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Pharmacokinetic and Glucodynamic Responses of Ultra Rapid Lispro vs Lispro Across a Clinically Relevant Range of Subcutaneous Doses in Healthy Subjects

Open AccessPublished:September 05, 2020DOI:https://doi.org/10.1016/j.clinthera.2020.07.005

      Highlights

      • Insulin absorption was up to 7-fold faster with URLi vs Lispro for all doses.
      • Early glucose lowering was greater with URLi vs Lispro across all dose levels.
      • Late insulin exposure and action were reduced with URLi vs Lispro for all doses.
      • Dose proportional increases in exposure were observed for URLi.
      • Both URLi and Lispro showed less than dose proportional increases in insulin action.

      Abstract

      Purpose

      Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic and glucodynamic parameters of URLi and Lispro (Humalog®) at 3 dose levels in healthy subjects.

      Methods

      This randomized, 6-period, subject- and investigator-blind, crossover study included 42 healthy subjects. At each period, subjects received a single subcutaneous dose of 7, 15, or 30 U of URLi or Lispro followed by a 10-h automated euglycemic clamp. Insulin lispro and blood glucose concentrations were measured.

      Findings

      Across all 3 doses, insulin lispro appeared in the serum 2–5 min faster, and exposure was 6- to 8-fold greater in the first 15 min, with URLi versus Lispro. Exposure beyond 3 h postdose was 45%–52% lower, and duration of exposure was 67–86 min shorter with URLi versus Lispro for all dose levels. Onset of insulin action was 7–9 min faster and insulin action was ~3-fold greater in the first 30 min with URLi versus Lispro across the dose levels. Insulin action beyond 4 h was reduced by 32%–45%, and duration of action was reduced by 47–67 min, with URLi versus Lispro for all 3 dose levels. Overall exposure and total glucose infused were similar between URLi and Lispro at each dose level. Dose proportionality was observed for maximum and overall exposure after URLi. Less than dose-proportional increases in maximum and total glucose infused were observed and were similar for both URLi and Lispro.

      Implications

      URLi exhibited ultra-rapid pharmacokinetic and glucodynamic parameters across all 3 dose levels studied and exhibited dose-proportional increases in exposure in healthy subjects. ClinicalTrials.gov identifier: NCT03286751.

      Key words

      Introduction

      Optimum postprandial glycemic control is crucial for achieving recommended glycosylated hemoglobin targets in diabetes.
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      Rapid-acting insulin analogues (eg, Lispro, insulin aspart, insulin glulisine) have faster onset and shorter duration of action than regular human insulin.
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      Thus, there is a need to develop even faster acting insulin preparations to match carbohydrate absorption profiles and to more closely match physiological insulin release.
      Lispro (Humalog®
      Trademark: Humalog® (Eli Lilly and Company, Indianapolis, Indiana).
      ) is a commercially available, rapid-acting human insulin analogue indicated for glycemic control in adults and children with diabetes mellitus.
      Eli Lilly and Company
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      Ultra rapid lispro (URLi) is a novel insulin lispro formulation that contains 2 locally acting excipients, citrate and treprostinil, with independent mechanisms of action that accelerate the absorption of insulin lispro.
      • Kapitza C.
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      • Liu R.
      • et al.
      A novel formulation of insulin lispro containing citrate and treprostinil shows significantly faster absorption and an improvement in postprandial glucose excursions vs. Humalog in patients with T2DM (abstract 978-P).
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      • et al.
      A novel formulation of insulin lispro containing citrate and treprostinil shows faster absorption and improved postprandial glucose excursions vs. Humalog in patients with T1DM.
      Microdoses of treprostinil, a prostacyclin analogue,
      United Therapeutics Corp
      REMODULIN® (Treprostinil) Injection, for Subcutaneous or Intravenous Use.
      in the URLi formulation enhance insulin lispro absorption by local vasodilation
      • Pratt E.
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      • Heilmann C.
      • Johnson J.
      • Landschulz W.
      Treprostinil causes local vasodilation, is well tolerated, and results in faster absorption of insulin lispro (Abstract 975-P).
      with no measurable systemic exposure. Sodium citrate further enhances the absorption of insulin lispro by increasing vascular permeability at the injection site.
      • Michael M.
      • Zhang C.
      • Siesky A.
      • et al.
      Exploration of the mechanism of accelerated absorption for a novel insulin lispro formulation.
      URLi was formulated to more closely match the secretion pattern of physiological prandial insulin and improve PPG control. In clinical studies, URLi exhibited accelerated absorption and faster onset of action than Lispro, with a similar overall safety profile, in patients with type 1 diabetes mellitus (T1DM)
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      Pharmacokinetics and glucodynamics of ultra rapid lispro (URLi) versus Humalog® (Lispro) in younger adults and elderly patients with type 1 diabetes mellitus: a randomised controlled trial.
      and type 2 diabetes mellitus (T2DM).
      • Leohr J.
      • Dellva M.A.
      • Coutant D.E.
      • et al.
      Pharmacokinetics and glucodynamics of ultra rapid lispro (URLi) versus Humalog® (Lispro) in patients with type 2 diabetes mellitus: a phase I randomised, crossover study.
      In clinical practice, patients with diabetes on insulin therapy individualize their prandial insulins based on various factors such as glucose level before a meal, carbohydrate content in the meal, and insulin sensitivity. Understanding the pharmacokinetic (PK) and glucodynamic (GD) effects across a broader dose range is important to ensure that the benefit of URLi is maintained across a range of therapeutic doses. The present study compared the insulin lispro PK and GD variables of a single subcutaneous (SC) injection of URLi with Lispro following 7-, 15-, and 30-U doses in healthy subjects. The study also assessed the dose proportionality of insulin lispro PK and GD profiles across these 3 dose levels of URLi.

