Comparative evaluation of pharmacokinetics and pharmacodynamics of insulin glargine (Glaritus®) and Lantus® in healthy subjects: a double-blind, randomized clamp study

Bhatia, Ashima; Tawade, Shraddha; Mastim, Mushtaque; Kitabi, Eliford; Gopalakrishnan, Mathangi; Shah, Manish K.; Yeshamaina, Sridhar; Gobburu, Joga; Sahib, Maharaj K.; Thakur, D K; Kumar, K M Prasanna

doi:10.1007/s00592-018-1113-3

Cited by 13 publications

(18 citation statements)

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“…Thus, the extent of the reduction in the C-peptide influences the assessment of PD and PK properties, and adequate suppression of endogenous insulin secretion is crucial for successful clamping. Consequently, we suggest that the ratio of C-peptide reduction should be higher than 50%, with which the clamp study immunes to the disturbance of endogenous insulin, and this conclusion was consistent with previous studies ( Bhatia et al, 2018 ).…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, insulin secretion in women may vary during the menstrual cycle, although it is unclear whether this may influence study results (European Medicines Agency, 2015). According to the EMA guidelines, commonly used insulin doses in the clamp study should range from 0.3 to 0.4 IU/kg bodyweight for intermediateacting insulin (European Medicines Agency, 2015), and considering previous studies and instruction on glargine administration (Heise et al, 2012;Heise et al, 2015a;Bhatia et al, 2018), we decided to use a dose of 0.4 IU/kg. Endogenous insulin secretion should be strictly controlled by the euglycemic clamp technique as endogenous insulin secretion interferes with PK and PD properties (Porcellati et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Reduction in C-Peptide Levels and Influence on Pharmacokinetics and Pharmacodynamics of Insulin Preparations: How to Conduct a High-Quality Euglycemic Clamp Study

Tao

Zhu

et al. 2021

Front. Pharmacol.

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Objective: The aim of the study was to investigate the different extent of inhibition of endogenous insulin secretion by the reduction of C-peptide levels in an euglycemic clamp study and its effects on the evaluation of pharmacokinetics, pharmacodynamics of insulin preparations, and quality of clamp study to determine the best reduction range of C-peptide levels.Methods: Healthy Chinese male volunteers were enrolled and underwent a single-dose euglycemic clamp test. Participants were subcutaneously injected with long-acting insulin glargine (0.4 IU/kg). Blood samples were collected pretest and up to 24 h post-test to assess pharmacokinetics (PK), pharmacodynamics (PD), and C-peptide levels.Results: We divided the 39 volunteers enrolled in the study into three groups according to the reduction of C-peptide levels: group A (ratio of C-peptide reduction <30%, n = 13), group B (ratio of C-peptide reduction between ≥ 30% and <50%, n = 15), and group C (ratio of C-peptide reduction ≥50%, n = 11); there were significant differences in the three groups (p= 0.000). The upper and lower limits of blood glucose oscillation in group C was statistically lower than the other groups, the range of oscillating glucose levels in group C was −17.0 ± 6.6% to −1.1 ± 6.7%. The AUC0–24 h in groups A, B, and C were 9.7 ± 2.2, 11.0 ± 2.9, and 11.9 ± 2.1 ng/ml × min, respectively, which indicated an increasing trend in the three groups (Ptrend = 0.041). For quality assessment, the average glucose (p = 0.000) and MEFTG (p = 0.001) levels in three groups were significantly different.Conclusion: The different extent of inhibition of endogenous insulin will influence the PK/PD of insulin preparations and the quality of the euglycemic clamp. Furthermore, the ratio of C-peptide reduction should be above 50% to free from the interference of endogenous insulin, and the range of blood glucose levels should be consistently maintained at −10% to 0 in the euglycemic clamp.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Reduction in C-Peptide Levels and Influence on Pharmacokinetics and Pharmacodynamics of Insulin Preparations: How to Conduct a High-Quality Euglycemic Clamp Study

Tao

Zhu

et al. 2021

Front. Pharmacol.

