Study Identifies Factors That Influence Bioequivalence Evaluations of Insulin Biosimilars

Factors that may affect the bioequivalence of test and reference insulin preparations were identified in a new study published in Frontiers in Pharmacology. Going forward, these factors can provide a scientific basis for consistency evaluations of the quality and efficacy of insulin biosimilars, authors wrote.

Findings from a structural equation model led researchers to conclude “adverse events and bioactive substance content should be optimized for consistency evaluation of the quality and efficacy of insulin biosimilars.”

The structural equation model allows for multivariable analysis, and compared with general regression analysis, it can better control measurement error. In addition, the authors wrote that “bioequivalence trials of insulin biosimilars should strictly obey inclusion and exclusion criteria to ensure the consistency of subjects and avoid confounding factors affecting the equivalence evaluation.”

For patients with diabetes, research has shown insulin biosimilars can better simulate the human physiological state of insulin secretion patterns and achieve a more flexible dosing time, along with other benefits.

“Bioequivalence evaluation is the established way for the review of generic drugs and occupies an important position in generic drug applications,” the authors explained, while biosimilars and their references should also be bioequivalent in safety and efficacy.

Several factors affect insulin preparations’ evaluations of bioequivalence, including the drugs’ properties and patients’ physiological status.

To better understand the factors affecting bioequivalence of 2 preparations, the researchers analyzed 177 healthy male patients between aged 18 to 45 years. Participants were divided into the equivalent group (n = 55) and nonequivalent group (n = 122) based on bioequivalence results according to European Medicines Agency guidelines.

Researchers used a 24-hour glucose clamp test to measure the glucose infusion rate and blood glucose. Liquid chromatography–mass spectrometry (LC-MS/MS) was also used to determine plasma insulin concentration.

A univariate analysis revealed statistical differences in “albumin, creatinine, T_max, bioactive substance content, and adverse events between the 2 groups,” data showed.

Furthermore, the structural equation model showed both adverse events (β = 0.342; P < .001) and bioactive substance content (β = −0.189; P = .007) had significant impacts on the 2 preparations’ bioequivalence, while “the bioactive substance content significantly affected adverse events (β = 0.200; P = .007).”

Adverse events included abnormalities in the liver and kidney function indicators, which could affect the drugs’ metabolic process. “Pharmaceutical preparation factors can also affect the occurrence of adverse events because of their active ingredients, impurity profiles, and excipients,” the authors added.

Because C-peptide levels in all insulin formulas were inhibited, they noted the bioequivalence evaluations carried out could exclude any interference from endogenous insulin.

The study marked the first time, to the authors’ knowledge, that researchers analyzed factors influencing the bioequivalence of insulin biosimilars based on structural equation models.

Overall, the authors offer the following advice based on the findings:

• Pharmacokinetic and pharmacodynamic bioequivalence evaluation indicators should consider specific drug characteristics
• Adverse events and active substance content should be optimized in consistency evaluation of quality and efficacy of insulin biosimilars
• In the process of development and production of insulin and its analog, it’s necessary to strictly control the quality of biosimilars, strengthen drug production supervision, and ensure that test preparation maintains similarity with reference preparation in terms of quality, safety, and efficacy
• Participants enrolled in bioequivalence trials should be homogeneous

A small sample size and lack of female participants mark limitations to the study. The indicators collected may also not comprehensively evaluate the influencing factors of bioequivalence, the researchers concluded.

Reference

Shao H, Tao Y, Tang C. Factors influencing bioequivalence evaluation of insulin biosimilars based on a structural equation model. Front Pharmacol. Published online April 3, 2023. doi:10.3389/fphar.2023.1143928