      Subjects and methods

      Study Design

      This Phase I, randomized, 6-period, subject- and investigator-blind, crossover, glucose clamp study was conducted in healthy subjects (Fig. 1). The study was conducted at a single center (Profil, Neuss, Germany) and in accordance with the principles of the Declaration of Helsinki (2000), the International Conference on Harmonisation, and the E6 Guideline for Good Clinical Practice. Institutional review board approval and written informed consent from all subjects were obtained before conduct of any evaluations or study procedures. This study was registered at ClinicalTrials.gov (ClinicalTrials.gov identifier, NCT03286751).
      Figure 1
      Figure 1Study design. The trial consisted of 8 visits: screening (≤28 days before enrollment), 6 treatment visits for dosing and clamp procedures (periods 1 to 6) with a washout duration of at least 3 days between clamp visits, and follow-up visit with a washout period of at least 14 days after the last dose. aStudy drug dosing was done after a fast of at least 8 h before each dose. All subjects participated in all 6 treatment periods according to their assigned sequence, with a 3-day minimum washout period between each clamp visit. CRU = clinical research unit; GD = glucodynamics; PK = pharmacokinetics; URLi = ultra rapid lispro.

      Subjects

      Healthy men and women (based on medical history and physical examination), aged 18–65 years with a body mass index of 18.0–30.0 kg/m2, were eligible to participate. The main exclusion criteria were: history of any medical or psychiatric illness; abnormal cardiac parameters or vital signs deemed clinically relevant by the investigator; smokers; and allergies to treprostinil, insulin lispro, or related compounds.

      Treatment and Procedures

      Subjects were randomized to 1 of 6 treatment sequences comprising single SC doses of 7, 15, and 30 U of URLi and Lispro U-100 formulations. The study was subject- and investigator-blind with reference to the identity of the study drug administered. The treatment dose (7, 15, and 30 U) was not blinded due to the difference in volume of injection. Injections were rotated across different injection sites on the anterior abdominal wall during the 6 study periods. Each study period was separated by a washout period of at least 72 h.

      Bioanalysis Procedures

      Serum free insulin lispro was analyzed by using a validated enymze-linked immunosorbent assay (ELISA) specific to insulin lispro without cross-reactivity to endogenous insulin. Blood samples for PK analysis were collected at time 0; every 5 min for the first 40 min; at 50, 60, 70, 90, 120, 150, 180, 210, and 240 min; and hourly from 300 to 600 min after drug administration. The lower limit of quantitation (LLOQ) was 8.6 pmol/L. The interassay accuracy (percent relative error) and interassay precision (percent relative SD) during validation were ≤16%.
      Serum samples were collected at time 0 and every hour for 10 h for assessment of C-peptide levels and were analyzed by using a validated ELISA. The LLOQ was 0.07 ng/mL. The interassay precision (%CV) was 5%–6%, and there was no cross-reactivity to insulin or proinsulin.

      Euglycemic Clamp Procedure

      At every dosing visit, each subject underwent an automated euglycemic clamp procedure of 10 h duration using the ClampArt device (Profil) under fasted conditions. Baseline blood glucose was calculated for each subject as the mean of blood glucose concentrations at 6, 4, and 2 min before study drug administration. Following drug administration, onset of insulin action was defined as when blood glucose levels dropped by 5 mg/dL (0.3 mmol/L) below the subject's fasting baseline, which was set as the target blood glucose level for the euglycemic glucose clamp procedure. Blood glucose level was maintained at target for each individual subject by variable intravenous glucose infusion with 20% d-glucose (dextrose) solution. Following onset of action, the glucose infusion rate (GIR) needed to maintain the target blood glucose level reflected the GD activity of the administered dose of insulin, and GIR was recorded every minute throughout the clamp procedure. Manual blood samples were collected and measured (Super GL glucose analyzer, Dr. Müller Gerätebau GmbH, Freital, Germany) for blood glucose assessment at least every 30 min during the clamp procedure to validate clamp glucose sensor measurements.

      End points and assessments

      PK Parameters

      Free serum insulin lispro PK parameters were calculated by using standard noncompartmental analyses with Phoenix version 7.0 (Certara USA Inc, Princeton, New Jersey) and S-PLUS version 8.2 (TIBCO software, Palo Alto, USA). Early insulin exposure was characterized by time to early half-maximal drug concentration (early 50% Tmax), area under the concentration versus time curve (AUC) from time 0–15 min (AUC0–15min), AUC from time 0–30 min (AUC0–30min), AUC from time 0–1 h (AUC0–1h), and onset of appearance, defined as time that serum insulin lispro reached the lower level of quantification. The determination of onset of appearance used a linear interpolation between the time of dosing (0 insulin lispro concentration) and the time of the first quantifiable insulin lispro measurement. Late insulin exposure was characterized by time to late half-maximal drug concentration (late 50% Tmax), AUC from time 2–10 h (AUC2–10h), AUC from time 3–10 h (AUC3–10h), and duration of exposure, defined as time from dosing until serum insulin lispro reached the LLOQ. Overall insulin exposure was determined by maximum observed drug concentration (Cmax), time to Cmax (Tmax), AUC from time 0 to infinity (AUC0–∞), and AUC from time 0–10 h (AUC0–10h). Dose proportionality for insulin lispro following URLi was assessed by using Cmax, AUC0–10h, and AUC0–∞.

