Pharmacokinetics, Pharmacodynamics, and Bioequivalence of Test Insulin Glargine Versus Reference Preparation (Lantus®) in Healthy Male Volunteers—By Euglycemic Clamp Technique
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Drugs
2.2. Study Subjects
2.3. Study Methods
2.3.1. Total Design
2.3.2. Clamping Test Process
2.3.3. Detection of Insulin Glargine and C-Peptide
2.3.4. Bioanalytical Methods
2.3.5. Safety Assessment
2.3.6. Statistical Analysis
- Log-Transform PK Parameter: log-transforming AUC and Cmax
- Check Normality Assumptions: Validate the normality of log-transformed parameters using the Shapiro–Wilk test.
- Fit a Mixed Model: Use a linear mixed effects model to account for crossover effects (sequence, period, treatment, and subject variability).
- Calculate the Geometric Mean Ratio (GMR): Extract the mean difference (estimate) for test vs. reference, computing the 90% CI on the log scale and exponentiate the values to convert to the original ratio scale after running the model.
3. Results
3.1. Basic Information of Subjects
3.2. Quality Evaluation of Clamp Test
3.2.1. Blood Glucose Level
3.2.2. C-Peptide Inhibition
3.3. Pharmacodynamic Evaluation
3.4. Pharmacokinetic Assessment
3.5. Bioequivalence Evaluation
3.6. Safety Evaluation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | TRTR (N = 19) | RTRT (N = 20) | Total (N = 39) |
---|---|---|---|
Age (year) | 26.5 (±4.48) | 28.7 (±5.74) | 27.6 (±5.21) |
Hight (cm) | 169.21 (±6.04) | 169.88 (±5.41) | 169.55 (±5.66) |
Weight(kg) | 62.95 (±5.30) | 64.30 (±5.73) | 63.64 (±5.49) |
BMI (kg/m2) | 21.98 (±1.24) | 22.25 (±1.20) | 22.12 (±1.21) |
Indicators | Arithmetic Mean (SD) | |||
---|---|---|---|---|
T1 (n = 38) | T2 (n = 36) | R1 (n = 39) | R2 (n = 38) | |
Mean pre-dose BG/mmol·L−1 | 5.31 (0.34) | 5.32 (0.33) | 5.29 (0.34) | 5.36 (0.30) |
Target BG/mmol·L−1 | 5.03 (0.34) | 5.04 (0.33) | 5.01 (0.34) | 5.08 (0.30) |
Mean post-dose BG/mmol·L−1 | 5.04 (0.32) | 5.05 (0.31) | 5.03 (0.33) | 5.07 (0.28) |
Difference between the mean postdose BG and the target BG/mmol·L−1 | 0.01(0.04) | 0.02 (0.06) | 0.01(0.06) | 0.00 (0.03) |
CVBG (%) | 3.58 | 3.55 | 3.73 | 3.58 |
T Geo Mean (Geo CV, %) | R Geo Mean (Geo CV, %) | |||
---|---|---|---|---|
Parameters (Unit) | T1 (n = 38) | T2 (n = 36) | R1 (n = 39) | R2 (n = 38) |
PD parameters | ||||
GIRmax (mg/kg/min) | 2.912 (38.22) | 2.890 (39.14) | 3.067 (42.69) | 3.116 (34.50) |
tGIRmax (h) a | 11.17 (5.50, 24.00) | 12.00 (4.83, 22.00) | 10.67 (3.17, 19.00) | 12.33 (3.67, 18.50) |
AUCGIR,0–24h (h·mg/kg/min) | 42.368 (40.85) | 42.577 (42.62) | 43.849 (46.21) | 46.635 (34.94) |
AUCGIR,0–12h (h·mg/kg/min) | 18.086 (58.51) | 18.646 (50.96) | 20.491 (53.56) | 20.383 (44.37) |
AUCGIR,12–24h (h·mg/kg/min) | 23.658 (36.39) | 23.631 (40.02) | 24.005 (36.06) | 25.746 (34.42) |
PK parameters | ||||
Cmax (ng/mL) | 0.587 (28.79) | 0.570 (31.57) | 0.618 (31.59) | 0.609 (28.85) |
AUC0–24h (h·ng/mL) | 9.919 (27.06) | 9.587 (25.41) | 10.494 (26.37) | 10.364 (27.20) |
AUC0–12h (h·ng/mL) | 4.899 (27.51) | 4.766 (29.28) | 5.229 (32.30) | 5.042 (31.30) |
AUC12–24h (h·ng/mL) | 4.980 (29.81) | 4.791 (23.75) | 5.209 (23.84) | 5.275 (26.37) |
Tmax (h) a | 12.00 (4.00, 18.01) | 12.00 (4.01, 15.03) | 12.00 (4.00, 18.00) | 12.00 (3.00, 18.01) |
t1/2 (h) b | 5.81 (±2.78) | 7.60 (±4.76) | 6.62(±4.29) | 7.05 (±4.26) |
Parameters | GM | Intra-Subject Variability (%) | ||||
---|---|---|---|---|---|---|
T (n = 36) | R (n = 38) | GMR (%) | 90%CI of GMR | T | R | |
PD parameters | ||||||
AUCGIR, 0–24 h (h·mg/kg/min) | 42.748 | 45.279 | 94.41 | (88.33, 100.91) | 25.35 | 25.32 |
GIRmax (mg/kg/min) | 2.924 | 3.096 | 94.45 | (88.78, 100.48) | 23.42 | 23.18 |
PK parameters | ||||||
AUC0–24 h (h·ng/mL) | 9.782 | 10.436 | 93.74 | (88.84, 98.91) | 18.90 | 22.16 |
cmax (ng/mL) | 0.580 | 0.614 | 94.56 | (88.86, 100.63) | 21.39 | 25.30 |
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Li, Z.; Liu, M.; Tao, Y.; Wan, L.; Chen, Y.; Zhu, M.; Zhao, H.; Tang, C. Pharmacokinetics, Pharmacodynamics, and Bioequivalence of Test Insulin Glargine Versus Reference Preparation (Lantus®) in Healthy Male Volunteers—By Euglycemic Clamp Technique. Pharmaceutics 2025, 17, 418. https://doi.org/10.3390/pharmaceutics17040418
Li Z, Liu M, Tao Y, Wan L, Chen Y, Zhu M, Zhao H, Tang C. Pharmacokinetics, Pharmacodynamics, and Bioequivalence of Test Insulin Glargine Versus Reference Preparation (Lantus®) in Healthy Male Volunteers—By Euglycemic Clamp Technique. Pharmaceutics. 2025; 17(4):418. https://doi.org/10.3390/pharmaceutics17040418
Chicago/Turabian StyleLi, Zhongping, Min Liu, Yi Tao, Lei Wan, Yuan Chen, Mingxue Zhu, Hongtao Zhao, and Chengyong Tang. 2025. "Pharmacokinetics, Pharmacodynamics, and Bioequivalence of Test Insulin Glargine Versus Reference Preparation (Lantus®) in Healthy Male Volunteers—By Euglycemic Clamp Technique" Pharmaceutics 17, no. 4: 418. https://doi.org/10.3390/pharmaceutics17040418
APA StyleLi, Z., Liu, M., Tao, Y., Wan, L., Chen, Y., Zhu, M., Zhao, H., & Tang, C. (2025). Pharmacokinetics, Pharmacodynamics, and Bioequivalence of Test Insulin Glargine Versus Reference Preparation (Lantus®) in Healthy Male Volunteers—By Euglycemic Clamp Technique. Pharmaceutics, 17(4), 418. https://doi.org/10.3390/pharmaceutics17040418