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“…The sustained suppression of endogenous insulin secretion in healthy subjects during the clamping process is critical for obtaining accurate PK/PD data of the tested insulin preparation. Since the clamp technique was first used to evaluate the PK/PD of insulin agents, in recent years, some technique modifications have been applied, such as (1) establishing a higher basal insulin level by continuous intravenous infusion (e.g., 1.0 mU/kg/min) of high amounts of insulin [4–7]; (2) establishing a relatively lower basal insulin level (e.g., 10–15 μU/mL) by continuous intravenous infusion (e.g., 0.1–0.2 mU/kg/min) of insulin [8–11]; and (3) sustaining the maintenance of blood glucose below the basal level (e.g., 10% or 5 mg/dL less) without continuous intravenous insulin infusion [12–15]. Regardless of the method implemented, adequate suppression of the subject's endogenous insulin is always a key factor to be evaluated in a clamp study.…”

Section: Introductionmentioning

confidence: 99%

Oscillations of C‐peptide in the euglycemic clamp and their effect on the pharmacodynamic assessment of insulin preparations

Liu

Qiao

et al. 2020

Fundamemntal Clinical Pharma

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C‐peptide should be continuously suppressed. However, increased postdosing C‐peptide is not an uncommon phenomenon in euglycemic clamp studies involving healthy participants. This study aimed to determine the extent to which the postdosing C‐peptide increases from the baseline that could affect the accuracy of glucodynamics in euglycemic clamp studies involving healthy subjects. First, 10 healthy males underwent a 10‐h euglycemic clamp without exogenous insulin administration to obtain a reference interval (RI) for the ratio of C‐peptide after 0 min (CPt) to baseline C‐peptide (CP0). Then, the data from a pharmacokinetic and pharmacodynamic study of insulin aspart (IAsp) were analyzed, and 70 eligible clamps were grouped by CPt/CP0: group A ([CPt/CP0]max > upper limit of RI), group B (1<[CPt/CP0]max ≤ upper limit of RI), and group C ([CPt/CP0]max ≤ 1). The differences in basal and clamped blood glucose, CPt/CP0, and the pharmacokinetics and pharmacodynamics of IAsp were compared, and the relationship between elevated CPt and the accuracy of pharmacodynamics was analyzed. The RI of CPt/CP0 was 22.7%‐152.1%; 1.5 × baseline might be a ceiling for the increase in CPt under stable conditions. The maximum glucose infusion rate (GIR) in group A tended to be higher than that in group B or C (Pfor trend = 0.033). The AUCGIR,0‐10h in groups A, B, and C was 1983 ± 650,1682 ± 454, and 1479 ± 440 mg/kg (P = 0.047), respectively, under comparable IAsp exposure. No intergroup difference was detected in clamped glucose, IAsp dose, or body mass index. In conclusion, postdosing C‐peptide over 1.5× baseline indicates insufficient inhibition of endogenous insulin secretion, which could compromise the pharmacodynamics of insulin preparations.

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“…As a part of physico-chemical-biological comparability exercise, Glaritus® was found comparable to Lantus® in in-vitro pharmacodynamics studies (receptor binding, receptor autophosphorylation and metabolic assays like glucose uptake and inhibition of lipolysis), in-vivo pharmacodynamics studies (hypoglycaemic potency studies in rodents and dogs) and sub chronic toxicity studies (in rodents including toxicokinetics and immunogenicity) [15]. In terms of human pharmacokinetics and pharmacodynamics, Glaritus® was found bioequivalent to Lantus® in 40 healthy volunteers [16] and 111 type 1 diabetics [17] under 24 hours euglycemic clamp settings glucose lowering effect and insulin glargine exposure.…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity, Safety and Efficacy Comparison of Wockhardt’s Biosimilar Insulin Glargine—Glaritus® with Reference Product— Lantus®: Study Protocol & Early Data Trends