      GD Analyses

      Analyses for GD parameters were conducted by using Phoenix version 6.4 or higher and S-PLUS version 8.2. A locally weighted scatterplot smoothing (LOESS) function with a span of 0.1 was applied to all individual GIR versus time profiles in each treatment group and/or period using S-PLUS. Fitted data for each patient were used to calculate GD parameters, except time to onset of insulin action (Tonset), which was based on raw GIR data. Early insulin action was characterized by Tonset, time to half-maximal GIR occurring before maximum GIR (early 50% tRmax), total amount of glucose infused over first 30 min (Gtot0–30min), total amount of glucose infused over first 1 h (Gtot0–1h), and total amount of glucose infused over first 2 h (Gtot0–2h). Late insulin action was characterized by time to half-maximal GIR occurring after maximum GIR (late 50% tRmax), total amount of glucose infused from 2 h to end of the clamp (Gtot2h–End), total amount of glucose infused from 3 h to end of the clamp (Gtot3h–End), total amount of glucose infused from 4 h to end of the clamp (Gtot4h–End) and duration of insulin action. The end of insulin action was calculated as the first time when the GIR was less than the average LOESS GIR, which was calculated from all patients from 9 to 10 h after injection and remained below this value for at least 30 min. Overall insulin action was characterized by total amount of glucose infused over the duration of the clamp (Gtot) and maximum GIR (Rmax). Dose proportionality for GD variables for URLi and Lispro was assessed by using the Rmax and Gtot.

      C-Peptide Response

      C-peptide levels during the clamp were measured to assess the effects of URLi and Lispro on endogenous insulin secretion.

      Safety Assessments

      Safety assessments included all adverse events (AEs), injection-site assessments at time 0, 1, 4, and 10 h after drug administration, clinical laboratory assessments, vital signs, and 12-lead ECG.

      Statistical analysis

      General Statistical Considerations

      Subjects who completed at least 1 period and had measurable insulin lispro concentrations were included in the PK analyses, and those who completed at least 1 clamp procedure were included in the GD analyses. The safety population comprised all enrolled subjects who received at least 1 dose of study drug.

      Sample Size Calculations

      A total of 34 subjects completing the study were needed to obtain ~98% power to show a 30% reduction in early 50% Tmax, and at least 85% power to detect at least a 40% increase in Gtot0–30min and Gtot0–1h between URLi and Lispro with an alpha level of 0.05 and a 2-sided CI.

      Analysis of PK and GD Variables

      All relevant PK and GD end points were log-transformed, except for the time parameters (early and late 50% Tmax, Tonset, and early and late 50% tRmax), and Gtot parameters that had patients with at least 1 value equal to 0 (Gtot0–30min, Gtot3h–End, and Gtot4h–End). For log-transformed end points, least squares (LS) geometric means, ratios of LS geometric means, and their corresponding 95% CIs were estimated for each dose level using the mixed effects model with treatment, dose level-by-treatment interaction, and period as fixed effects and subject as random effects. For non–log-transformed end points, LS means, treatment differences in LS means, and the corresponding 95% CIs for the treatment differences were estimated from the same model, but treatment ratios and 95% CIs were calculated by using the Fieller method. Statistical analyses were conducted by using SAS version 9.4 (SAS Institute, Inc, Cary, North Carolina) at a 5% significance level.

      Analysis of Dose Proportionality of PK and GD Assessments

      Dose proportionality for PK variables was estimated by using a power model that was applied to AUC0–10h, AUC0–∞, and Cmax versus dose for each dose level of URLi.
      • Smith B.P.
      • Vandenhende F.R.
      • DeSante K.A.
      • et al.
      Confidence interval criteria for assessment of dose proportionality.
      Dose-normalized geometric means of PK parameters, slope and its 95% CI, and the geometric LS means for each dose level tested were estimated. The same power model for GD was applied to Gtot and Rmax versus dose for each dose level of URLi to estimate the dose–response relationship for insulin lispro. The same analysis for GD variables was also conducted for Lispro.

      Results

      Demographic Characteristics

      A total of 42 healthy subjects (27 [64.3%] male and 15 [35.7%] female), aged between 18 and 60 years (mean [SD], 41.9 [11.6] years) and with a mean (SD) body mass index of 24.8 (2.6) kg/m2, participated in this study. Most subjects were white (95.2%), and 4.8% were American Indian or Alaska Native. Thirty-nine subjects completed the study. Three subjects discontinued the study: 1 due to subject's decision, 1 due to personal reasons, and 1 due to an AE not considered related to the study treatment. All 42 subjects received at least 1 dose of study treatment and were included in the safety analysis.

      PK action

      Insulin Lispro Concentration Profiles

      The mean serum insulin lispro concentration–time profile after URLi was shifted to the left compared with Lispro, across all 3 dose levels (Fig. 2), demonstrating accelerated insulin lispro absorption, reduced late exposure, and overall shorter exposure duration with URLi compared with Lispro.
      Figure 2
      Figure 2Mean (SE) serum insulin lispro concentration–time profile for ultra rapid lispro (URLi) and Lispro. (A) Zero to 8 h after subcutaneous (SC) injection of 7 U; (B) 1 h after SC injection of 7 U; (C) 0–8 h after SC injection of 15 U; (D) 1 h after SC injection of 15 U; (E) 0–8 h after SC injection of 30 U; and (F) 1 h after SC injection of 30 U. The dotted line represents the lower limit of quantitation (8.6 pmol/L).

