquid chromatography-tandem mass spectrometry assay. Lower limit of quantification was 0.2 ng · mL(-1) (33 pmol · L(-1)) per analyte. RESULTS: Plasma M1 concentration increased with increasing dose; geometric mean (percent coefficient of variation) M1-area under the curve between time of dosing and 30 h after dosing (AUC(0-30h)) was 1,261 (66), 2,867 (35), and 4,693 (22) pmol · h · L(-1) at doses of 0.3, 0.6, and 1.2 units · kg(-1), respectively, and correlated with metabolic effect assessed as pharmacodynamics-AUC(0-30h) of the glucose infusion rate following glargine administration (r = 0.74; P < 0.01). Glargine and M2 were detectable in only one-third of subjects and at a few time points. CONCLUSIONS: After subcutaneous injection of glargine in male subjects with type 1 diabetes, exposure to glargine is marginal, if any, even at supratherapeutic doses. Glargine is rapidly and nearly completely processed to M1 (21(A)-Gly-human insulin), which mediates the metabolic effect of injected glargine.

Clinical pharmacokinetics and pharmacodynamics of insulin glulisine.

Insulin glulisine injection [3(B)-Lys, 29(B)-Glu-human insulin] is the newest human insulin analogue product for the control of mealtime blood sugar. As with insulin aspart and insulin lispro products, the insulin glulisine product displays faster absorption and onset of action, with a shorter duration of action than that of regular human insulin. The modifications of the amino acid sequence at positions 3 and 29 in the B chain of human insulin simultaneously provide stability to the molecular structure and render the insulin glulisine molecule less likely to self-associate, compared with human insulin, while still allowing the formation of dimers at pharmaceutical concentrations. Unlike other insulin analogue products, this allows for a viable drug product in the absence of hexamer-promoting zinc and, thus, provides immediate availability of insulin glulisine molecules at the injection site for absorption. Pharmacokinetic studies with insulin glulisine have shown an absorption profile with a peak insulin concentration approximately twice that of regular human insulin, which is reached in approximately half the time. Dose proportionality in early, maximum and total exposure is observed for insulin glulisine over the therapeutic relevant dose range up to 0.4 U/kg. The pharmacodynamic profile of insulin glulisine reflects the absorption kinetics by demonstrating a greater rate of glucose utilization, which is completed earlier and at equipotency on a molar base compared with regular human insulin. Dose-proportionality in glucose utilization has been established for insulin glulisine in patients with type 1 diabetes mellitus in the dose range of 0.075-0.15 U/kg, and a less than dose-proportional increase above 0.15 U/kg, indicating saturation of insulin action in general. The rapid absorption and action of insulin glulisine show similar low intrasubject variability compared with insulin lispro and regular human insulin when given repeatedly, and have been confirmed in healthy subjects of different body mass indices (BMIs) and ethnic groups, as well as adults and children with type 1 and type 2 diabetes. Furthermore, the early insulin exposure and action of insulin glulisine were slightly -- but consistently -- greater than those of insulin lispro in healthy volunteers across a wide range of BMIs.Meal studies in patients with type 1 diabetes show that insulin glulisine provides better postprandial blood glucose control than regular human insulin when administered immediately pre-meal, and equivalent control when given after the meal. In a study in patients with type 2 diabetes, the overall postprandial blood glucose excursions were lower with insulin glulisine than with insulin lispro. Therefore, by virtue of its primary structure, insulin glulisine demonstrates both low self-association in solution and stability for a viable insulin product in the absence of zinc, thereby maintaining immediate availability for absorption after subcutaneous injection. This confers the most rapid onset of glucose-lowering activity and adds to the flexibility in postprandial blood glucose control.

Insulin glulisine complementing basal insulins: a review of structure and activity.

The advancement in protein engineering offers targeted development of insulin analogs that display either faster absorption kinetics or longer time-action profiles compared with human insulin and, therefore, more closely mimic endogenous insulin secretion. Insulin glulisine (3(B)Lys29(B) Glu-human insulin) is a new fast-acting analog that provides absorption and onset of action more rapidly with a shorter duration of action compared with regular human insulin, and thus better resembles physiologic mealtime insulin requirements. Insulin glulisine has been designed to exhibit intrinsic stability while maintaining rapid deployment of insulin monomers. Pharmacokinetic and pharmacodynamic profiling of insulin glulisine in healthy subjects and patients with type 1 and type 2 diabetes not only confirms the rapid absorption and fast action of insulin glulisine compared with human insulin, but also provides evidence that the unique drug formulation may offer additional benefits. Insulin glulisine complements insulin glargine (21(A)-Gly30(Ba)-L-Arg-30(Bb)-L-Arg-human insulin), the first long-acting basal insulin analog that displays a smoothed time-action profile with a 24-h duration of action. Together these analogs offer patients a more physiologic approach to insulin replacement.

