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Evaluation of the Pharmacokinetic Profile of Ultra Rapid Lispro Administered Subcutaneously at Different Injection Sites

Open AccessPublished:May 13, 2022DOI:https://doi.org/10.1016/j.clinthera.2022.04.001

      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 profile and glucodynamic response of URLi when administered subcutaneously into the abdomen, upper arm, or thigh. An intravenous (IV) bolus administration was included to determine the absolute bioavailability at each injection site.

      Methods

      In this Phase I, randomized, open-label, 4-period, crossover study, healthy subjects received a single dose of 15 U URLi subcutaneously into the abdomen, upper arm, or thigh, or by intravenous injection. Serum insulin lispro concentrations and glucodynamic response during a 10-hour euglycemic clamp procedure were assessed after URLi administration.

      Findings

      Total insulin lispro exposure was similar for the abdomen, upper arm, and thigh, and absolute bioavailability was ∼65% at each subcutaneous (SC) injection site. Total and peak insulin action were similar across these SC injection sites. The onset of appearance was <1 minute, and the time to early half-maximal drug concentration occurred at ∼10 minutes across these three SC injection sites. Onset of insulin action occurred at ∼22 minutes, and the early insulin action (for the first hour) was also similar across these SC injection sites. URLi was well tolerated after single SC injections and IV bolus administration.

      Implications

      The pharmacokinetic and glucodynamic profiles of URLi were similar after a single SC dose into the abdomen, upper arm, or thigh. The rate of insulin lispro absorption and early insulin action were maintained regardless of the SC injection site. The current study supports SC injection of URLi into the abdomen, upper arm, and thigh. ClinicalTrials.gov identifier: NCT03232983.

      Key words

      Introduction

      An important component of diabetes management to achieve an optimal glucose control, which can be measured through glycosylated hemoglobin or time in target glucose range,
      American Diabetes Association
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      is the use of rapid-acting insulin as a bolus insulin or in continuous subcutaneous (SC) insulin infusion systems.
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      Despite advancements, effectively and consistently controlling postprandial glucose (PPG) levels while avoiding hypoglycemia remains a clinical challenge.
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      Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological prandial insulin secretion and improve PPG control, and was first approved as Lyumjev® (Eli Lilly and Company, Indianapolis, IN, USA) in the United States, the European Union, and Japan in 2020 and in Canada in 2021. URLi contains 2 locally acting excipients, treprostinil and citrate, which act independently to accelerate the absorption of insulin lispro from the site of injection. Microdoses of treprostinil induce local vasodilation,
      • Pratt E
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      Treprostinil causes local vasodilation, is well tolerated, and results in faster absorption of insulin lispro.
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      In clinical studies, URLi has exhibited ultra-rapid pharmacokinetic (PK) and glucodynamic (GD) profiles with an accelerated insulin lispro absorption and faster onset of action compared with Humalog® (Eli Lilly and Company) in healthy subjects
      • Leohr J
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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.
      and patients with type 1 diabetes (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 (T2DM).
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      Pharmacokinetics and glucodynamics of ultra rapid lispro (URLi) versus Humalog® (lispro) in patients with type 2 diabetes mellitus: a phase I randomised, crossover study.
      Phase III studies have shown that URLi is superior to Humalog for PPG control in patients with T1DM
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      It is recommended that patients rotate insulin injection sites, and they may inject insulin at different regions of the body.
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      However, different anatomical regions could have differences in absorption rates due to SC blood flow and anthropometry.
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      Relationship between absorption of radiolabeled soluble insulin, subcutaneous blood flow, and anthropometry.
      Because the key attribute of URLi is the accelerated insulin absorption and faster insulin action, which provide a better match to carbohydrate absorption, understanding the PK and GD properties when administered at different tissue sites is important.
      The aim of the present study was to compare the PK and GD variables of URLi in healthy subjects after SC injection into the abdomen, upper arm, or thigh, or after intravenous (IV) injection.