      Early Insulin Lispro Exposure

      URLi significantly accelerated insulin lispro absorption compared with Lispro across all 3 doses. After SC injection of URLi, the onset of insulin lispro appearance occurred at 1.2 min for 7 U, 0.7 min for 15 U, and 0.4 min for 30 U. The onset of appearance was 4.6, 3.9, and 2.1 min earlier, and early 50% Tmax was 11.3, 14.1, and 16.6 min faster for 7, 15, and 30 U of URLi, respectively, versus Lispro (p < 0.0001) (Fig. 3A). This accelerated absorption increased the early serum insulin lispro exposure, as AUC0–15min was increased by 6.1- to 7.9-fold, AUC0–30min by 2.3- to 3.6-fold, and AUC0–1h by 1.4- to 1.6-fold after URLi compared with Lispro for all 3 dose levels (all, p < 0.0001) (Fig. 3B).
      Figure 3
      Figure 3Forest plots of the difference (A, C, and E) and ratio (B, D, and F) of geometric least square means and 95% CI for onset of exposure (A), early exposure (B), late exposure (C and D), and overall exposure (E and F) for ultra rapid lispro (URLi) versus Lispro. AUC0–15min = AUC from 0 to 15 min; AUC0–30min = AUC from 0 to 30 min; AUC0–1h = AUC from 0 to 1 h; AUC0–10h = AUC from 0 to 10 h; AUC2–10h = AUC from 2 to 10 h; AUC3–10h = AUC from 3 to 10 h; early 50% Tmax = time to early half-maximal drug concentration; late 50% Tmax = time to late half-maximal drug concentration; LS = least squares.

      Late Insulin Lispro Exposure

      The late 50% Tmax was reduced by 18–26 min with URLi versus Lispro across these 3 dose levels (p < 0.01) (Fig. 3C). Correspondingly, the duration of insulin lispro exposure was significantly reduced by 70.7 min for 7 U, 67.4 min for 15 U, and 86.3 min for 30 U, compared with Lispro (all, p < 0.0001). Similarly, late insulin exposure was also reduced with URLi compared with Lispro as measured by a 22%-29% reduction in AUC2-10h, and a 45%-52% reduction in AUC3-10h for all 3 doses (p < 0.0001) (Fig. 3D).

      Overall Insulin Lispro Exposure

      The overall insulin exposure (AUC0–10h and AUC0–∞) and Tmax were not significantly different between URLi and Lispro across the tested dose range. The faster absorption and reduced late insulin exposure resulted in a slightly higher Cmax for URLi compared with Lispro (13%–19%; p < 0.001) across the tested dose range (Fig. 3E and F).

      GD action

      Glucose Insulin Profiles

      Mean LOESS curves were shifted to the left for URLi compared with Lispro at all 3 doses, indicating a faster onset of insulin action, a reduced late insulin action, and a shorter duration of insulin action with URLi compared with Lispro (Fig. 4). Importantly, the mean blood glucose level was maintained at the predefined target throughout the procedure for both URLi and Lispro (see Supplemental Figure 1 in the online version at doi: https://doi.org/10.1016/j.clinthera.2020.07.005).
      Figure 4
      Figure 4Mean glucose infusion rates vs time profiles for ultra rapid lispro (URLi) and Lispro. (A) Ten hours after subcutaneous (SC) injection of 7 U; (B) 2 h after SC injection of 7 U; (C) 10 h after SC injection of 15 U; (D) 2 h after SC injection of 15 U; (E) 10 h after SC injection of 30 U; and (F) 2 h after SC injection of 30 U. GIR = glucose infusion rate.

      Early Insulin Action

      The onset of insulin action of URLi occurred at 17.5 min for the 7 U dose, 17.4 min for the 15 U dose, and 15.5 min for the 30 U dose, which was 7.1–9.2 min earlier than Lispro (p < 0.0001). At all 3 dose levels, the early 50% tRmax was reduced by 11.9–15.4 min with URLi compared with Lispro (p < 0.0001) (Fig. 5A). The faster onset of insulin action resulted in increase amount of glucose infused in the early part of the euglycemic clamp. The amount of glucose infused was significantly increased by 2.5- to 3.2-fold (39.1 vs 12.2, 50.2 vs 17.7, and 81.2 vs 32.4 mg/kg for 7, 15, and 30 U, respectively; p < 0.0001 for all differences) during the first 30 min (Gtot0–30min), by 1.6- to 1.9-fold (p < 0.0001) over the first 1 h (Gtot0–1h), and by 1.2- to 1.3-fold (p < 0.0001) over the first 2 h (Gtot0–2h) of the clamp with URLi compared with Lispro across the dose range 7–30 U (Fig. 5B).
      Figure 5
      Figure 5Forest plots of the difference (A, C, and E) and ratio (B, D, and F) of geometric least squares (LS) means and 95% CI for onset of insulin action (A), early insulin action (B), late insulin action (C and D), and overall insulin action (E) for ultra rapid lispro (URLi) versus Lispro. ∗For glucodynamic parameters with at least 1 patient with a value of 0, treatment ratios of LS means and their 95% CIs were estimated by using the Fieller theorem, and p values were not calculable; presented p values are for treatment difference in geometric LS means. Early 50% tRmax = time to half-maximal glucose infusion rate before maximum glucose infusion rate; Gtot = total amount of glucose infused over the duration of the clamp procedure; Gtot0–30min = total amount of glucose infused over 30 min; Gtot0–1h = total amount of glucose infused over 1 h; Gtot0–2h = total amount of glucose infused over 2 h; Gtot2h–End = total amount of glucose infused from 2 h postdose until the end of the clamp; Gtot3h–End = total amount of glucose infused from 3 h postdose until the end of the clamp; Gtot4h–End = total amount of glucose infused from 4 h postdose until the end of the clamp; late 50% tRmax = time to half-maximal glucose infusion rate after maximum glucose infusion rate; Tonset = time to onset of insulin action; tRmax = time of Rmax.

