Maximum Glucose Infusion Rate Research Articles

Vietnam National Survey on Parenteral Nutrition Practice in Preterm Neonates: Practice Status, Barriers, and Implications.

Due to high risks of feeding intolerance, preterm infants often receive parenteral nutrition (PN) to ensure sufficient nutrition and energy intake. However, there is a lack of data on the status of clinical PN practice and barriers among neonatal care units in low- to middle-income countries like Vietnam. This extensive survey explores the status and barriers of PN practice for preterm infants in neonatal units across Vietnam and identifies the practical implications of enhancing nutritional outcomes in preterm infants. A multicenter nationwide web-based survey on PN practice in preterm infants was conducted across 114 neonatal units from 61 provinces in Vietnam. Among 114 neonatal units receiving a request for surveys, 104 units (91.2%) from 55 provinces participated. Neonatal units were categorized as level I (2/104, 1.9%), II (39/104, 37.5%), III (56/104, 53.8%), and IV (7/104, 6.8%). We found that the initiations of PN within the first hour and the first two hours of life occurred in 80.8% (84/104) and 95.2% (99/104) of the units, respectively. The early provision of amino acids, or AA (within the first day of life) and lipids (within two days of life) were documented by 85% (89/104) and 82% (84/104) of the respondents, respectively. The initial dose of AA ranged from 0.5 to 3 g/kg/day; the dose of AA less than 1 g/kg/day was reported by 7.7% (8/104) of the respondents; the maximum dose of AA ranged from 2 to over 4.5 g/kg/day, with 4 g/kg/day reported by 47.1% (49/104) of the respondents. The initial dose of lipids was between 0.5 and 2 g/kg/day, frequently 1 g/kg/day, reported by 51.9% (54/104) of the respondents; the target lipid dose ranged from 3 to 4 g/kg/day in 93.3% (97/104) respondents; the maximum target dose for lipid was 4 g/kg/day in 36.5% (38/104) of the respondents. The initial glucose dose was distributed as follows: 46.2% of respondents (48/104) administered 4 mg/kg/minute, 21.2% (22/104) used 5 mg/kg/minute, 28.8% (30/104) used 6 mg/kg/minute, and 3.8% (4/104) used 3 mg/kg/minute. Additionally, 48.1% of respondents (50/104) reported a maximum glucose infusion rate above 13 mg/kg/min and 19.2% (20/104) above 15 mg/kg/min. Nineteen percent (20/104) of the respondents reported a lack of micronutrients. Barriers to PN initiation included difficulty in establishing intravenous lines, the absence of standardized protocols, the lack of lipids and micronutrients, infections, and unavailable software supporting neonatologists in calculating nutrition paradigms. This study's findings highlight the highly variable PN practice across neonatal units in Vietnam. Deviations from current practical guidelines can be explained by various barriers, most of which are modifiable. A monitoring network for nutritional practice status and a database to track the nutritional outcomes of preterm infants in Vietnam are needed.

Pharmacokinetic and pharmacodynamic bioequivalence of Gan & Lee insulin analogues aspart (rapilin®), lispro (prandilin®) and glargine (basalin®) with EU- und US-sourced reference insulins.

For the successful approval and clinical prescription of insulin biosimilars, it is essential to show pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence to the respective reference products sourced from the European Union and the United States. Three phase 1, randomized, double-blind, three-period crossover trials compared single doses of the proposed biosimilar insulin analogues aspart (GL-Asp, n = 36), lispro (GL-Lis, n = 38) and glargine (GL-Gla, n = 113), all manufactured by Gan & Lee pharmaceuticals, to the respective EU- and US-reference products in healthy male participants (GL-Asp and GL-Lis) or people with type 1 diabetes (GL-Gla). Study participants received 0.2 U/kg (aspart and lispro) or 0.5 U/kg (glargine) of each treatment under automated euglycaemic clamp conditions. The clamp duration was 12 h (aspart and lispro) or 30 h (glargine). Primary PK endpoints were the total area under the PK curves (AUCins.total ) and maximum insulin concentrations (Cins.max ). Primary PD endpoints were the total area under the glucose infusion rate curve (AUCGIR.total ) and maximum glucose infusion rate (GIRmax ). Bioequivalence to both EU- and US-reference products were shown for all three GL insulins. Least squares mean ratios for the primary PK/PD endpoints were close to 100%, and both 90% and 95% confidence intervals were within 80%-125% in all three studies. There were no noticeable differences in the safety profiles between test and reference insulins, and no serious adverse events were reported for the GL insulins. GL-Asp, GL-Lis and GL-Gla are bioequivalent to their EU- and US-reference products.