      Participants and Methods

      Study Design

      This was a Phase I, open-label, 4-period, randomized, crossover, up to 10-hour euglycemic clamp study in healthy subjects. The study was conducted at a single center (Lilly-NUS Centre for Clinical Pharmacology, Singapore) in accordance with the principles of the Declaration of Helsinki (2000), the International Conference on Harmonisation Guidelines for Good Clinical Practice, and guidelines on bioavailability trials.

      European Medicines Agency, Committee for Medical Products for Human Use. Guideline on the Investigation of Bioequivalence. CPMP/EWP/QWP/1401/98 Rev. 1/Corr. 20. January 2010; https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf. Accessed 25 June 2021.

      ,

      Food and Drug Administration. Code of Federal Regulations. 21 CFR Part 320. Bioavailability and Bioequivalence Requirements. http://www.ecfr.gov/cgi-bin/text-idx?SID=b77b9e6e4aea3cdbd753c6bbd1b98077&mc=true&node=pt21.5.320&rgn=div5. Accessed 25 June 2021.

      Institutional review board approval and written informed consent from all subjects were obtained before any evaluations or study procedures. This study was registered at ClinicalTrials.gov as NCT03232983.
      An overview of the study design is outlined in Figure 1. Patients were randomized to 1 of 4 treatment sequences comprising single doses of 15 U of U100 URLi (Eli Lilly and Company) administered subcutaneously into the abdomen, thigh, or upper arm (deltoid), or by IV injection. The study included a screening period (≤28 days) followed by 4 inpatient treatment periods (3 days each) and a ≥14-day follow-up period. At least 3 days of washout occurred between each treatment period.
      Figure 1
      Figure 1Study design. The trial consisted of 6 visits: screening (≤28 days before enrollment), 4 treatment visits for dosing and clamp procedures (periods 1–4) with a washout period of at least 3 days between visits, and follow-up visit with a washout period of at least 14 days after the last dose. A total of 24 of 28 subjects completed all study periods. Single doses of 15 U ultra rapid lispro (URLi) were administered either subcutaneously in the abdomen, thigh, or upper arm, or intravenously. An up to 10-hour euglycemic clamp procedure was performed after each dose. IV = intravenous; SC = subcutaneous.

      Participants

      Eligible participants were overtly healthy men and women based on medical history, aged 21 to 65 years, body weight ≥45 kg, and body mass index 18.0 to 30.0 kg/m2. The main exclusion criteria were smoking, history of any medical or psychiatric illness, abnormal cardiac parameters or vital signs deemed clinically relevant by the investigator, allergies to any components of URLi, or use of prescription or nonprescription medication (apart from vitamin/mineral supplements, occasional paracetamol, thyroid replacement medication, or contraceptives).

      Bioanalytical Methods

      Serum-free insulin lispro was analyzed by using a validated ELISA specific for insulin lispro (Charles River Laboratories Montreal, Senneville, Quebec, Canada). Blood samples for PK analysis were collected at time 2.5, 5, 10, 15, 20, 25, 30, 40, 60, 70, 90, 120, 150, 180, and 210 minutes, and every 60 minutes from 240 to 600 minutes after drug administration. The lower limit of quantitation was 50.0 pg/mL (8.6 pmol/L), and the inter-assay accuracy (percent relative error) and inter-assay precision (percent relative SD) were ≤12%. Quantification of insulin lispro was not affected by the presence of lipemic serum, hemolyzed serum, treprostinil (1 ng/mL), or human insulin (1722 pmol/L).