      Late Insulin Action

      URLi reduced the late 50% tRmax by ~31.4–58.4 min across all 3 dose levels (p < 0.001) and the duration of insulin action by ~67.1, 47.4, and 51.3 min for 7, 15, and 30 U compared with the same dose of Lispro, respectively (p < 0.05) (Fig. 5C). Similarly, URLi reduced the amount of glucose infused from 2 h to the end of the clamp (Gtot2h–End) by 17%–25% (p < 0.07), from 3 h to the end of the clamp (Gtot3h–End) by 22%–32% (p < 0.05), and from 4 h to the end of the clamp (Gtot4h–End) by 32%–45% (p < 0.05) compared with Lispro (Fig. 5D).

      Total Insulin Action

      Overall insulin action (Gtot) was not significantly different between URLi and Lispro for all 3 dose levels. The Rmax was significantly higher (p < 0.01) following URLi compared with Lispro for the 7 U dose but was not significantly different for the 15 or 30 U doses (Fig. 5E).

      Dose Proportionality for PK and GD Parameters

      Mean insulin lispro concentration–time profile for URLi increased with increasing dose levels (Fig. 6A), and insulin lispro exposure increased with increasing dose (see Supplementary Figure 2 in the online version at doi: https://doi.org/10.1016/j.clinthera.2020.07.005). Analysis of dose proportionality for PK parameters for URLi showed that increases in insulin lispro exposure with increasing dose of URLi were dose proportional, as the exponent of the power model and their respective 95% CIs for Cmax, AUC0–∞, and AUC0–10h were close to 1 (Table I).
      Figure 6
      Figure 6(A) Mean (SE) serum insulin lispro concentration–time profile following single subcutaneous doses of 7 U, 15 U, and 30 U of ultra rapid lispro (URLi). (B) Mean glucose infusion rate (GIR) versus time after administration of single subcutaneous doses of 7 U, 15 U, and 30 U of URLi.
      Table IDose proportionality for insulin lispro exposure for ultra rapid lispro (URLi).
      VariablePower Model Equation95% CI of ExponentPredicted Dose-Normalized Geometric MeansRatio of Dose-Normalized Geometric Means (30 U vs 7 U) (95% CI)
      Cmax, pmol/L(eˆ3.84)∗(Doseˆ0.959)0.910–1.01
       7 U (n = 40)42.80.942 (0.877–1.01)
       15 U (n = 40)41.5
       30 U (n = 41)40.3
      AUC0–∞, pmol∙h/L(eˆ4.38)∗(Doseˆ1.08)1.05–1.10
       7 U (n = 40)93.31.12 (1.08–1.16)
       15 U (n = 40)99.1
       30 U (n = 41)105
      AUC0–10h, pmol∙h/L(eˆ4.38)∗(Doseˆ1.08)1.05–1.10
       7 U (n = 40)93.31.12 (1.08–1.16)
       15 U (n = 40)99.1
       30 U (n = 41)105
      AUC0-∞ = concentration versus time curve from time 0 to infinity; AUC0–10h = AUC from time 0–10 h postdose; Cmax = maximum observed drug concentration; CI = confidence interval.
      The mean LOESS GIR profile increased with increasing dose levels of URLi (Fig. 6B), and the overall insulin action of URLi increased with increasing doses of URLi as indicated by increased Rmax and Gtot (see Supplemental Figure 2 Supplemental Material S2 in the online version at doi: https://doi.org/10.1016/j.clinthera.2020.07.005). However, the increase in URLi dose did not elicit a corresponding proportional increase in Rmax and Gtot. Compared with 7 U, the dose-normalized geometric LS means of Rmax and Gtot at 30 U reduced by ~50% (0.85 vs 0.39 mg/kg/min) and 30% (154.3 vs 100.7 mg/kg), respectively (Table II). This was consistent with the observations for Lispro within this dose range. The ratio of dose-normalized geometric LS means (95% CI) for Rmax and Gtot across the dose range of 7–30 U were 0.46 (0.42–0.51) and 0.65 (0.59–0.72) for URLi, and 0.49 (0.45–0.55) and 0.69 (0.61–0.77) for Lispro.
      Table IIDose proportionality of insulin action for ultra rapid lispro (URLi) and Lispro.
      VariablePower Model Equation95% CI of ExponentPredicted Dose-Normalized Geometric MeansRatio of Dose-Normalized Geometric Means (30 U vs 7 U) (95% CI)
      Dose proportionality of insulin action for URLi
      Rmax, mg/kg/min(eˆ0.86)∗(Doseˆ0.47)0.41–0.530.46 (0.42–0.51)
       7 U (n = 40)0.85
       15 U (n = 40)0.56
       30 U (n = 41)0.39
       Gtot, mg/kg(eˆ5.61)∗(Doseˆ0.71)0.64–0.780.65 (0.59–0.72)
       7 U (n = 40)154.32
       15 U (n = 40)123.41
       30 U (n = 41)100.71
      Dose proportionality of insulin action for Lispro
      Rmax, mg/kg/min(eˆ0.64)∗(Doseˆ0.52)0.45–0.580.49 (0.45–0.55)
       7 U (n = 40)0.74
       15 U (n = 41)0.51
       30 U (n = 40)0.37
       Gtot, mg/kg(eˆ5.56)∗(Doseˆ0.74)0.66–0.820.69 (0.61–0.77)
       7 U (n = 40)157.69
       15 U (n = 41)129.61
       30 U (n = 40)108.43
      CI = confidence interval; Gtot = weight-normalized total glucose infused during clamp; Rmax = weight-normalized maximum glucose infusion rate.