Factors Associated with Need for Intravenous Glucose Infusion for the Treatment of Early Neonatal Hypoglycemia in Late Preterm and Term Neonates.

To determine which late-preterm (35-36wk gestational age [GA]) and term neonates with early-onset hypoglycemia in the first 72 hours postnatal required a continuous glucose infusion in order to achieve and successfully maintain euglycemia. Retrospective cohort study of late preterm and term neonates born in 2010-2014 and admitted to the Mother-Baby Unit at Parkland Hospital who had laboratory-proven blood glucose concentration <40 mg/dL (2.2 mmol/L) during the first 72h of life. Among the subgroup needing iv glucose infusion, we analyzed which factors predicted a maximum glucose infusion rate (GIR) ≥10 mg · kg-1 · min-1. The entire cohort was randomly divided into a derivation cohort (n=1288) and a validation cohort (n=1298). In multivariate analysis, the need for intravenous glucose infusion was associated with small size for GA, low initial glucose concentration, early-onset infection and other perinatal variables in both cohorts. A GIR ≥10 mg · kg-1 · min-1 was required in 14% neonates with blood glucose value <20 mg/dL during the first 3h of observation. The likelihood of a GIR ≥10 mg · kg-1 · min-1 was associated with lower initial blood glucose value and lower umbilical arterial pH. Need for intravenous glucose infusion was associated with small size for GA, low initial glucose concentration, early-onset infection and variables associated with perinatal hypoxia-asphyxia. The likelihood of a maximum GIR ≥10 mg · kg-1 · min-1 was greater in neonates with lower blood glucose value during the first 3 hours of observation and lower umbilical arterial pH.

Bioequivalence and immunogenicity of insulin LisPro biosimilar compared to reference drug

Introduction. Insulin therapy is the only treatment for type 1 DM and one of the options for intensifying the treatment for type 2 DM. The production of own insulin biosimilars will increase patients access to the providing drugs and can potentially reduce medical costs on healthcare for government. Aim. Compare the equivalence of pharmacokinetics (PK) and pharmacodynamics (PD), safety, efficacy, and immunogenicity between insulin biosimilar RinLis®, 100 IU/ml (LLC GEROPHARM, Russia) to original Humalog®, 100 IU/ml (Lilly France, France). Materials and methods. The clinical trial was conducted in two phases. Phase I – randomized double-blind, two-arm crossover study of PK and PD using hyperinsulinemic euglycemic clamp (HEC) method in 28 healthy volunteers (NCT03604575). During HEC regular blood sampling was performed to assess glucose and insulin concentrations. The glucose infusion rate (GIR) was adjusted based on glycemia measurement. These data were used to calculate the PD parameters: the total area under the GIR-time curve (AUCGIR) and the maximum GIR over the observation period (GIRmax); PK parameters: the total area under the concentration – time curve (AUCins.) and the maximum insulin concentration over the HEC (Сins. max). Phase II – randomized multicenter open-label comparative study in parallel groups with an assessment the frequency of an immune response after 26 weeks of therapy (NCT04023344). The comparability of the studied drugs was considered proven if 90% confidence intervals (CI) for the ratio of geometric means of FC and PD were in the range of 80–125%. Results. In the course of the study, it was revealed that RinLiz® and Humalog® insulin had comparable PK and PD profiles. The ratio of the geometric mean values of the AUCGIR and GIRmax were in the range of 80–125% and amounted to 106 [95–118] % and 108 [97–121] %, respectively. The equivalence also was confirmed by the ratio of the geometric mean values of the AUCins. and Сins. max, which amounted to 91 [86–97] % and 94 [91–97] %. In the second phase of the study after 26 weeks of therapy the frequency of immune response between two groups did not differ. Conclusion. The obtained data have demonstrated the bioequivalence and immunogenicity of RinLiz® insulin to the original Humalog® in terms of PK, PD and safety parameters.

The Effect of BMI on Pharmacokinetic and Pharmacodynamic Parameters of Insulin Degludec: Results from an Euglycemic Glucose Clamp Study.