      Euglycemic Clamp Procedure

      At each dosing visit, subjects fasted for at least 8 hours before administration of URLi. After administration, subjects underwent a euglycemic clamp procedure for up to 10 hours. Baseline fasting blood glucose levels were calculated for each subject as the mean of blood glucose concentrations at 10, 20, and 30 minutes before URLi administration. After drug administration, the glucose infusion was initiated at the time that the blood glucose dropped by 5 mg/dL (0.3 mmol/L) below the individual subject's fasting baseline, which was then used as the target blood glucose level for the euglycemic glucose clamp procedure. The time when the clamp was initiated was defined as the onset of insulin action. The clamp procedure was not performed in subjects with baseline blood glucose targets ≤63 mg/dL (3.5 mmol/L). After onset of insulin action, the glucose infusion rate (GIR) was adjusted manually to maintain the predetermined target blood glucose concentration for each individual subject. Blood glucose was maintained at target by variable infusion of IV 20% d-glucose (dextrose) solution. The GIR was recorded throughout the clamp procedure by the clamp operator and reflected the activity of the administered dose of insulin. The clamp operator was blinded to randomization. Blood samples were collected and measured for blood glucose every 2.5 minutes for the first 30 minutes, every 5 minutes from 30 to 120 minutes, every 10 minutes from 120 to 480 minutes, and every 20 minutes from 480 to 600 minutes after URLi injection.
      Glucose levels were measured by using glucose analyzers (YSI 23000 STAT Plus Glucose and Lactate Analyzer, YSI Inc, Yellow Springs, OH, USA). The clamp was discontinued if the GIR fell to 0 for at least 30 minutes.
      The variability (%CV) in the glucose target during the euglycemic clamp was consistent between treatment arms and similar to data reported for short-acting insulins (Supplemental Table 1).
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      PK Analyses

      PK analyses were conducted by using standard noncompartmental methods of analysis with Phoenix version 7.0 (Certara USA Inc, Princeton, NJ, USA) and S-PLUS version 8.2 (TIBCO Software, Palo Alto, CA, USA).
      Free serum insulin lispro concentrations were used to calculate PK parameters, including Cmax, AUC0–∞, and Tmax. Insulin lispro absorption was characterized by time to early half-maximal drug concentration (early 50% Tmax), and the onset of appearance, defined as time that serum insulin lispro reached the lower limit of quantitation. The determination of onset of appearance used a linear interpolation between the time of dosing (zero insulin lispro concentration) and the time of the first quantifiable insulin lispro.
      The absolute bioavailability was calculated by using the ratio of the insulin lispro AUC0–∞ after SC injection into the abdomen, or upper arm, or thigh to the insulin lispro AUC0–∞ after IV administration.

      GD Analyses

      GD parameters were derived from the GIR during the glucose clamp procedure, using Phoenix version 6.4 and S-PLUS version 8.2. A locally weighted scatterplot smoothing function using a span of 0.2 was applied to all individual GIR versus time profiles in each treatment group using S-PLUS software version 8.2. The fitted data for each subject were used to calculate the following GD parameters: maximum GIR (Rmax), time of maximum GIR (TRmax), total amount of glucose infused over the duration of the clamp procedure (Gtot), total amount of glucose infused over the first 30 minutes (Gtot[0–30min]), and total amount of glucose infused over 1 hour (Gtot[0–1h]). Time to onset of insulin action was based on the raw observed GIR data.

      Safety and Tolerability Assessments

      Safety and tolerability assessments included adverse events, clinical laboratory parameters, vital signs, ECGs, and hypoglycemic events. In addition, injection site assessment (erythema, pain, induration, edema, and itching) was performed at protocol-defined time points: immediately after injection, and 1, 4, and 10 hours after injection. Any injection site reaction findings were also recorded as adverse events.

      Statistical Analysis

      General Considerations

      Unless otherwise specified, testing for significance was done at an α level of 0.1 with two-sided CIs. Statistical significance was claimed if the P value of a test was <0.1. For selected analyses in which no P values were calculated, statistical significance was claimed if the corresponding 90% CI did not contain 0 (difference between treatment groups) or did not contain 1 (ratio of treatment groups).

      Sample Size Considerations

      A sample size of 22 completing subjects was estimated to provide the two-sided 90% CIs of the ratios of geometric means for AUC0–∞ after SC injection into the thigh and upper arm, compared with the abdomen, to be within ∼0.8 to 1.25 when the observed ratio is 1. This calculation is based on the assumption of a log-normal distribution and an estimate of intrasubject log-scale SD of 0.2.

