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

Abstract

Background: 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 pharmacokinetics, glucodynamics, safety, and tolerability of URLi and Humalog® in patients with type 1 diabetes mellitus (T1DM).

Methods: This was a phase I, two-period, randomised, double-blind, crossover glucose clamp study in younger adult (aged 18-45 years; n = 41) and elderly (aged ≥65 years; n = 39) patients with T1DM. At each dosing visit, patients received either URLi or Humalog (15 units subcutaneously) followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured.

Results: Insulin lispro appeared in serum 6 min faster, and exposure was 7.2-fold greater over the first 15 min postdose with URLi versus Humalog in both age groups. Exposure beyond 3 h postdose was 39-41% lower, and exposure duration was reduced by 72-74 min with URLi versus Humalog in both age groups. Onset of insulin action was 11-12 min faster, and insulin action was 3-fold greater over the first 30 min postdose with URLi versus Humalog in both age groups. Insulin action beyond 4 h postdose was 44-54% lower, and duration of action was reduced by 34-44 min with URLi versus Humalog in both age groups. Overall exposure and total insulin action remained similar for both treatments. URLi and Humalog were well tolerated.

Conclusion: In patients with T1DM, URLi showed ultra-rapid pharmacokinetics and glucodynamics, with the differences between URLi and Humalog in elderly patients mirroring those in younger adults. ClinicalTrials.gov identifier: NCT03166124.

Conflict of interest statement

Helle Linnebjerg, Qianyi Zhang, Elizabeth LaBell, Mary Anne Dellva, David E. Coutant, and Jennifer Leohr are employees and shareholders of Eli Lilly and Company. Ulrike Hövelmann, Leona Plum-Mörschel, and Theresa Herbrand are employees of Profil.

Figures

Fig. 1

Trial design. SC subcutaneous, U units, URLi ultra rapid lispro

Fig. 2

Mean (±SE) serum insulin lispro concentration-time profile for URLi and Humalog. a 0–8 h after injection in younger adult patients; b 0–8 h after injection in elderly patients; c 0–1 h after injection in younger adult patients; and d 0–1 h after injection in elderly patients. Dashed line shows LLOQ for the assay. LLOQ lower limit of quantification, SE standard error, U units, URLi ultra rapid lispro

Fig. 3

Forest plots of insulin lispro pharmacokinetic parameters. AUC area under the concentration-time curve, AUC0–15min AUC from 0 to 15 min, AUC0–30min AUC from 0 to 30 min, AUC0–1h AUC from 0 to 1 h, AUC2–10h AUC from 2 to 10 h, AUC3–10h AUC from 3 to 10 h, AUC0–∞ AUC from time 0 to infinity, CI confidence interval, Cmax maximum observed drug concentration, early 50% tmax time to early half-maximal drug concentration, late 50% tmax time to late half-maximal drug concentration, LSM least squares means, URLi ultra rapid lispro

Fig. 4

Mean LOESS fits of glucose infusion rate over time for URLi and Humalog. a 0–8 h after injection in younger adult patients; b 0–8 h after injection in elderly patients; c 0–2 h after injection in younger adult patients; and d 0–2 h after injection in elderly patients. LOESS locally weighted scatterplot smoothing, U units, URLi ultra rapid lispro

Fig. 5

Forest plots of insulin lispro glucodynamic parameters. a For glucodynamic parameters with at least one patient with a value of 0, treatment ratios of LSM and 95% CIs were estimated using Fieller’s theorem, and p-values were not calculable; presented p-values are for treatment difference in LSM. CI confidence interval, 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, Gtot,0–30min total amount of glucose infused over the first 30 min, Gtot,0–1h total amount of glucose infused over the first hour, Gtot,0–2h total amount of glucose infused over the first 2 h, Gtot,3h–End total amount of glucose infused from 3 h to end of the clamp, Gtot,4h–End total amount of glucose infused from 4 h to end of the clamp, late 50% tRmax time to half–maximal glucose infusion rate after maximum glucose infusion rate, LSM least squares means, Rmax maximum glucose infusion rate, Tonset time to onset of insulin action, URLi ultra rapid lispro