This study evaluated the effect of body mass index (BMI) on pharmacokinetic (PK) and pharmacodynamic (PD) parameters of insulin degludec in healthy Chinese males, depending on an euglycemic glucose clamp study. Sixty-five healthy male subjects were divided into four groups according to quartile of BMI value. Group A: BMI ≤ 20.7 kg/m2; group B: 20.7 < BMI ≤ 22.5 kg/m2; group C: 22.5 < BMI ≤ 23.6 kg/m2; group D: BMI > 23.6 kg/m2. Each volunteer received a single subcutaneous dose (0.4 U/kg) of insulin degludec and accepted a 24-h euglycemic glucose clamp study. The primary PK parameters were maximum observed drug concentration (Cmax) and the area under the curve (AUCINS) for the specified time intervals. The primary PD parameters were the time to the start of glucose infusion (Tonset), maximal glucose infusion rate (GIRmax) and area under the curve (AUCGIR) for the specified time intervals. The differences of these PK/PD parameters were compared among groups. Cmax and the AUC of insulin (0-6 h, 6-12 h and 0-24 h) were more than onefold higher in group A than those in groups B, C, D, and the concentration-time curve of group A was significantly shifted to the left compared with the other three groups. The GIRmax, total AUCGIR, and AUCGIR for each time interval were significantly higher in group A than those in other three groups. The proportion of AUCGIR in group A was the lowest proportion among four groups seen in the late stage. Multiple linear regression analysis showed that BMI was negatively correlated with AUCGIR,0-24 h. Insulin degludec in healthy Chinese male subjects with BMI ≤ 20.7 kg/m2 had a faster absorption, clearance, and a stronger glucose-lowering effect, but a steeper decrease of insulin action in the late stage after dosing.

Pharmacokinetics and Pharmacodynamics of a Novel U500 Insulin Aspart Formulation: A Randomized, Double-Blind, Crossover Study in People With Type 1 Diabetes.

To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 U500) compared with insulin aspart (IAsp U100). This single-center, randomized, double-blind study was conducted in 38 men with type 1 diabetes (body weight ≤100 kg and total insulin dose <1.2 units/kg/day). Participants received a single dose of either AT278 U500 or IAsp U100 (0.3 units/kg s.c.) in a crossover design, followed by an 8-h euglycemic clamp in the absence of basal insulin. With AT278 U500, onset of appearance in serum was 6 min earlier (P < 0.0001) and reached 50% of maximum concentration 23 min faster (P < 0.0001). Insulin exposure with AT278 U500 was 4.0-fold higher within the first 30 min (95% CI 3.29, 4.90), 1.5-fold higher within the first 60 min (95% CI 1.35, 1.76), and statistically superior up to 90 min postdose (P < 0.05). With AT278 U500, onset of action was 10 min earlier (P < 0.0001) and reached 50% of maximum glucose infusion rate 20 min faster (P < 0.0001). The glucose-lowering effect with AT278 U500 was 8.9-fold higher within the first 30 min (95% CI 5.96, 17.46), 2.4-fold higher within the first 60 min (95% CI 1.92, 3.22), and statistically superior up to 2 h postdose (P < 0.0001). Overall insulin exposure and glucose-lowering effect were comparable. No significant safety findings were observed. AT278 U500 offers rapid-acting characteristics in a reduced dose volume, with accelerated absorption and onset of action compared with IAsp U100 in the studied population.

Predictors of the Need to Use Medications in the Management of Neonatal Hypoglycemia.