      C-Peptide Response

      The C-peptide response was similar between URLi and Lispro for each dose level. After administration of study drug, C-peptide concentrations decreased from baseline, indicating a suppression of endogenous insulin secretion by both study drugs. C-peptide levels remained low for the first 6 h of the clamp, after which they approached predose levels. This corresponds to the time when the insulin lispro concentration approached or reached the LLOQ (see Supplemental Figure 3 in the online version at doi: https://doi.org/10.1016/j.clinthera.2020.07.005).

      Safety and Tolerability

      A total of 29 subjects (69.0%) reported 76 treatment-emergent AEs (TEAEs) during the study, of which 34 (URLi, 25; Lispro, 9) in 19 subjects (45.2%; URLi, 15 [36.6%]; Lispro, 8 [19.5%]) were considered by the investigator to be related to study drug. All TEAEs were of mild or moderate severity, and no severe TEAEs were reported for either treatment. The most common types of TEAEs reported for both URLi and Lispro were headache, injection-site reaction, nausea, vomiting, and viral upper respiratory tract infection (see Supplemental Table 1 in the online version at doi: https://doi.org/10.1016/j.clinthera.2020.07.005). Based on investigator assessment of the injection site, at 4 prespecified time points postdose, 9 subjects reported mild and transient injection-site reactions (7 subjects after URLi and 2 subjects after Lispro); the majority of these were transient erythema. No severe hypoglycemic events were reported. No clinically relevant alterations in laboratory values, vital signs, or ECG profiles were observed.