Advantage of premeal-injected insulin glulisine compared with regular human insulin in subjects with type 1 diabetes.

OBJECTIVE: Insulin glulisine, a rapid-acting insulin analog, provides prandial insulin replacement. In this study, we compared postprandial blood glucose control after pre- and postmeal insulin glulisine with regular human insulin (RHI). RESEARCH DESIGN AND METHODS: In a single-dose, randomized, four-way complete cross-over study, subjects received standardized, 15-min meals, covered by subcutaneous injections of either insulin glulisine (immediately premeal or 15 min postmeal; 0.15 unit/kg per injection) or RHI (30 min or immediately premeal; 0.15 unit/kg per injection). Twenty-one patients with type 1 diabetes (mean age 36.4 years; mean BMI 26.0 kg/m(2)) were enrolled; 20 patients completed the study. Postprandial baseline-subtracted blood glucose exposure, maximum excursion, maximum and minimum blood glucose concentrations, and time to the maximum excursion and minimum concentration were assessed, along with serum insulin concentrations. RESULTS: Lower maximum blood glucose excursion (65 vs. 89 mg/dl), total blood glucose exposure within 2 h (279 vs. 334 mg . h/dl, maximum blood glucose concentration (180 vs. 209 mg/dl), and less time to maximum blood glucose excursion (48 vs. 70 min) were seen with immediately premeal insulin glulisine versus immediately premeal RHI. The maximum serum concentration of insulin glulisine was almost double that of RHI (82 vs. 45 microU/ml), achieved in approximately half the time (55 vs. 97 min). Conversely, insulin glulisine (15 min postmeal) versus RHI (immediately premeal) and RHI (30 min premeal) versus insulin glulisine (immediately premeal) resulted in comparable blood glucose control. CONCLUSIONS: Insulin glulisine renders postprandial glucose disposal closer to physiologic requirements compared with RHI and enables appropriate timing of prandial insulin administration.

Fluctuation of serum basal insulin levels following single and multiple dosing of insulin glargine.

BACKGROUND: The large fluctuations in blood concentrations and activity observed with insulin therapies such as NPH insulin or insulin ultralente may result in hyper- or hypoglycemia. METHODS: We compared the fluctuations of these insulins with the long-acting basal insulin analog insulin glargine as a re-analysis of three Phase I studies: (I) glargine with NPH or ultralente [single-dose (0.4 IU/kg), randomized study in healthy volunteers (n = 36)]; (II) glargine or NPH [single-dose (0.3 IU/kg), randomized study in patients with diabetes mellitus Type 1 (DMT1) (n = 20)]; and (III) glargine (tailor-made dose) plus insulin lispro in DMT1 (n = 15 over 11 days). Percent deviation around average serum concentration over 24 h (PF24) was used to determine within-patient fluctuation and mean fluctuation value for each treatment group. RESULTS: Mean PF24 in healthy volunteers (Study I) was significantly lower with glargine (19.8%) than with NPH and ultralente (31.9% and 47.2%, respectively; both P < 0.001 vs. glargine). Similarly, about half the fluctuation observed with NPH (PF24 25.8%) was seen with glargine (PF24 14.2%; P < 0.001) in DMT1 (Study II). In ambulatory DMT1 patients receiving multiple glargine doses, PF24 values demonstrated that the same low fluctuations (PF24 20%) were retained throughout near-maintenance treatment (Study III). CONCLUSIONS: Glargine provided less diurnal fluctuation in serum insulin levels than NPH and ultralente in healthy volunteers and patients with DMT1. This lower fluctuation of glargine over NPH or ultralente can help to reduce hyper- or hypoglycemia risks associated with insulin therapy and accordingly encourage achievement of better blood glucose control.

The effect of smoking cessation and subsequent resumption on absorption of inhaled insulin.