      PK and GD Statistical Methods

      All relevant PK and GD parameters were log transformed, except for the time parameters. For log-transformed end points AUC0–∞, Cmax, Gtot, and Rmax, geometric least squares means (LSM), ratios of geometric LSM, and their corresponding 90% CIs were estimated for each injection site using the statistical model that includes injection site, period, and sequence as fixed effects, and subject within sequence as a random effect. Data from the upper arm, thigh, and abdomen injection sites were included in the same model. The same model without log transformation was used for the analysis of the time parameters Tmax and TRmax. The LSM, injection site differences in LSM, and the corresponding 90% CIs for the injection site differences were estimated from the model. The ratios between injection sites and 90% CIs for the ratios were calculated by using Fieller's theorem. A nonparametric approach was used to test the median of injection site differences for time parameters using the Wilcoxon signed rank test and approximate 90% CIs.

      Results

      Demographic Characteristics

      A total of 28 healthy male subjects, aged between 24 and 63 years (mean [SD], 39.8 [8.6] years) and with a mean (SD) body mass index of 24.3 (3.08) kg/m2, participated in this study. All subjects were Asian.
      Twenty-four subjects completed the study. Four subjects discontinued the study: one due to subject's decision, one after experiencing redness and swelling over the cannulation site (physician's decision), one after cannulation issues (physician's decision), and one due to work commitments. No subject discontinued the study due to an adverse event considered related to the study treatment.

      PK Parameters

      The mean insulin lispro concentration versus time profiles after SC injection into the abdomen and upper arm are superimposable, whereas the profile was marginally broader after injection into the thigh (Figure 2). Overall insulin lispro exposure (AUC0–∞) was consistent between all 3 injection sites. The 90% CI for the ratio of AUC0–∞ mean values between (thigh or upper arm) and the abdomen included 1 and were contained within 0.8 to 1.25 for both comparisons (Table I). Cmax was similar between the abdomen and upper arm but slightly lower (17%–20%) for the thigh. The 90% CI treatment ratio between the upper arm and abdomen for Cmax was contained within 0.8 to 1.25; however, the lower limit of the 90% CI of the ratio between thigh and abdomen was 0.737 and fell outside the 0.8 to 1.25 limits. The median (minimum–maximum) time of Cmax (Tmax) occurred at 0.67 hour (0.25–2.5 hours) for the abdomen, 0.67 hour (0.25–2.0 hours) for the upper arm, and 1.5 hours (0.17–2.5 hours) for the thigh.
      Figure 2
      Figure 2Arithmetic mean (SE) serum concentration versus time profiles for single subcutaneous injections of 15 U ultra rapid lispro into the abdomen, upper arm, or thigh of healthy subjects.
      Table IStatistical comparison between subcutaneous injection sites (upper arm/abdomen and thigh/abdomen).
      ParameterInjection SiteNGeometric Least Squares MeansRatio of Geometric Least Squares Means (Thigh or Upper Arm vs Abdomen)90% CI for the Ratio (Lower, Upper)
      Pharmacokinetics
       AUC0–∞, pmol·h/LAbdomen251744
      Upper arm2617991.030.99, 1.07
      Thigh2617441.000.96, 1.04
       Cmax, pmol/LAbdomen25731
      Upper arm267621.040.92, 1.18
      Thigh266080.830.74, 0.94
      Glucodynamics
       Gtot, mg/kg  Abdomen251516
      Upper arm2616581.091.00, 1.20
      Thigh2617291.141.04, 1.25
       Rmax, mg/kg/minAbdomen256.52
      Upper arm266.861.050.96, 1.15
      Thigh266.731.030.94, 1.13
      Gtot = total amount of glucose infused over the duration of the clamp procedure; Rmax = maximum glucose infusion rate.
      Mean treatment ratios (%CV) for AUC0–∞ for the abdomen, upper arm, or thigh compared with IV administration were 0.65 (18), 0.65 (14), and 0.64 (19), respectively. Thus, absolute bioavailability of URLi was ∼65% after SC administration in all 3 injection regions. The observed mean PK time profiles after IV administration or SC administration into the abdomen, upper arm, and thigh of URLi are shown in Supplemental Figure 1.

