How to Accurately Establish Pharmacokinetics/Pharmacodynamics of Long-Acting Insulins in Humans: Relevance to Biosimilar Insulins

Porcellati, Francesca; Lucidi, Paola; Bolli, Geremia B.; Fanelli, Carmine G.

doi:10.2337/dc15-1848

Cited by 20 publications

(37 citation statements)

References 21 publications

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“…Overall, the whole set‐up of glucose clamp studies aims for a high degree of standardization: study participants are required to fast for at least 10‐12 hours before the start of the clamp, should avoid any strenuous exercise as well as certain foods and drinks in the last days before the clamp, should wash out potentially interfering antidiabetic compounds, in particular insulin, and are required to stay in a supine or semi‐supine position and remain fasted throughout the whole experiment. Thus, as for many other pharmaceutical test procedures, the set‐up of the PD clamp is aimed at optimizing the sensitivity for identifying potential differences between the investigated insulins rather than at establishing real‐life conditions …”

Section: Glucose Clamps: Design Issuesmentioning

confidence: 99%

“…Basal insulins with ongoing metabolic activity after 24 hours will show some accumulation, that is, a rise in their PK/PD effect over the first treatment days, with a once‐daily dosing regimen. It has therefore been proposed that basal insulins should be studied in steady‐state rather than single‐dose conditions; however, the difference between single‐dose and steady‐state conditions is quite small for traditional basal insulin analogues such as glargine and detemir, with a duration of action close to 24 hours, so that single‐dose data are fairly representative of steady‐state conditions …”

Section: Glucose Clamps: Design Issuesmentioning

confidence: 99%

“…The hyperinsulinaemic‐euglycaemic glucose clamp, originally designed for the assessment of insulin sensitivity, quickly became the “gold standard” for the assessment of pharmacodynamic (PD) characteristics of insulin preparations more than 25 years ago, and regulatory guidelines required glucose clamp results for the development of new insulin preparations . The value of glucose clamps for PD assessments per se had not been questioned until recently, when two commentaries queried the suitability of the glucose clamp technique for the demonstration of bioequivalence between insulin preparations because of alleged methodological shortcomings . However, even before this, clamp experts had discussed and sometimes disagreed on methodological details, making it difficult to assess the PD results of glucose clamp studies for non‐experts, particularly when these results differed between clamp groups.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Euglycaemic glucose clamp: what it can and cannot do, and how to do it

Heise

Zijlstra

Nosek

et al. 2016

Diabetes Obesity Metabolism

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The hyperinsulinaemic-euglycaemic glucose clamp has always been regarded as the "gold standard" for the assessment of pharmacodynamic (PD) properties of insulin preparations; however, there has been controversy over a variety of methodogical details, such as study population, dosing time and the initial stabilization of blood glucose (BG) concentrations at the clamp target level, among clamp groups. As the impact of these details on PD results is unclear, the present review provides an overview of different methodological approaches for both the man- However, even before this, clamp experts had discussed and sometimes disagreed on methodological details, 5 making it difficult to assess the PD results of glucose clamp studies for non-experts, particularly when these results differed between clamp groups. It might therefore be time to review both the strengths and the limitations of the clamp technique, addressing the most important methodological issues and discussing their potential impact on PD outcomes. | GLUCOSE CLAMP STUDIES: PRINCIPLE AND BASIC CONSIDERATIONSThe principle of the PD glucose clamp is quite simple 1 : the blood glucose (BG)-lowering effect of an insulin is antagonized by glucose

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Section: Glucose Clamps: Design Issuesmentioning

confidence: 99%

Section: Glucose Clamps: Design Issuesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Euglycaemic glucose clamp: what it can and cannot do, and how to do it

Heise

Zijlstra

Nosek

et al. 2016

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

show abstract

“…28 As the majority of patients using basal analogue insulins administer these at night, the same dosing schedule should be followed in glucose clamp studies. 27 However, a direct comparison of the results of glucose clamp studies of Gla-100 using morning and evening administration did not reveal a marked difference between the dosing times.…”