Background and objective Neonatal hypoglycemia (NH) is one of the most common causes of admission to the neonatal intensive care unit (NICU). Persistent NH despite adequate feeding and intravenous dextrosemay often require medications to maintain normal blood glucose levels (BGL). Several medications are used in the management of persistent NH, such as glucagon, diazoxide, and octreotide. In this study, we aimed to determine the factors that predict the need for medications to treat persistent NH. Methods This was a retrospective cohort studyconducted at the Sultan Qaboos University Hospital (SQUH), Muscat, Oman. Infants admitted to the NICU between 2015 and 2019 with hypoglycemia (capillary blood glucose <2.6 mmol/l) were eligible to be included in the study. A prespecified dataset was collected from electronic patientrecords, including birth weight (BW), APGAR scores, gestational age, BGL, maternal risk factors such as diabetes mellitus (DM), hypertension, or antenatal use of medications, and the NICU management during admission. Data analysis was performed usingSPSS Statistics for Windows, version 27.0 (IBM Corp., Armonk, NY). Results A total of 89 neonates were admitted due to NH during the study period. Of them, 10 (11.2%) patients had received medication (diazoxide). Use of medication for persistent NH was significantly associated with maternal gestational diabetes/diabetes mellitus (GDM/DM) status (p=0.041), higher BW (p=0.001), and large for gestational age [LGA (defined as BW >90th percentile)] (p=0.014), severe hypoglycemia (mean glucose level of 1-1.5 mmol/l) at two hours of life and at admission, and elevated maximum glucose infusion rate (GIR). GIR for the medication-requiring cohort was 12.95 mg/kg/min and that for the non-medication-requiring cohort was 6.77 mg/kg/min (p<0.001). Conclusion Based on our findings, the need for using certain medications to treat persistent NH, such as diazoxide in neonates admitted with NH, can be predicted byfactors such as maternal GDM/DM status, BW >90th percentile, very low BGL at two hours of age and on admission, and elevated GIR. Elevated maximum GIR was a leading indicator for using medications in the treatment of NH.

Pharmacokinetic and pharmacodynamic equivalence of Biocon's biosimilar Insulin 70/30 with US-licensed HUMULIN® 70/30 formulation in healthy subjects: Results from the RHINE-3 (Recombinant Human INsulin Equivalence-3) study.

AimTo establish the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of proposed biosimilar insulin 70/30 (Biocon's Insulin‐70/30) and HUMULIN® 70/30 (HUMULIN‐70/30; Eli Lilly and Company, IN).Materials and MethodsIn this phase 1, automated euglycaemic glucose clamp study, 78 healthy subjects were randomized (1:1) to receive a single dose of 0.4 IU/kg of Biocon's Insulin‐70/30 and HUMULIN‐70/30. Plasma insulin concentrations and glucose infusion rates (GIRs) were assessed over 24 hours. Primary PK endpoints were area under the insulin concentration‐time curve from 0 to 24 hours ‐ AUCins.0−24h ‐ and maximum insulin concentration ‐ Cins.max. Primary PD endpoints were area under the GIR time curve from 0 to 24 hours ‐ AUCGIR.0−24h ‐ and maximum GIR ‐ GIRmax.ResultsEquivalence was shown between Biocon's Insulin‐70/30 and HUMULIN‐70/30 for the primary PK/PD endpoints. The 90% confidence intervals of the treatment ratios were entirely within the acceptance range of 80.00%‐125.00%. The secondary PK/PD profiles were also comparable. There were no clinically relevant differences in the safety profiles of the two treatments and no serious adverse events were reported.ConclusionPK/PD equivalence was demonstrated between Biocon's Insulin‐70/30 and HUMULIN‐70/30 in healthy subjects. Treatment with Biocon's Insulin‐70/30 and HUMULIN‐70/30 was well tolerated.

A Randomized, Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Novel Insulin Dimer.

Insulin molecules of size much greater than natural insulin have been synthesized and studied with the intention of widening the therapeutic window between adequate glycemic control and hypoglycemia as compared with conventional insulins. MK-1092 is a synthetic insulin dimer with favorable properties demonstrated in preclinical studies. Here, we report the results of the first-in-human, randomized, double-blind, active-control, single ascending dose trial of MK-1092, conducted in healthy adults, adults with type 1 diabetes (T1D), and adults with type 2 diabetes (T2D). MK-1092 was well tolerated in all study populations, and no dose-related adverse events were identified across the evaluated dose range (4-64nmol/kg). Circulating concentrations of MK-1092 were approximately dose-proportional. Maximum glucose infusion rate (GIR) and 24-hour time-weighted average GIR were evaluated under euglycemic clamp conditions. These pharmacodynamic measurements were approximately dose-proportional in all study populations; at similar doses, the GIR parameters were lower in adults with T2D than in healthy adults or adults with T1D, likely due to the influence of insulin resistance. At doses ≥16nmol/kg, MK-1092 had similar or greater effects than glargine 3nmol/kg (0.5 units/kg) on increasing GIR in each study population and on suppressing free fatty acids and ketone generation in adults with T1D. MK-1092 did not prevent a subsequent high dose of lispro from increasing the GIR in healthy adults. Additional studies in adults with T1D and T2D are needed to further evaluate the safety, tolerability, and efficacy profile of MK-1092 and its potential for differentiation from more conventional insulins. (ClinicalTrials.gov: NCT03170544).