      GD Responses

      After SC injection of URLi into the abdomen, thigh, or upper arm, the mean GIR profiles were comparable (Figure 3). The maximum GIR (Rmax) and total insulin action (Gtot) were similar across injection sites with the 90% CI for the ratio of means including 1 and contained within 0.8 to 1.25 for both comparisons between (thigh or upper arm) and the abdomen (Table I). The median (minimum–maximum) TRmax occurred at 96 minutes (30–216 minutes) for the abdomen, 123 minutes (36–228 minutes) for the upper arm, and 168 minutes (30–234 minutes) for the thigh.
      Figure 3
      Figure 3Arithmetic mean locally weighted scatterplot smoothing–fitted glucose infusion rate profiles during euglycemic clamps for single SC injections of 15 U ultra rapid lispro into the abdomen, upper arm, or thigh of healthy subjects.

      Early Insulin Lispro Exposure and Insulin Action

      The insulin lispro concentration time profiles for the different injection sites overlapped during the first 30 minutes after dosing (Figure 2). The time to early half-maximal drug concentration (early 50% Tmax) across injection sites was similar, occurring at ∼10 minutes after SC injection (Table II). The median onset of appearance was 0.79 minute for the abdomen, 0.48 minute for the upper arm, and 1.16 minutes for the thigh. Although there were differences in the medians between injection sites, the range for the onset of appearance for these injection sites overlapped. Thus, the average onset of appearance of insulin lispro across all injection sites following URLi SC injection was ∼1 minute.
      Table IISummary of the pharmacokinetic parameters for insulin absorption and glucodynamic parameters for early insulin action after a single subcutaneous injection of 15 U ultra rapid lispro into the abdomen, upper arm, or thigh of healthy subjects. Data are %CV geometric mean unless otherwise stated.
      ParameterAbdomen (n = 25)Upper Arm (n = 26)Thigh (n = 26)
      Pharmacokinetics
       Early 50% Tmax, min
      Median (minimum–maximum).
      9.8 (5.8–15.2)9.1 (4.6–15.4)10.9 (3.9–29.9)
      N = 25.
       Onset of appearance, min
      Median (minimum–maximum).
      0.8 (0.1–3.5)0.5 (0.1–3.4)1.2 (0.1–3.7)
      Glucodynamics
       Tonset, min
      Median (minimum–maximum).
      22.8 (2.4–30)22.8 (2.4–42)19.8 (7.8–45)
       Gtot (0–30min), mg/kg37 (97)33.2 (147)28 (186)
       Gtot (0–1h), mg/kg181 (58)183 (51)148 (77)
      Early 50% Tmax = time to early half-maximal drug concentration; Gtot (0–30min) = total amount of glucose infused over the first 30 minutes; Gtot (0–1h) = total amount of glucose infused over the first hour; Onset of appearance = time that serum insulin lispro reached the lower level of quantification; Tonset = time to onset of insulin action.
      low asterisk Median (minimum–maximum).
      N = 25.
      The early insulin action was also similar between SC injection sites, as shown by the overlap of the GIR during the first hour after injection (Figure 3). Correspondingly, the onset of insulin action occurred at approximately the same time (abdomen, 22.8 minutes; upper arm, 22.8 minutes; and thigh, 19.8 minutes). In addition, the amount of glucose infused in the first 30 minutes (Gtot [0-30min]) and in the first hour (Gtot [0-1h]) of the clamp was comparable across the injection sites (Table II).

      Endogenous Insulin Secretion (C-peptide)

      Mean C-peptide profiles during the euglycemic clamp were similar across the SC injection sites after a 15 U dose of URLi (Supplemental Figure 2).

      Safety and Tolerability

      A total of 75 treatment-emergent adverse events (TEAEs) were reported by 23 subjects. All TEAEs were mild in severity, and no serious adverse events were reported. The frequency of TEAEs was comparable between the three SC injection sites and IV administration. The majority of TEAEs were related to study procedures, mainly bruising, pain, swelling, and erythema associated with blood sampling cannulation and infusion catheter sites.
      Five subjects reported TEAEs deemed to be related to study treatment: mild headache was reported by 1 subject; mild transient injection site pain was reported by 3 subjects after SC administration (abdomen and upper arm); and mild transient injection site pruritus was reported by 1 subject.
      No hypoglycemic events were reported during the study. No clinically relevant alterations in laboratory parameters, vital signs, or ECGs were observed.