      Discussion

      This study is the first to report the PK and GD effects of a single SC injection of URLi versus Lispro across a therapeutic dose range in healthy subjects. This study showed that URLi accelerated insulin lispro absorption with a reduction in the late exposure and an overall shorter exposure duration compared with Lispro, consistently across the doses of 7, 15, and 30 U. This resulted in earlier insulin action, as well as a reduction in late insulin action and an overall shorter duration of insulin action compared with Lispro, across all 3 dose levels. After SC administration, URLi exhibited dose-proportional increases in insulin lispro exposure (Cmax and AUC) over the range of 7–30 U. Less than dose-proportional increases in maximum and overall glucose infused during the clamp were observed with URLi over the dose range of 7–30 U, and were similar for both URLI and Lispro. All 3 dose levels of URLi were well tolerated.
      Current rapid-acting insulins provide the best possible PPG control when administered 15–20 min before a meal.
      • Slattery D.
      • Amiel S.A.
      • Choudhary P.
      Optimal prandial timing of bolus insulin in diabetes management: a review.
      Premeal injection compensates for the lag time occurring between SC injection and sufficient insulin absorption into the circulation to handle carbohydrate uptake after meal ingestion. However, this is not always possible in certain special circumstances such as people working in critical environments or at social gatherings, when patients may be unable to use the optimal injection-to-meal interval.
      In the present study, URLi had accelerated insulin lispro absorption and insulin action compared with Lispro at all 3 dose levels, suggesting it may better align with carbohydrate absorption and may improve PPG control versus current rapid-acting insulins. The onset of insulin lispro appearance in the serum following URLi occurred within ~1 min after SC injection and was 2–5 min faster than Lispro across the dose range. This resulted in a 6- to 8-fold increase in exposure within the first 15 min postadministration with URLi compared with Lispro. Correspondingly, the onset of insulin action of URLi was observed within 16–18 min postadministration, which was 12–15 min earlier than Lispro across this dose range. This faster insulin action produced ~3-fold greater early insulin action in the first 30 min with URLi compared with Lispro for all dose levels (p < 0.0001).
      Beyond the data presented in this study, similar findings were observed for URLi versus Lispro in Phase I studies conducted in patients with T1DM and T2DM receiving a 15 U dose, in which onset of insulin lispro appearance in the serum with URLi was ~5 min faster accompanied with a significantly greater exposure within the first 15 min postdose (T1DM, 7.2-fold [p < 0.0001]; T2DM, 6.4-fold [p < 0.0001]) than Humalog.
      • Linnebjerg H.
      • Zhang Q.
      • LaBell E.
      • et al.
      Pharmacokinetics and glucodynamics of ultra rapid lispro (URLi) versus Humalog® (Lispro) in younger adults and elderly patients with type 1 diabetes mellitus: a randomised controlled trial.
      ,
      • Leohr J.
      • Dellva M.A.
      • Coutant D.E.
      • et al.
      Pharmacokinetics and glucodynamics of ultra rapid lispro (URLi) versus Humalog® (Lispro) in patients with type 2 diabetes mellitus: a phase I randomised, crossover study.
      Concurrently, URLi exhibited significantly faster onset of insulin action (T1DM, 10.8–11.8 min [p < 0.001]; T2DM, 12.7 min [p < 0.001]) and greater early insulin action in the first 30 min (T1DM, 3.2-fold; T2DM, 4.3-fold) compared with Lispro. Correspondingly, Phase III studies of URLi in subjects with T1DM (PRONTO-T1D) and T2DM (PRONTO-T2D) treated with a bolus-basal regimen have shown superior PPG lowering of URLi compared with Lispro when the insulins were dosed immediately (within 2 min) before a meal.
      • Blevins T.
      • Zhang Q.
      • Frias J.P.
      • Jinnouchi H.
      • Chang A.M.
      Randomized Double-Blind Clinical Trial Comparing Ultra Rapid Lispro With Lispro in a Basal-Bolus Regimen in Patients with Type 2 Diabetes: PRONTO-T2D.
      ,
      • Klaff L.J.
      • Cao D.
      • Dellva M.A.
      • et al.
      Ultra Rapid Lispro Improves Postprandial Glucose Control Compared With Lispro in Patients With Type 1 Diabetes: Results From the 26-Week PRONTO-T1D Study.
      In addition, the faster absorption profile may reduce PPG excursions in patients who choose to dose their prandial insulin after meals.
      Beyond an accelerated absorption, URLi may also provide a benefit for late postprandial hypoglycemia, which occurs when the duration of insulin action of exogenous insulin exceeds the duration of elevated blood glucose levels. Late insulin action and duration of insulin action were significantly reduced with URLi compared with Lispro in this study. This finding is consistent with that observed in the PRONTO-T1D and PRONTO-T2D studies, in which URLi exhibited a reduction in hypoglycemia rates in the period >4 h postdose.
      • Blevins T.
      • Zhang Q.
      • Frias J.P.
      • Jinnouchi H.
      • Chang A.M.
      Randomized Double-Blind Clinical Trial Comparing Ultra Rapid Lispro With Lispro in a Basal-Bolus Regimen in Patients with Type 2 Diabetes: PRONTO-T2D.
      ,
      • Klaff L.J.
      • Cao D.
      • Dellva M.A.
      • et al.
      Ultra Rapid Lispro Improves Postprandial Glucose Control Compared With Lispro in Patients With Type 1 Diabetes: Results From the 26-Week PRONTO-T1D Study.
      Compared with Lispro, the hypoglycemia rate in the period >4 h postdose was reduced by 37% (glucose level, <54 mg/dL [3.0 mmol/L]) in patients with T1DM23 and by 27% (glucose level ≤70 mg/dL [3.9 mmol/L]) in patients with T2DM.
      • Blevins T.
      • Zhang Q.
      • Frias J.P.
      • Jinnouchi H.
      • Chang A.M.
      Randomized Double-Blind Clinical Trial Comparing Ultra Rapid Lispro With Lispro in a Basal-Bolus Regimen in Patients with Type 2 Diabetes: PRONTO-T2D.
      Patients with diabetes are required to adjust their prandial insulin doses based on size and content of a meal and premeal blood glucose levels to achieve optimum PPG control.
      • Krzymien J.
      • Ladyzynski P.
      Insulin in type 1 and type 2 diabetes—should the dose of insulin before a meal be based on glycemia or meal content?.
      Across the 3 clinically relevant doses studied, insulin lispro exposure after URLi increased proportionally with increasing dose. In addition, the accelerated insulin lispro absorption, reduction in late exposure, and an overall shorter PK duration with URLi compared with Lispro was consistent across the doses (7, 15, and 30 U). These findings indicate that dose adjustment of URLi would result in proportional changes in insulin lispro exposure, and the accelerated PK profile of URLi over Lispro is maintained. Therefore, dose adjustment of URLi could be made while maintaining the benefits of URLi.
      Similarly, the maximum (Rmax) and overall glucose (Gtot) infused during the clamp increased with URLi dose over the range of 7–30 U; however, it was less than dose-proportional but was consistent with that of Lispro within this dose range. The slightly less than dose-proportional increase in GD parameters at higher doses of URLi observed in this study are also consistent with those observed for faster insulin aspart and insulin aspart.
      • Heise T.
      • Stender-Petersen K.
      • Hovelmann U.
      • et al.
      Pharmacokinetic and pharmacodynamic properties of faster-acting insulin aspart versus insulin aspart across a clinically relevant dose range in subjects with type 1 diabetes mellitus.
      It has been suggested that this is likely caused by the saturation of insulin action at high dose levels due to achieving maximum insulin-simulated glucose disposal, which lies in the range of 10–15 mg/kg/min.
      • DeFronzo R.A.
      • Ferrannini E.
      • Hendler R.
      • Felig P.
      • Wahren J.
      Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man.
      ,
      • Freidenberg G.R.
      • Suter S.L.
      • Henry R.R.
      • Reichart D.
      • Olefsky J.M.
      In vivo stimulation of the insulin receptor kinase in human skeletal muscle. Correlation with insulin-stimulated glucose disposal during euglycemic clamp studies.
      The Rmax in this study was ~11 mg/kg/min for the 30-U dose, suggesting that this dose likely caused saturation of insulin-simulated glucose disposal, which may have resulted in a limited increase in insulin action.
      The main strength of the present study was that the dose range evaluated was relevant to doses administered to patients with diabetes in clinical practice.
      • Heller S.
      • Koenen C.
      • Bode B.
      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.
      • Herbst K.L.
      • Hirsch I.B.
      Insulin strategies for primary care providers.
      • Rosenstock J.
      • Ahmann A.J.
      • Colon G.
      • Scism-Bacon J.
      • Jiang H.
      • Martin S.
      Advancing insulin therapy in type 2 diabetes previously treated with glargine plus oral agents: prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy.
      The crossover study design enabled patients to serve as their own control for each dose and study treatment, and inclusion of a washout period between dosing periods allowed removal of previous study drug. Other strengths included the use of a specific assay to measure PK (preventing interference from endogenous insulin) and stability of the glucose levels during the clamp procedure allowing successful comparison between treatment periods. A potential limitation of this study was the study population of healthy subjects who have endogenous insulin secretion. However, there was no difference in C-peptide concentrations between subjects receiving URLi versus those receiving Lispro, suggesting that suppression of endogenous insulin secretion was similar between the treatment groups and confirming a valid comparison between the 2 treatments. In addition, although the glucose clamp is the gold standard to measure insulin action, this method does not include a measurement of the glucose-lowering effects after oral carbohydrate intake.