Similar Pharmacokinetics and Pharmacodynamics of Biosimilar SAR342434 Insulin Lispro and Japan-Approved Humalog Insulin Lispro in Healthy Japanese Subjects.

This phase 1 study compared the pharmacokinetic (PK) and glucose pharmacodynamic (PD) characteristics of biosimilar SAR342434 insulin lispro and Japan‐reference Humalog insulin lispro. This was a randomized, double‐blind, 2‐period, crossover study. Thirty‐six healthy Japanese male subjects underwent a 10‐hour euglycemic clamp following a single subcutaneous 0.3‐U/kg dose of SAR342434 or Humalog. Insulin lispro concentration and blood glucose were measured, and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. Primary PK end points were maximum plasma insulin lispro concentration and area under the plasma insulin concentration–time curve (AUC) from time 0 to the last quantifiable concentration. Primary PD end points were area under the GIR–time curve from time 0 to 10 hours and maximum GIR. PK exposure (maximum plasma concentration and AUC from time 0 to the last quantifiable concentration) and PD activity (GIR‐AUC from time 0 to 10 hours and maximum GIR) were similar between treatments. Geometric mean ratios were close to 1, and the corresponding 90% and 95%CIs (PK and PD activity, respectively) were within the 0.80 to 1.25 equivalence range. SAR342434 and Humalog were well tolerated. In healthy Japanese males, SAR342434 and Humalog showed similar PK exposure profiles and PD potency, in support of SAR342434 use as a biosimilar product.

Pharmacokinetic and pharmacodynamic equivalence of Biocon's biosimilar Insulin-R with the US-licensed Humulin® R formulation in healthy subjects: Results from the RHINE-1 (Recombinant Human INsulin Equivalence-1) study.

AimTo establish equivalence in the pharmacokinetic (PK) and pharmacodynamic (PD) endpoints between proposed biosimilar Insulin‐R (Biocon's Insulin‐R) and Humulin® R using the euglycaemic clamp technique in healthy subjects.Materials and MethodsIn this phase‐1 automated euglycaemic glucose clamp study, 42 healthy subjects were randomized (1:1) to receive a single dose of 0.3 IU/kg of Biocon's Insulin‐R and Humulin‐R. Plasma insulin concentrations and glucose infusion rates (GIRs) were assessed over 12 hours. Primary PK endpoints were area under the insulin concentration‐time curve from 0 to 12 hours (AUCins.0‐12h) and maximum insulin concentration (Cins.max). Primary PD endpoints were area under the GIR time curve from 0 to 12 hours (AUCGIR.0‐12h) and maximum GIR (GIRmax).ResultsEquivalence was demonstrated between Biocon's Insulin‐R and Humulin‐R for the primary PK and PD endpoints. The 90% confidence intervals were within 80.00% to 125.00% limits. The PK and PD profiles were comparable. There were no significant differences in the safety profiles of the two treatments, and no serious adverse events were reported.ConclusionPK and PD equivalence was demonstrated between Biocon's Insulin‐R and Humulin‐R in healthy subjects. Treatment with Biocon’s Insulin‐R and Humulin‐R was well tolerated.

Pharmacokinetic and pharmacodynamic similarity between SAR341402 insulin aspart and Japan-approved NovoRapid in healthy Japanese subjects

This study compared the pharmacokinetic and glucodynamic profiles of biosimilar SAR341402 insulin aspart to Japan-approved insulin aspart (NovoRapid) in healthy Japanese males. In this single-center, randomized, double-blind, single-dose, two-period, crossover study, subjects received 0.3 U/kg of SAR341402 or NovoRapid before undergoing a 10 h euglycemic clamp procedure. Plasma insulin aspart concentrations and blood glucose levels were measured, and glucose infusion rates (GIRs) were assessed. Primary endpoints were maximum plasma insulin aspart concentration (INS-Cmax), area under the plasma insulin concentration–time curve to the last quantifiable concentration (INS-AUClast), area under the GIR–time curve during the clamp (GIR-AUC0–10 h), and maximum GIR (GIRmax). Forty subjects were randomized with 39 completing both treatment periods. Pharmacokinetic exposure showed a mean ratio between products of 1.00 (90% confidence interval [CI] 0.94–1.05) for INS-Cmax and 1.02 (90% CI 1.00–1.04) for INS-AUClast. Glucodynamic activity showed a mean ratio between products of 1.00 (95% CI 0.93–1.06) for GIR-AUC0–10 h and 1.01 (95% CI 0.95–1.08) for GIRmax. The 90% CIs for pairwise treatment ratios were within the predefined equivalence range of 0.80–1.25. Both treatments were well tolerated. We concluded that similar pharmacokinetic exposure and glucodynamic potency were shown for SAR341402 and NovoRapid in healthy Japanese males.