      Discussion

      This study is the first, to the best of our knowledge, to compare the PK and GD effects of a single SC injection of URLi at different injection sites of the body. After a single SC injection of URLi into the upper arm, thigh, or abdomen, the insulin exposure and insulin action were similar across these injection sites. Importantly, the rate of absorption of insulin lispro and early insulin action of URLi were maintained regardless of SC injection site.
      The inclusion of an IV study arm enabled the determination of absolute bioavailability of URLi, which was ∼65% for all three SC injection sites. This is consistent with the reported absolute bioavailability of Humalog, which was 55% to 77% for SC doses between 0.1 and 0.2 U/kg.

      Eli Lilly and Company. Humalog (insulin lispro) Prescribing Information. Nov 2019; http://pi.lilly.com/us/humalog-pen-pi.pdf. Accessed 25 June 2021.

      After SC injection of URLi into the abdomen, upper arm, or thigh, the total insulin lispro exposure was similar across the injection sites. This is consistent with other mealtime insulins, such as Humalog,
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      Consistent with a similar total insulin lispro exposure, the total insulin action after URLi was also similar across the injection sites.
      The Cmax was lower after injection into the thigh compared with abdomen and upper arm injections, but this was not observed with the GD response, as the Rmax was similar across these injection sites.
      It has generally been observed that insulin absorption is slower in the thigh than from the abdomen.
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      This has been attributed to differences in absorption rate between injection sites, which have been shown to vary due to differences in SC blood flow and anthropometry. Within this study, the median Tmax and TRmax occurred later in the thigh compared with the abdomen or upper arm after injection of URLi, but the range for both the Tmax and TRmax overlapped across these injection sites. Importantly, numerous clinical studies with ultra-rapid mealtime insulins have shown that timing of the Tmax is not correlated with postprandial glucose lowering.
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      Rather, the faster rate of insulin absorption, as measured by the timing of the early 50% Tmax, or the amount of early insulin exposure, resulted in a greater postprandial glucose lowering. Consistent with this finding, Tmax was not significantly different after SC injection of URLi compared with Humalog in patients with T1DM
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      and was significantly later with URLi compared with Humalog in patients with T2DM.
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      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.
      In contrast, the timing of the early 50% Tmax occurred earlier and there was a greater amount of insulin exposure within the first hour after dosing with URLi versus Humalog.
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      Pharmacokinetics and glucodynamics of ultra rapid lispro (URLi) versus Humalog® (lispro) in patients with type 2 diabetes mellitus: a phase I randomised, crossover study.
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      • et al.
      Ultra rapid lispro lowers postprandial glucose and more closely matches normal physiological glucose response compared to other rapid insulin analogues: a phase 1 randomized, crossover study.
      This has resulted in a consistent improvement in postprandial glucose lowering with URLi compared with Humalog in adults with T1DM or T2DM.
      • Klaff L
      • Cao D
      • Dellva MA
      • 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.
      ,
      • Blevins T
      • Zhang Q
      • Frias JP
      • Jinnouchi H
      • Chang AM.
      Randomized double-blind clinical trial comparing ultra rapid lispro with lispro in a basal-bolus regimen in patients with type 2 diabetes: PRONTO-T2D.
      ,
      • Kapitza C
      • Leohr J