OBJECTIVE: To assess the absorption profile of inhaled insulin in healthy, actively smoking subjects at baseline, after smoking cessation, and after smoking resumption and compare it with nonsmoking subjects. RESEARCH DESIGN AND METHODS: Insulin pharmacokinetics and glucodynamics were measured in 20 male smoking subjects (10-20 cigarettes/day) and 10 matched nonsmoking subjects after receiving inhaled insulin (1 mg) or the approximate subcutaneous insulin equivalent (3 units) in a randomized cross-over fashion. All smokers then received inhaled insulin 12 h, 3 days, and 7 days into a smoking cessation period. They then resumed smoking for 2-3 days before again receiving inhaled insulin 1 h after the last cigarette. RESULTS: Before smoking cessation, maximum insulin concentration (Cmax) and area under the curve (AUC) for insulin concentration time (AUC-Insulin(0-360)) with inhaled insulin were higher, and time to Cmax (t(max)) shorter, in smokers than nonsmokers (Cmax 26.8 vs. 9.7 microU/ml; AUC-Insulin(0-360) 2,583 vs. 1,645 microU x ml(-1) x min(-1); t(max) 20 vs. 53 min, respectively; all P < 0.05), whereas with subcutaneous insulin, systemic exposure was unchanged (AUC-Insulin(0-360) 2,324 vs. 2,269 microU x ml(-1) x min(-1); P = NS). After smoking cessation, AUC-Insulin(0-360) decreased with inhaled insulin by up to 50% within 1 week and approached nonsmoker levels. Cmax decreased and t(max) increased relative to baseline but were still not comparable with nonsmoker values. Smoking resumption completely reversed the effect of smoking cessation. Glucodynamics corroborated the observed findings in insulin pharmacokinetics. CONCLUSIONS: Cessation and resumption of smoking greatly altered the pharmacokinetics of inhaled insulin. As rapid changes in systemic insulin exposure increase hypoglycemia risk, inhaled insulin should not be used in people with diabetes who choose to continue smoking. This is consistent with recommendations that people with diabetes refrain from smoking altogether.

Pharmacokinetics, prandial glucose control, and safety of insulin glulisine in children and adolescents with type 1 diabetes.

OBJECTIVE: The aim of this study was to investigate the pharmacokinetics, postprandial blood glucose excursions, and safety of insulin glulisine as compared with regular human insulin (RHI), both administered immediately before meals in pediatric patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 10 children (aged 5-11 years) and 10 adolescents (aged 12-17 years) were enrolled in a randomized, single-center, single-dose, double-blind, cross-over study. The blood glucose of fasting patients was stabilized with intravenous insulin, following which patients received 0.15 IU/kg of subcutaneously injected insulin glulisine or RHI 2 min before a weight-adjusted standardized liquid meal. RESULTS: For insulin glulisine versus RHI, maximum insulin concentrations (58 vs. 33 microIU/ml, P < 0.05) and initial insulin concentrations (insulin [area under the curve] AUC(0-2h) 5,232 vs. 2,994 microIU.min(-1).ml(-1), P < 0.05; data are geometric means) were higher after insulin glulisine than RHI. Both time to maximum insulin concentration (54 vs. 66 min) and mean residence time (88 vs. 137 min, P < 0.05) were shorter with insulin glulisine versus RHI. Postprandial glucose excursions after insulin glulisine were lower than after RHI (glucose AUC(0-6h) 641 vs. 801 mg.h(-1).dl(-1), P < 0.05). The pharmacokinetic profile for insulin glulisine was similar for children and adolescents, whereas the pharmacokinetic profile for RHI demonstrated a 64% higher concentration in adolescents. Insulin glulisine was safe and well tolerated. CONCLUSIONS: The rapid-acting properties of insulin glulisine that have been previously demonstrated in adults are also observed in children and adolescents with type 1 diabetes. Further, these initial data indicate that insulin glulisine is safe and well tolerated in this patient population.

Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin.

OBJECTIVE: This study compares the time-action profile of inhaled insulin (INH; Exubera) with that of subcutaneously injected insulin lispro (ILP) or regular human insulin (RHI) in healthy volunteers. RESEARCH DESIGN AND METHODS: In this open-label, randomized, three-way, crossover study, 17 healthy male volunteers were given each of the following treatments in random order: INH (6 mg), ILP (18 units), or RHI (18 units). Glucose infusion rates and serum insulin concentrations were monitored over 10 h. RESULTS: INH had a faster onset of action than both RHI and ILP, as indicated by shorter time to early half-maximal effect (32 vs. 48 and 41 min, respectively; P < 0.001 for IHN vs. RHI and P < 0.05 for IHN vs. ILP). Time to maximal effect was comparable between INH and ILP (143 vs. 137 min; NS) but was shorter for INH than RHI (193 min; P < 0.01). The maximal metabolic effect of INH was comparable with RHI but lower than ILP (8.7 vs. 9.8 vs. 11.2 mg . kg(-1) . min(-1), respectively; P < 0.01 for INH vs. ILP). The duration of action of INH, indicated by time to late half-maximal effect (387 min), was longer than ILP (313 min; P < 0.01) and comparable to RHI (415 min; NS). Total glucodynamic effect after inhalation of INH was comparable to both ILP and RHI (NS). Relative bioefficacy of INH was 10% versus RHI and 11% versus ILP. No drug-related adverse events were observed. CONCLUSIONS: INH had a faster onset of action than RHI or ILP and a duration of action longer than ILP and comparable to RHI. These characteristics suggest that inhaled insulin is suitable for prandial insulin supplementation in patients with diabetes.