Comparison of Pharmacokinetics and Pharmacodynamics of Inhaled Technosphere Insulin and Subcutaneous Insulin Lispro in the Treatment of Type 1 Diabetes Mellitus.

BackgroundThis study was performed to satisfy a US Food and Drug Administration post-marketing requirement to compare the dose responses for Technosphere® Insulin (TI; MannKind Corporation, Westlake Village, CA, USA) and subcutaneous insulin lispro (LIS) across a wide range of doses.ObjectivesThis single-center, open-label, randomized, cross-over study defined the pharmacokinetic/pharmacodynamic curves for inhaled TI vs subcutaneous LIS in persons with type 1 diabetes mellitus.MethodsEach volunteer received six treatments while undergoing euglycemic clamps: three doses of TI (10, 30 and 120 U) and LIS (8, 30, and 90 U). Primary endpoint was area under the glucose infusion rate vs time curve from start of treatment administration to end of clamp. Key secondary endpoints included readouts of insulin exposure and timing of pharmacokinetic/pharmacodynamic profiles.ResultsInsulin exposure was more than dose proportional, increasing with dose1.08 for LIS and dose1.35 for TI. Time to reach 10% of the maximum glucose infusion rate was 7 to 15 min for TI vs 21 to 38 min for LIS. End of effect was dose dependent for both treatments, ranging from 2 to 6 h (TI) and 5 to 10 h (LIS). Glucose infusion rate exhibited saturation for both treatments. Technosphere Insulin produced a lesser total effect per unit insulin than LIS due to its faster absorption and correspondingly shorter duration of exposure. The difference was large enough to require significantly different doses to achieve the same total effect.ConclusionsTechnosphere Insulin has a considerably faster onset and shorter duration of action than LIS. Consequently, the overall effect of TI is smaller than that of LIS and unit-for-unit dose conversion is not appropriate.Clinical Trial RegistrationClinicalTrials.gov, NCT02470637; 12 June, 2015Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01084-0.

Pharmacokinetic and pharmacodynamic bioequivalence of biosimilar MYL-1601D with US and European insulin aspart in healthy volunteers: A randomized, double-blind, crossover, euglycaemic glucose clamp study.

AimTo evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence (BE) of MYL‐1601D biosimilar with originator, NovoLog (Ref‐InsAsp‐US), and NovoRapid (Ref‐InsAsp‐EU).Materials and MethodsThis was a double‐blind, randomized, crossover study that enrolled 71 healthy subjects to receive a single subcutaneous dose (0.2 U/kg) of each formulation under automated euglycaemic clamp conditions (ClampArt, level 81 mg/dL, duration 12 hours postdose). Primary PK endpoints were area under the plasma insulin aspart concentration‐time curve from 0 to 12 hours (AUC0‐12h) and maximum plasma insulin aspart concentration (Cmax). Primary PD endpoints were area under the glucose infusion rate (GIR) time curve from 0 to 12 hours (AUCGIR0‐12h) and maximum GIR (GIRmax). Insulin aspart in plasma was quantified using immunoaffinity purification followed by ultraperformance liquid chromatography and tandem mass spectrometric detection. The pairwise comparisons of geometric least square mean (LS‐mean) ratio for a 90% confidence interval (CI) of primary PK, and 90% CIs (MYL‐1601D vs. Ref‐InsAsp‐US) and 95% CIs (MYL‐1601D vs. Ref‐InsAsp‐EU) of primary PD variables, were to be within 80% to 125% to show BE.ResultsMYL‐1601D showed PK BE to both Ref‐InsAsp‐US (AUC0‐12h geometric LS‐mean ratio 102.17, 90% CI [100.26; 104.11]; Cmax 106.13 [100.71; 111.85]) and Ref‐InsAsp‐EU (AUC0‐12h 101.84 [100.04; 103.67]; Cmax 105.74 [101.09; 110.60]). Likewise, MYL‐1601D showed PD BE to Ref‐InsAsp‐US (AUCGIR_0‐last 99.93; 90% CI [95.74; 104.30]; GIR_max 100.12 [94.46; 106.12]) and Ref‐InsAsp‐EU (AUCGIR_0‐last 96.42; 95% CI [91.17; 101.98]; GIR_max 95.10 [89.37; 101.19]). All three insulin aspart products were well tolerated.ConclusionMYL‐1601D showed BE to Ref‐InsAsp‐US and Ref‐InsAsp‐EU with a comparable safety profile.