      • Liu R
      • 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.
      ,
      • Kapitza C
      • Leohr J
      • 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.
      Similarly, a faster rise in the insulin lispro concentration in the first 15 minutes was observed after URLi administration in adults with T1DM compared with endogenous insulin levels in healthy subjects following the same test meal.
      • Heise T
      • Linnebjerg H
      • Coutant D
      • et al.
      Ultra rapid lispro lowers postprandial glucose and more closely matches normal physiological glucose response compared to other rapid insulin analogues: a phase 1 randomized, crossover study.
      This faster rise in insulin lispro concentration resulted in a numerically greater PPG lowering at 1 hour after a test meal with URLi compared with what was observed in healthy subjects. These results show that a faster rate of insulin absorption results in greater PPG lowering, rather than differences in Tmax or Rmax.
      Within this study, the onset of insulin lispro appearance was <1 minute, and the early 50% Tmax was comparable between injection sites, occurring at ∼10 minutes postdose. The onset of insulin action and early insulin activity (Gtot [0–30min] and Gtot [0–1h]) were also similar across injection sites. Thus, there were no differences in the early insulin exposure or insulin action between the abdomen, upper arm, or thigh. We would therefore expect similar glucose lowering when URLi is injected into the abdomen, upper arm, or thigh.
      Although Humalog was not included in this study, we can compare the data within this study as URLi has consistently shown a faster insulin lispro absorption and earlier insulin action compared with Humalog.
      • Leohr J
      • Dellva MA
      • LaBell E
      • et al.
      Pharmacokinetic and glucodynamic responses of ultra rapid lispro vs lispro across a clinically relevant range of subcutaneous doses in healthy subjects.
      • 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 MA
      • Coutant DE
      • 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 a dose range study conducted in healthy subjects,
      • Leohr J
      • Dellva MA
      • LaBell E
      • et al.
      Pharmacokinetic and glucodynamic responses of ultra rapid lispro vs lispro across a clinically relevant range of subcutaneous doses in healthy subjects.
      a single 15 U SC dose of URLi administered into the abdomen had an onset of appearance at ∼1 minute, 3.9 minutes faster than Humalog, and the early 50% Tmax occurred at 13.6 minutes, which was 14 minutes faster than Humalog. The timing of the onset of appearance and early 50% Tmax are consistent with the present findings and infers that the ultra-rapid action of URLi is maintained for all injection sites studied.
      In some patients, buttocks is a preferred injection site for SC injection of insulin as described by the American Association of Diabetes Educators and in a pan-European epidemiologic study of insulin injection technique in patients with diabetes.
      • Strauss K
      • Gols HD
      • Hannet I
      • Partanen T-M
      • Frid A.
      A pan-European epidemiologic study of insulin injection technique in patients with diabetes.
      In the Phase III studies evaluating URLi in patients with T1DM and T2DM (PRONTO-T1D and PRONTO-T2D), patients were encouraged to rotate injection sites and allowed for injection in the abdomen, thigh, upper arm, and buttocks.
      • Klaff L
      • Cao D
      • Dellva MA
      • 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.
      ,
      • Blevins T
      • Zhang Q
      • Frias JP
      • Jinnouchi H
      • Chang AM.
      Randomized double-blind clinical trial comparing ultra rapid lispro with lispro in a basal-bolus regimen in patients with type 2 diabetes: PRONTO-T2D.
      Although the buttocks was not studied as a site of injection in this study, the abdomen, upper arm, thigh, and buttocks can be used in SC injection of URLi according to the dosage and administration of the prescribing information,

