LY2963016 Insulin Glargine and Insulin Glargine (Lantus) Produce Comparable Pharmacokinetics and Pharmacodynamics at Two Dose Levels

Abstract

LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products with identical amino acid sequences. This was a phase 1 single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period crossover study to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of LY IGlar and IGlar at 2 different doses. Fasted healthy subjects were randomly assigned to receive 2 single doses of LY IGlar and IGlar (0.3 and 0.6 U/kg for each product). Blood samples were collected up to 24 hours postdose to assess PK, and a euglycemic clamp lasting up to 24 hours postdose was conducted to assess PD. Twenty-four healthy subjects aged 23 to 52 years participated in the study. The primary PK parameters (area under the concentration versus time curve from 0 to 24 hours [AUC ] and maximum observed drug concentration [C ]) and PD parameters (total amount of glucose infused during the clamp [G ] and maximum glucose infusion rate [R ]) were not statistically different between LY IGlar and IGlar at either dose. No safety concerns were noted with either drug. The study demonstrated that the PK and PD parameters for LY IGlar and IGlar were comparable following single doses at both 0.3 and 0.6 U/kg.

Pharmacokinetic and pharmacodynamic bioequivalence of proposed biosimilar MYL‐1501D with US and European insulin glargine formulations in patients with type 1 diabetes mellitus

“…Patients with T1DM were chosen for this study not only to provide data relevant to real‐world populations who use IG but also because these patients lack endogenous insulin, allowing the accurate determination of each insulin's time–action profile without the confounder of competing endogenous insulin . This is in contrast with some biosimilar IG programmes that focus on euglycaemic clamp studies in healthy people without T1DM . There is agreement among clamp experts that PD outcomes such as overall activity, particularly toward the end of clamp procedures, may be affected by endogenous insulin secretion during glucose clamp tests in both healthy people and in people with T2DM, which may lead to an increase in GIR .…”

“…15 This is in contrast with some biosimilar IG programmes that focus on euglycaemic clamp studies in healthy people without T1DM. 14,16,17 There is agreement among clamp experts that PD outcomes such as overall activity, particularly toward the end of clamp procedures, may be affected by endogenous insulin secretion during glucose clamp tests in both healthy people and in people with T2DM, which may lead to an increase in GIR. 18,19 Variables such as AUC and total AUC can therefore only be reliably determined in people with T1DM, which may explain why other IG biosimilar programmes included clamp tests in this population.…”

Efficacy and Safety of Biosimilar Insulins Compared to Their Reference Products: A Systematic Review

“…The remaining 11 studies, all RCTs, met eligibility criteria and were included in the data synthesis [28][29][30][31][32][33][34][35][36][37][38]. Two open-label trials that studied LY2963016 and SAR342434 included an extension study that followed patients for up to 52 weeks to assess for immunogenicity and additional adverse events [33,35].…”

“…Each of the 11 trials was judged as having a low risk of detection or attrition bias (S2 Fig). Ten of the 11 studies had an unclear risk of selection bias, primarily due to lack of information or uncertainty about the potential for bias. Similarly, 5 of the 11 trials had an unclear risk of reporting bias, while Verma (2011), Zhang (2017), and Garg (2017) had high risk and Linnebjerg (2015), Linnebjerg (2016), and Kapitza (2016) had low risk of such bias. Nine trials had low risk of performance bias, while Cheng …”

“…Four studies included healthy adults and 3 studies evaluated patients with type 1 diabetes (S3 Table). Notably, Linnebjerg (2015) and Crutchlow (2017) Zhang (2017), and Crutchlow (2017) all specified an equivalence margin of 80% to 125% for both AUC and C max outcomes. In the Cheng trial (2010), AUC had an equivalence margin of 80% to 125% while C max had an equivalence of 70% to 143%.…”