A Euglycemic Glucose Clamp Study to Evaluate the Bioavailability of LY2963016 Relative to Insulin Glargine in Healthy Chinese Subjects.

Insulin glargine (IGlar) and LY2963016 (LY IGlar) are long-acting insulin analogs with identical primary amino acid sequences. We conducted a randomized, open-label, 2-treatment, 2-period, crossover study in healthy Chinese subjects to evaluate the relative bioavailability of LY IGlar to IGlar and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of LY IGlar. Subjects (n = 58) were randomized to receive single subcutaneous doses (0.5 U/kg) of LY IGlar and IGlar with a ≥7-day washout period between study treatments. Serum was collected before and up to 24 hours after dosing to assess PK characteristics. PD characteristics were assessed by euglycemic clamp up to 24 hours after dosing. Linear mixed-effects models were used to fit the log-transformed primary PK (maximum observed concentration and area under the concentration-time curve from time 0 to 24 hours) and PD parameters (maximum glucose infusion rate and total amount of glucose infused during clamp period). The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar for maximum observed concentration and area under the concentration-time curve from time 0 to 24 hours were 0.961 (0.887-1.04) and 0.941 (0.872-1.01), respectively. The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar were 0.91 (0.85-0.98) for maximum glucose infusion rate and 0.89 (0.82-0.97) for total amount of glucose infused during clamp period. LY IGlar demonstrated similarity to IGlar in PK and PD characteristics following single-dose (0.5 U/kg) administration in healthy Chinese subjects.

Improved Methods for Mid-Term Blood Glucose Level Prediction Using Dietary and Insulin Logs.

Background and Objectives: The daily lifestyle management of diabetes requires accurate predictions of the blood glucose level between meals. The objective of this study was to improve the accuracy achieved by previous work, especially on the mid-term, i.e., 120 to 180 min prediction horizons, for insulin-dependent patients. Materials and Methods: An absorption model-based method is proposed to train an artificial neural network with the bolus and basal insulin dosing and timing, the baseline blood glucose level, the maximal glucose infusion rate, and the total carbohydrate content as parameters. The approach was implemented in various algorithmic setups, and it was validated on data from a small-scale clinical trial with continuous glucose monitoring. Results: Root mean square error results for the mid-term horizons are 1.72 mmol/L (120 min) and 1.95 mmol/L (180 min). The accuracy of the proposed model measured on the clinical data is better than the accuracy reported by any other currently available and comparable models. Conclusions: A relatively short (ca. two weeks) training sample of a continuous glucose monitor and dietary/insulin log is sufficient to provide accurate predictions. For the outpatient application in practice, a hybrid model is proposed that combines the present mid-term method with the authors’ previous work for short-term predictions.

Similar pharmacokinetics and pharmacodynamics of a new biosimilar and reference insulin aspart in healthy Chinese males

Insulin aspart (IAsp) is one of the main therapies used to control blood glucose after a meal. This study aimed to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 2 rapid-acting IAsp products: a new IAsp biosimilar (RD10046) and NovoRapid. In a single-center, randomized, single-dose, 2-period, crossover, euglycemic clamp study (registry number: CTR20180517, registration date: 2018-05-30), healthy Chinese males were randomized to receive 0.2 U/kg of the IAsp biosimilar RD10046 and NovoRapid under fasted conditions on two separate occasions. PK and PD were assessed for up to 10 h. Of the 30 randomized subjects, all 30 completed both treatment periods. The PK (area under the curve [AUC] of total IAsp; maximum observed IAsp concentration [Cmax]) and PD (maximum glucose infusion rate [GIRmax]; total glucose infusion during the clamp [AUCGIR,0–10h]) were similar between the new IAsp biosimilar RD10046 and NovoRapid. In all cases, the 90% CIs for the ratios of the geometric means were completely contained in the prespecified acceptance limits of 0.80–1.25. No hypoglycemic events, allergic reactions, or local injection adverse reactions occurred in this trial. We concluded that the studied IAsp biosimilar (RD10046) was bioequivalent to NovoRapid.