      Eli Lilly and Company. Lyumjev (ultra rapid lispro) prescribing information. Aug 2021; http://pi.lilly.com/us/lyumjev-uspi.pdf. Accessed 29 June, 2021.

      which is consistent with the recommendations for Humalog

      Eli Lilly and Company. Humalog (insulin lispro) Prescribing Information. Nov 2019; http://pi.lilly.com/us/humalog-pen-pi.pdf. Accessed 25 June 2021.

      and NovoRapid.

      Novo Nordisk. NovoRapid (Insulin Aspart) Summary of Product Characteristics. Oct 2020; https://www.medicines.org.uk/emc/product/7921. Accessed 01 Nov 2021.

      Although the present study was conducted in healthy subjects, the results are applicable to patients with T1DM and T2DM. Clinical pharmacology studies comparing the PK and GD profiles of URLi versus Humalog have been conducted in healthy subjects
      • Leohr J
      • Dellva MA
      • LaBell E
      • et al.
      Pharmacokinetic and glucodynamic responses of ultra rapid lispro vs lispro across a clinically relevant range of subcutaneous doses in healthy subjects.
      and patients with T1DM
      • 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.
      and T2DM.
      • Leohr J
      • Dellva MA
      • Coutant DE
      • 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.
      Across the studied dose range and study populations, including elderly patients with T1DM,
      • 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.
      URLi consistently exhibited a faster absorption, reduced late exposure, and overall shorter exposure duration compared with Humalog.
      • Heise T
      • Linnebjerg H
      • Coutant D
      • et al.
      Ultra rapid lispro lowers postprandial glucose and more closely matches normal physiological glucose response compared to other rapid insulin analogues: a phase 1 randomized, crossover study.
      Similarly, URLi showed earlier insulin action while reducing late insulin action, resulting in a shorter duration of insulin action compared with Humalog across the study populations (healthy subjects and patients with T1DM and T2DM) and dose range reflected in the individual studies and in the pooled analysis.
      • Leohr J
      • Dellva MA
      • Carter K
      • LaBell E
      • Linnebjerg H.
      Ultra rapid lispro (URLi) accelerates insulin lispro absorption and insulin action vs Humalog® consistently across study populations: a pooled analysis of pharmacokinetic and glucodynamic data.
      Also, although all participants in the study were male, the data are expected to be representative of both male and female subjects because no difference in sex has been identified with URLi in previous studies.

      Eli Lilly and Company. Lyumjev (ultra rapid lispro) prescribing information. Aug 2021; http://pi.lilly.com/us/lyumjev-uspi.pdf. Accessed 29 June, 2021.

      Despite the euglycemic clamp being the gold standard for assessing insulin action, a limitation of this procedure is that it does not measure the glucose-lowering effects of the insulin after oral carbohydrate intake.
      Strengths of this study were the crossover design, which enabled patients to act as their own control; the inclusion of a washout period between dosing periods, which ensured no presence of previously administered study drug; and the use of a specific assay to measure insulin lispro concentrations, ensuring no interference from endogenous insulin.

      Conclusions

      This study showed that the PK and GD profiles of URLi in healthy subjects were similar after SC injection of 15 U of URLi into the upper arm or thigh, compared with injection into the abdomen. The rate of insulin lispro absorption and early insulin action were maintained regardless of the SC injection site. The current study supports SC injection of URLi into the abdomen, upper arm, and thigh. This allows patients to inject at their preferred site while maintaining the rapid absorption with URLi.

      Declaration of Interest

      All authors are employees and shareholders of Eli Lilly and Company. Ms LaBell is a shareholder of Johnson & Johnson and Novartis, outside of the submitted work. 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; collection, analysis, and interpretation of data; preparation of the manuscript; and decision to submit the article for publication.

      Acknowledgments

      Eli Lilly and Company funded the study.
      The authors thank the study participants and investigators. The authors also thank Michelle Yi Xiu Lim (Eli Lilly and Company) for study operational oversight and Alastair Knights (Eli Lilly and Company) for medical writing and editing assistance.
      Dr Leohr, Ms Dellva, and Dr Linnebjerg were involved in the study design; Dr Linnebjerg was involved in medical monitoring; Dr Leohr, Dr Coutant and Ms LaBell conducted data analyses; and Ms Dellva was involved in the statistical analysis. All authors participated in the interpretation of the study results and in the drafting and critical revision of the manuscript. All authors approved the final version of the manuscript to be published.

      Data Sharing

      Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of PK or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data-sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.

      Appendix

      Supplementary Figure 1
      Supplementary Figure 1Arithmetic mean (±SE) serum insulin lispro concentration-versus-time profiles for single IV and SC injections of 15 U URLi in healthy subjects
      Abbreviations: SC = subcutaneous; IV = intravenous; SE = standard error; U = units; URLi = ultra rapid lispro.
      Supplementary Figure 2
      Supplementary Figure 2Arithmetic mean (±SE) C-peptide concentration profiles for single SC injections of 15 U URLi in healthy subjects
      Abbreviations: SC = subcutaneous; SE = standard error; U = units; URLi = ultra rapid lispro.
      Supplementary Table 1Mean glucose level for each participant and % CV of individual glucose level during clamp procedures
      TreatmentNMean (mg/dL)%CV
      15U URLi IV2881.17.1
      15U URLi SC Abdomen2580.18.1
      15U URLi SC Upper Arm2680.37.5
      15U URLi SC Thigh2681.47.4
      Abbreviations: CV = coefficient of variation; SC = subcutaneous; SE = standard error; U = units; URLi = ultra rapid lispro.

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