Section: Dose Of Study Insulinmentioning

confidence: 94%

“…27 Glucose clamp studies have been performed using a single dose of study insulin. However, this does not reflect the use of long-acting analogue insulins in the treatment population.…”

Section: Dose Of Study Insulinmentioning

confidence: 99%

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

Greeff

Tonder

Naidu

et al. 2018

Journal of Endocrinology, Metabolism and Diabetes of South Afri

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Glucose clamp studies are used to determine pharmacokinetics (PK) and pharmacodynamics (PD) of analogue insulins. With the development of longer-acting basal analogue insulins, including glargine 300 (Gla-300) and insulin degludec (IDeg), results from numerous glucose clamp studies are readily available. However, interpreting PK/PD profiles in a scientifically sound manner can be a challenging feat. This is the first in a series of publications that will suggest practical tips for interpreting and comparing results from glucose clamp studies. Variations in the glucose clamp methodology, duration of clamp studies and glucose clamp targets influence the study design and results significantly. Selection of study populations, including healthy patients or patients with Type 1 or 2 diabetes mellitus, has important implications. The dose of study insulin should reflect that of the general treatment population, and ideally steady-state conditions should be used. During the study the plasma insulin concentration and glucose infusion rate describe the pharmacokinetics and pharmacodynamics of the study insulin. With these practical tips in mind, results of glucose clamp studies can be interpreted in a scientifically correct manner. The next article in this series will discuss the interpretation of PK/PD profiles using two newly developed longer-acting basal analogue insulins: Gla-300 and IDeg.

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Effects of Unsuppressed Endogenous Insulin on Pharmacokinetics and/or Pharmacodynamics of Study Insulin in the Healthy: A Retrospective Study

Liu

Sun

et al. 2022

Clinical Pharm in Drug Dev

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C‐peptide, a marker of endogenous insulin, should be consistently inhibited during euglycemic clamping, while an elevated postdosing C‐peptide (CPpostdosing) is not an occasional phenomenon. This was a retrospective study that included 33 men who underwent a manual euglycemic clamp with a subcutaneous injection of insulin aspart (IAsp) aiming to describe the effects of insufficient suppression of endogenous insulin on estimates of the pharmacokinetics and pharmacodynamics of injected insulin. The time profiles of whole blood glucose, human insulin, glucose infusion rate (GIR), and C‐peptide were recorded. The subjects were divided into 2 groups at a ratio of 2:1: group A ([CPpostdosing]max>baseline CP [CPbaseline]), group B ([CPpostdosing]max ≤ CPbaseline). The endogenous insulin was approximately equal to the measured value of human insulin or calculated from the C‐peptide. The basal glucose, CPbaseline, basal human insulin, homeostatic model assessment of insulin resistance, IAsp dose, and demographic statistics were all comparable between the 2 groups except the “clamped” glucose. The average clamped glucose was 99.7% (group A) and 94.9% (group B) of baseline. After correction for clamped glucose, GIR area under the concentration‐time curve from time 0 to 8 hours was higher in group A (P < .05) under comparable IAsp exposure. Endogenous insulin area under the concentration‐time curve from time 0 to 8 hours calculated from C‐peptide was different from that measured from human insulin in group A (P < .05), whereas no statistical difference between these measures was observed in group B. Hence, blood glucose should be controlled below the baseline to ensure the inhibition of endogenous insulin. Unsuppressed endogenous insulin may contribute to observed GIR, and the endogenous insulin–corrected pharmacokinetics estimated by C‐peptide may be inaccurate with insufficient endogenous insulin suppression.

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How to Accurately Establish Pharmacokinetics/Pharmacodynamics of Long-Acting Insulins in Humans: Relevance to Biosimilar Insulins

Cited by 20 publications

References 21 publications

Euglycaemic glucose clamp: what it can and cannot do, and how to do it

Euglycaemic glucose clamp: what it can and cannot do, and how to do it

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

Effects of Unsuppressed Endogenous Insulin on Pharmacokinetics and/or Pharmacodynamics of Study Insulin in the Healthy: A Retrospective Study

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