Comparison of the Pharmacokinetics and Pharmacodynamics of LY2963016 Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies

Abstract

OBJECTIVELY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes but with identical amino acid sequences. Three studies evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of LY IGlar and the European Union-and US-approved versions of IGlar. RESEARCH DESIGN AND METHODSThese were three single-site, randomized, double-blind, two-treatment, fourperiod, crossover, euglycemic clamp studies. In each study, fasted healthy subjects received 0.5 units/kg s.c. doses of two different insulin glargine products on two occasions each, following a randomized sequence. A ‡7-day washout period separated the doses. Blood samples were collected predose and up to 24 h postdose to assess PK; PD was assessed by a euglycemic clamp lasting up to 24 h. RESULTSA total of 211 subjects participated in the three studies. The PK (area under the curve [AUC]; maximum observed concentration [C max ]) and PD (maximum glucose infusion rate [R max ]; total glucose infusion during the clamp [G tot ]) were similar between LY IGlar and IGlar, with the ratios of geometric means ranging from 0.90 to 0.95 for PK parameters and from 0.91 to 0.99 for PD parameters across studies. In all cases, the 90% CIs for the ratios of geometric means were completely contained in the prespecified acceptance limits of 0.80-1.25. Adverse events were similar between treatments. CONCLUSIONSThese studies demonstrated that the PK and PD properties of LY IGlar and IGlar were similar after single 0.5 units/kg s.c. doses in healthy subjects, contributing to the totality of evidence supporting similarity of these products.

A practical guide to the interpretation of PK/PD profiles of longer-acting analogue insulins. Part one: The principles of glucose clamp studies

“…biosimilarity between drugs as demonstrated by a recent study that evaluated the biosimilarity between different insulin glargine products. 9 While this approach may reduce the reported effect of endogenous insulin on glucose concentration, it does not entirely eliminate this confounding metabolic effect of the endogenous insulin.…”

“…Results from glucose clamp studies performed in healthy volunteers, 9,30 patients diagnosed with Type 1 diabetes mellitus 7,8,21 and Type 2 diabetes mellitus 22,23 have been published. However, for each population a number of potentially confounding factors must be considered when interpreting the results.…”

“…6 A vast collection of data describing the time-action profiles of analogue insulins has been published recently. [7][8][9][10] However, while the correct interpretation of these profiles can guide the prescriber in selecting the most appropriate treatment for a patient, this proves to be a challenging feat. This series of publications will discuss practical tips for the accurate interpretation of pharmacokinetic and pharmacodynamic profiles of analogue insulins obtained from glucose clamp studies.…”

Introduction of biosimilar insulins in Europe

“…Relative magnitudes of clinical studies for generic medicines 64, biosimilar LY insulin glargine 32, 35, 37, 38, 41, 43 and new molecular entities 65. The sizes of the circles do not necessarily represent the relative sizes of the trials between categories.…”

Duration of Action of Insulin Products in Diabetic Mellitus Patients-Possible Implications on Bio-similarity Assessment

“…LY IGlar has been previously confirmed to be biosimilar to IGlar in terms of its pharmacokinetic and pharmacodynamic profiles in healthy volunteers [2]. In particular, such data appears to raise the bar in our understanding of what needs to be a scientifically relevant package for showing bio-similarity of insulin products.…”