Survival assessment of the extended-wear insulin infusion set featuring lantern technology in adults with type 1 diabetes by the glucose clamp technique.

Maintaining good glycaemic control with the same infusion set for longer than 3 days may improve the quality of life of insulin pump users. The aim of the current study was to assess the efficacy and safety of the novel, extended‐wear infusion set over 7 days of wear in adults with type 1 diabetes. Sixteen participants completed three identical 8‐hour euglycaemic clamp experiments on Days 1, 4 and 7 of infusion set wear. Between the experiments, the participants were discharged home for routine diabetes management while wearing the same extended‐wear infusion set throughout the study. Time to reach the maximum glucose infusion rate (TGIRmax) on Day 7 was reduced by 67% compared with Day 1 (p < .001). The corresponding area under the glucose infusion rate curve (AUCGIR) was comparable for the first 2 h of the clamp (p = .891) but decreased by 28% over time (p < .008). While the extent of insulin absorption decreased with prolonged wear, it was accompanied by an increase in insulin absorption rate. The infusion set survival rate was 100% without leakages, occlusion alarms, severe hypoglycaemia or ketoacidosis. The extended‐wear infusion set proved safe and effective during prolonged wear in real‐life conditions.

Oscillations of C-peptide in the euglycemic clamp and their effect on the pharmacodynamic assessment of insulin preparations.

C-peptide should be continuously suppressed. However, increased postdosing C-peptide is not an uncommon phenomenon in euglycemic clamp studies involving healthy participants. This study aimed to determine the extent to which the postdosing C-peptide increases from the baseline that could affect the accuracy of glucodynamics in euglycemic clamp studies involving healthy subjects. First, 10 healthy males underwent a 10-h euglycemic clamp without exogenous insulin administration to obtain a reference interval (RI) for the ratio of C-peptide after 0min (CPt ) to baseline C-peptide (CP0 ). Then, the data from a pharmacokinetic and pharmacodynamic study of insulin aspart (IAsp) were analyzed, and 70 eligible clamps were grouped by CPt /CP0 : group A ([CPt /CP0 ]max >upper limit of RI), group B (1<[CPt /CP0 ]max ≤upper limit of RI), and group C ([CPt /CP0 ]max ≤1). The differences in basal and clamped blood glucose, CPt /CP0 , and the pharmacokinetics and pharmacodynamics of IAsp were compared, and the relationship between elevated CPt and the accuracy of pharmacodynamics was analyzed. The RI of CPt /CP0 was 22.7%-152.1%; 1.5×baseline might be a ceiling for the increase in CPt under stable conditions. The maximum glucose infusion rate (GIR) in group A tended to be higher than that in group B or C (Pfor trend =0.033). The AUCGIR,0-10h in groups A, B, and C was 1983±650,1682±454, and 1479±440mg/kg (P=0.047), respectively, under comparable IAsp exposure. No intergroup difference was detected in clamped glucose, IAsp dose, or body mass index. In conclusion, postdosing C-peptide over 1.5× baseline indicates insufficient inhibition of endogenous insulin secretion, which could compromise the pharmacodynamics of insulin preparations.

Factors related to passing the safety fast test among neonates with hypoglycaemia in the neonatal intensive care unit.

To investigate the success rates and predictors of safety fast test among neonates admitted to the neonatal intensive care unit for hypoglycaemia. A retrospective review of neonates transferred from the newborn nursery unit to the neonatal intensive care unit for intravenous dextrose therapy for hypoglycaemia from January 2016 to June 2019. Neonatal clinical and demographic variables were abstracted from the medical records. A successful safety fast test was defined by blood glucose >60 mg/dL (3.3 mmol/L) at 3, 4, 5 and 6 h after a feed. Of the 76 neonates who had a safety fast test, 80% passed on their first attempt. Neonates who passed the safety fast test were less likely to be premature/small for gestational age (54.1% vs. 92.9%, P = 0.03), required less maximum glucose infusion rate (median 6 vs. 7 mg/kg/min; P = 0.04), and were younger at fasting challenge (median 5 vs. 9 days; P = 0.02), required lower overall intravenous glucose load (median 12 vs. 24 g/kg; P = 0.006). Safety fast test may be a useful tool evaluating discharge readiness of neonates with persistent hypoglycaemia.