Sharma¹,

Ajmani²,

Khosla³

et al. 2018

OJEMD

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Objective: Present Phase IV Trial is aimed at evaluating the immunogenicity, safety, and efficacy of Wockhardt's insulin glargine, Glaritus® in comparison with reference insulin glargine, Lantus® in subjects with type 2 diabetes mellitus (T2DM), inadequately controlled on oral hypoglycaemics. Setting: A head-to-head, prospective, open-label, parallel group, randomized, Phase IV, non-inferiority study over 6 months treatment conducted in 10 centres in India. Participants: Considering 20% drop-out rate, 180 subjects of either sex, age 18 -55 years, diagnosed with T2DM with body mass index (BMI) 18 -38 kg/m 2 and HbA1c levels 8.0% -10.0% inadequately controlled by 1 or more oral hypoglycaemics and according to investigator needed glargine treatment were enrolled in the study. Interventions: Subjects self-administered insulin glargine (Glaritus® or Lantus®) subcutaneously once daily for 6 months. Treatment in Glaritus® arm was continued till 12 months. Percentage change in anti-insulin antibody (AIA) titre and HbA1C was ascertained at every 3 months interval. The tests were performed at accredited central laboratory.Treat-to-target dose titration: Starting doses of Glaritus® and Lantus® was 10 units (or 0.2 units/kg) once daily. The target fasting blood glucose was 70 to 130 mg/dL. Daily glargine dose was titrated by ±10% based on average of last 3 FBG values being out of target range and presence of nocturnal hypoglycemia. Early data trends: First interim analysis was planned once 100 subjects complete visit 8 (6 months treatment). By then, 119 subjects (78 males and 41 females) with mean age 46.3 years were enrolled, of which 90 (75.6%) subjects had evaluable data. The results of analysis indicated trend of comparability between Glaritus® and Lantus® at the end of 6 months in terms of immunogenicity (% change in AIA titre from baseline, −10.52 ± 23.06 vs. 0.48 ± 63.95), glycemic control (change in HbA1c from baseline, −1.09% ± 1.29% vs. 0.63% ± 1.19%) and hypoglycemic events (reported by 1 vs. 2 patients), respectively. Conclusion: The present study represents a robust design in line with international guidelines on biosimilar insulin development and the early data trends presents expected similarity of Glaritus® in immunogenicity, efficacy and safety to that of Lantus® in treatment of T2DM.

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Comparative evaluation of pharmacokinetics and pharmacodynamics of insulin glargine (Glaritus®) and Lantus® in healthy subjects: a double-blind, randomized clamp study

Abstract: CTRI/2015/06/005890; http://www.ctri.nic.in/ .

Cited by 13 publications

References 18 publications

Reduction in C-Peptide Levels and Influence on Pharmacokinetics and Pharmacodynamics of Insulin Preparations: How to Conduct a High-Quality Euglycemic Clamp Study

Reduction in C-Peptide Levels and Influence on Pharmacokinetics and Pharmacodynamics of Insulin Preparations: How to Conduct a High-Quality Euglycemic Clamp Study

Oscillations of C‐peptide in the euglycemic clamp and their effect on the pharmacodynamic assessment of insulin preparations

Immunogenicity, Safety and Efficacy Comparison of Wockhardt’s Biosimilar Insulin Glargine—Glaritus® with Reference Product— Lantus®: Study Protocol & Early Data Trends

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Comparative evaluation of pharmacokinetics and pharmacodynamics of insulin glargine (Glaritus®) and Lantus® in healthy subjects: a double-blind, randomized clamp study

Abstract: CTRI/2015/06/005890; http://www.ctri.nic.in/ .

Cited by 13 publications

References 18 publications

Reduction in C-Peptide Levels and Influence on Pharmacokinetics and Pharmacodynamics of Insulin Preparations: How to Conduct a High-Quality Euglycemic Clamp Study

Reduction in C-Peptide Levels and Influence on Pharmacokinetics and Pharmacodynamics of Insulin Preparations: How to Conduct a High-Quality Euglycemic Clamp Study

Oscillations of C‐peptide in the euglycemic clamp and their effect on the pharmacodynamic assessment of insulin preparations

Immunogenicity, Safety and Efficacy Comparison of Wockhardt’s Biosimilar Insulin Glargine—Glaritus&#174; with Reference Product— Lantus&#174;: Study Protocol &amp; Early Data Trends

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Immunogenicity, Safety and Efficacy Comparison of Wockhardt’s Biosimilar Insulin Glargine—Glaritus® with Reference Product— Lantus®: Study Protocol & Early Data Trends