      Conclusions

      This study showed that URLi had accelerated insulin lispro absorption with reduced late insulin exposure and shorter duration compared with Lispro after 7, 15, and 30 U doses in healthy subjects. This corresponded to a significantly earlier onset of insulin action and greater early insulin action with a reduction in late insulin action and shorter duration of action compared with Lispro. The overall insulin exposure and insulin action were similar between the 2 treatments, and URLi was well tolerated at all administered doses. Dose-proportional increases in insulin lispro exposure after URLi administration were observed. The corresponding increase in insulin action was slightly less than dose proportional for both URLi and Lispro. The faster absorption and insulin action of URLi compared with Lispro is likely to explain the greater PPG lowering in patients with T1DM and T2DM, which has been reported in two Phase III studies.
      • Blevins T.
      • Zhang Q.
      • Frias J.P.
      • Jinnouchi H.
      • Chang A.M.
      Randomized Double-Blind Clinical Trial Comparing Ultra Rapid Lispro With Lispro in a Basal-Bolus Regimen in Patients with Type 2 Diabetes: PRONTO-T2D.
      ,
      • Klaff L.J.
      • Cao D.
      • Dellva M.A.
      • et al.
      Ultra Rapid Lispro Improves Postprandial Glucose Control Compared With Lispro in Patients With Type 1 Diabetes: Results From the 26-Week PRONTO-T1D Study.

      Disclosures

      Ms. Leohr, Ms. Dellva, Ms. LaBell, Dr. Coutant, and Dr. Linnebjerg are employees and shareholders of Eli Lilly and Company. Dr. Klein is an employee of Profil. Dr. Plum-Moerschel is an employee of Profil and has received speaker fees and travel grants from Eli Lilly and Company and Novo Nordisk. Dr. Zijlstra is an employee of Profil and has received speaker fees and travel grants from Aerami Therapeutics, Eli Lilly and Company, Novo Nordisk, and Roche Diabetes Care. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
      Eli Lilly and Company was involved in the study design, data analysis, and preparation of the manuscript.

      Acknowledgments

      This study was sponsored by Eli Lilly and Company. Medical writing assistance was provided by Sandra Kurian, MPharm, and Tania Dickson, PhD, CMPP, of ProScribe–Envision Pharma Group, and was funded by Eli Lilly and Company. ProScribe's services complied with international guidelines for Good Publication Practice (GPP3).
      The authors thank the patients, investigators, and the institution involved in this study. They also thank Shane Pin Chung Chua for study management and the medical writers for medical writing assistance.
      All authors participated in the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. Drs. Klein and Plum-Moerschel were involved in data collection; Dr. Linnebjerg, Ms. Leohr, Dr. Coutant, Ms. Dellva, Dr. Klein, and Dr. Zijlstra were involved in the study design; Dr. Linnebjerg was involved in medical monitoring; Drs. Klein and Plum-Moerschel were investigators in the study; Ms. Dellva was involved in statistical analysis; and Ms. LaBell and Ms. Leohr conducted the pharmacodynamic and pharmacokinetic analyses.
      The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.

      Appendix.

      Supplementary Material S1
      Supplementary Material S1Mean (±SE) blood glucose following URLi and Humalog in healthy subjects during the euglycemic clamp. U = units; URLi = ultra rapid lispro.
      Supplementary Material S2
      Supplementary Material S2Box plots of insulin lispro (A) AUC0-∞, (B) Cmax, (C) Gtot and (D) Rmax, showing dose proportionality of PK and GD parameters across the three URLi dose levels. AUC0–∞ = area under the concentration versus time curve from time 0 to infinity; Cmax=maximum observed drug concentration; Gtot = total amount of glucose infused; Rmax = maximum glucose infusion rate; U = units; URLi = ultra rapid lispro.
      Supplementary Material S3
      Supplementary Material S3Mean (±SE) C-peptide concentration profiles during the euglycemic clamp for (A) 7 U, (B) 15 U, and (C) 30 U doses of URLi versus Humalog. SE = standard error; U = units; URLi = ultra rapid lispro.
      Supplementary Material S4Overall summary of TEAEs between URLi and Lispro
      Safety ParametersURLiLispro
      7 U (n = 40)15 U (n = 40)30 U (n = 41)7 U (n = 40)15 U (n = 41)30 U (n = 40)
      Number of TEAEs, n15121811128
      Subjects with TEAEs, n (%)12 (30.0)7 (17.5)16 (39.0)9 (22.5)10 (24.4)7 (17.5)
      Severity of TEAEs, n
       Mild810128104
       Moderate726324
       Severe000000
      TEAEs reported in ≥2 subjects, n (% of subjects with TEAE)
       Headache6 (15.0)4 (10.0)6 (14.6)8 (20.0)3 (7.3)3 (7.5)
       Nausea1 (2.5)2 (5.0)3 (7.3)1 (2.5)1 (2.4)2 (5.0)
       Vomiting2 (5.0)1 (2.4)1 (2.5)1 (2.4)1 (2.5)
       Injection-site reaction1 (2.5)1 (2.5)6 (14.6)2 (4.9)
       Viral upper respiratory tract infection2 (5.0)1 (2.5)1 (2.4)
      TEAE = treatment-emergent adverse event; U = units; URLi = ultra rapid lispro.

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