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

Abstract

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.

How to Achieve Sufficient Endogenous Insulin Suppression in Euglycemic Clamps Assessing the Pharmacokinetics and Pharmacodynamics of Long-Acting Insulin Preparations Employing Healthy Volunteers

“…Since a C-peptide suppression of more than 50% is widely recognized as sufficient endogenous insulin suppression, the subjects fell into two groups based on the ratio of C-peptide reduction from baseline (group A: C-peptide reduction <50%; group B: C-peptide reduction ≥50%). The data were collected from a clinical trial (NCT03555305) (Liu et al, 2021), which was conducted to evaluate the pharmacokinetic and pharmacodynamic equivalence of an IGlar biosimilar (LY2963016) manufactured by Eli Lilly to Lantus manufactured by Sanofi.…”

“…A previous study showed (Liu et al, 2021) that for IGlar max, and AUC IGlar, 0-24 h , geometric least-squares mean ratios (90% confidence interval) of LY2963016 to Lantus were 0.961 (0.887-1.04) and 0.941 (0.872-1.01), respectively, and dosage proportion of Lantus was significantly different between two groups (Table 1), therefore, matching for dosage proportion of Lantus was performed.…”

“…A 6-ml blood sample for analysis of C-peptide and total insulin levels were collected before drug administration (0.5 and 0 h before dosing) and every 0.5-3 h throughout the clamp as described before (Liu et al, 2021). The whole blood sample was drawn into a serum tube and gently mixed by inversion (>5 times).…”

Efficacy and Safety of LY2963016 Insulin Glargine in Chinese Patients with Type 1 Diabetes Previously Treated with Insulin Glargine (Lantus®): a Post Hoc Analysis of a Randomized, Open-Label, Phase 3 Trial

“…It was the first approved insulin biosimilar in the European Union and has also been authorized as a follow-on insulin in the USA [ 17 , 18 ]. The biosimilarity of LY IGlar vs. IGlar was established in a comprehensive clinical development program that included studies in both Chinese and international populations [ 14 , 16 , 19 – 24 ]. LY IGlar and IGlar demonstrated comparable pharmacokinetic and pharmacodynamic characteristics in healthy volunteers in separate phase I euglycemic clamp trials conducted in China, Singapore, and South Africa [ 19 – 21 ].…”

“…The biosimilarity of LY IGlar vs. IGlar was established in a comprehensive clinical development program that included studies in both Chinese and international populations [ 14 , 16 , 19 – 24 ]. LY IGlar and IGlar demonstrated comparable pharmacokinetic and pharmacodynamic characteristics in healthy volunteers in separate phase I euglycemic clamp trials conducted in China, Singapore, and South Africa [ 19 – 21 ]. In randomized phase III studies in patients with T1DM already receiving basal-bolus regimens, LY IGlar and IGlar showed similar efficacy, safety, and immunogenicity in the ABES trial in Chinese patients [ 22 ], and in the global ELEMENT-1 trial in predominantly white patients [ 14 , 25 ].…”